Multivitamin supplementation improves nutritional status and bone quality in aged care residents Is Antioxidant and n–3 Supplementation Able to Improve Functional Status in Poststroke Patients? Results from the Nutristroke Trial A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. RETRACTED: Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial Response of oral leukoplakias to the administration of vitamin A. National Institutes of Health State-of-the-Science Conference Statement: Multivitamin/Mineral Supplements and Chronic Disease Prevention The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial. Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis. A randomized, double-masked, placebo-controlled clinical trial of multivitamin supplementation for age-related lens opacities. Clinical trial of nutritional supplements and age-related cataract report no. 3. Monitoring the randomized trials of the Women's Health Initiative: the experience of the Data and Safety Monitoring Board Alpha-Tocopherol Supplementation in Healthy Individuals Reduces Low-Density Lipoprotein Oxidation but Not Atherosclerosis: The Vitamin E Atherosclerosis Prevention Study (VEAPS) Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2-2 Genotype: A Prospective Double-Blinded Clinical Trial Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. Effect of glutathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers. Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. Effect of multivitamin and mineral supplementation on episodes of infection in nursing home residents: a randomized, placebo-controlled study. Vitamin E and donepezil for the treatment of mild cognitive impairment. Dietary antioxidants and DNA damage in patients on long-term acid-suppression therapy: a randomized controlled study. Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study Chemoprevention of precancerous gastric lesions with antioxidant vitamin supplementation: a randomized trial in a high-risk population. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. Randomized clinical trial of ascorbic acid in the treatment of pressure ulcers. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. Effects of vitamins C and E on oxidative stress markers and endothelial function in patients with systemic lupus erythematosus: a double blind, placebo controlled pilot study. Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network. A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Antioxidant vitamin supplementation reduces benzo(a)pyrene-DNA adducts and potential cancer risk in female smokers. Effects of long-term vitamin E supplementation in alcoholic cirrhotics. Effect of vitamin and trace element supplementation on immune indices in healthy elderly. The effect of 5‐year vitamin C supplementation on serum pepsinogen level and Helicobacter pylori infection Impact of Vitamin E supplementation on lipoprotein peroxidation and composition in Type 1 diabetic patients treated with Atorvastatin. Effects of one year of supplementation with zinc and other micronutrients on cellular immunity in the elderly. Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo‐controlled, cross‐over trial Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. Antioxidant vitamins or lactulose for the prevention of the recurrence of colorectal adenomas Can a short period of micronutrient supplementation in older institutionalized people improve response to influenza vaccine? A randomized, controlled trial. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial. The Roche European American Cataract Trial (REACT): A randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract The Melbourne Atherosclerosis Vitamin E Trial (MAVET): a study of high dose vitamin E in smokers A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study Impact of vitamin A supplementation on the incidence of infection in elderly nursing-home residents: a randomized controlled trial. Effects of a 6-month vitamin intervention on DNA damage in heavy smokers. A randomized trial of ascorbic acid in polyposis coli Brief Communication: The Prevalence of High Intake of Vitamin E from the Use of Supplements among U.S. Adults Vitamin E and respiratory tract infections in elderly nursing home residents: 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. Vitamin E supplementation and cataract: randomized controlled trial. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. Effects on Health of Dietary Supplementation with 100 mg d-α-Tocopheryl Acetate, Daily for 6 Years MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomised placebo-controlled trial Nutritional supplementation in elderly medical in-patients: a double-blind placebo-controlled trial. Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. NO EFFECT OF RIBOFLAVINE, RETINOL, AND ZINC ON PREVALENCE OF PRECANCEROUS LESIONS OF OESOPHAGUS: Randomised Double-blind Intervention Study in High-risk Population of China Quantitative evaluation of vitamin E in the treatment of angina pectoris. Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial. Influence of Reported Study Design Characteristics on Intervention Effect Estimates From Randomized, Controlled Trials
Objectives : To assess the effectiveness of a multivitamin ( MV ) tablet on nutritional status , quantitative heel ultrasound ( QUS ) , mobility , muscle strength and falls . The design comprised two groups matched on mobility levels , r and omized to receive a daily MV or placebo ( P ) tablet for 6 months . The setting was an Australian residential care facility . Subjects : A total of 92 aged care residents . Serum micronutrients , body weight , QUS , rate of falls , h and grip strength , and the timed up and go test were assessed at baseline and 6 months . Results : A total of 49 participants consumed a MV and 43 , a matched P for 6 months . There was a greater increase in the MV vs P group for serum 25(OH)D ( mean difference±st and ard error , 33.4±2.6 nmol l−1 ) , folate ( 13.4±2.8 nmol l−1 ) , and vitamin B12 ( 178.0±40.3 pmol l−1 ) ( all P<0.001 ) . Adequate 25(OH)D concentrations ( ⩾50 nmol l−1 ) were found among 77 % of participants in the MV group vs 10 % taking P ( P<0.001 ) . Adjusting for baseline levels , the increase in QUS was greater in the MV vs P group ( 3.0±2.0 dB MHz−1 vs −2.9±2.1 dB MHz−1 , respectively , P=0.041 ) . There was a trend towards a 63 % lower mean number of falls in the MV vs P group ( 0.3±0.1 falls vs 0.8±0.3 falls , P=0.078 ) . Conclusions : MV  supplementation raised serum vitamin B12 and folate concentrations and increased serum 25(OH)D , which was accompanied by an apparent positive effect on bone density . We also found a trend towards a reduction in falls and this could contribute to a reduction in fractures Background : To test whether supplementary antioxidants and n–3 fatty acids , alone or in combination , could improve functional status in stroke survivors . Methods : We performed a r and omized , double-blind , placebo-controlled clinical trial in 72 stroke patients ( 47 males ; age 65.3 ± 12.9 years ) admitted to a rehabilitation hospital for sequelae of first-ever ischemic stroke , and divided them into 4 subgroups . Group 1 patients received daily oral antioxidants , group 2 received n–3 polyunsaturated fatty acids , group 3 both supplements , and group 4 placebo , all for 12 months . No difference at baseline was observed among groups in neurological severity or in disability . All measures were repeated after 6 and 12 months of treatment . All major clinical events were recorded . Results : At baseline , 25 % of the patients had a low plasma vitamin status , and 48.5 % was at risk of undernutrition . At the 1-year follow-up , we observed a trend for lower mortality ( p = 0.060 ) in subgroups treated with n–3 fatty acids , but without significant differences in rehabilitation result status among groups . Conclusions : Malnutrition is widely observed in patients admitted to a rehabilitative hospital for stroke rehabilitation , and dietary supplementation , even if not able to improve rehabilitation results , is likely to reduce mortality at the 1-year follow-up BACKGROUND / AIMS The effect of vitamin E administration on clinical and laboratory parameters of liver function and on markers of fibrogenesis was assessed in patients with mild to moderate alcoholic hepatitis in a double blind placebo controlled r and omized trial . METHODS Twenty-five patients received 1000  I.U.  of vitamin E per day , while 26 patients received placebo for 3 months . The patients were followed for 1 year after entry into the trial . RESULTS Vitamin E did not result in significant greater decreases in serum aminotransferases and serum bilirubin or in greater increases in serum albumin as compared with placebo .  Prothrombin time did not change , while serum creatinine remained in the normal range . Monocyte nuclear nuclear factor-kappa B binding activity decreased in patients who remained abstinent , regardless of whether they received vitamin E. As regards markers of hepatic fibrogenesis , vitamin E treatment decreased serum hyaluronic acid ( P<0.05 ) while serum aminoterminal peptide of type III procollagen did not change in either group . Four patients in the treatment group and five in the placebo group died during the 1-year study . CONCLUSIONS Vitamin E treatment improves serum hyaluronic acid but has no beneficial effects on tests of liver function in patients with mild to moderate alcoholic hepatitis Ageing is associated with impaired immune responses and increased infection-related morbidity . This study assessed the effect of physiological amounts of vitamins and trace elements on immunocompetence and occurrence of infection-related illness .  96 independently living , healthy elderly individuals were r and omly assigned to receive nutrient supplementation or placebo .  Nutrient status and immunological variables were assessed at baseline and at 12 months , and the frequency of illness due to infection was ascertained . Subjects in the supplement group had higher numbers of certain T-cell subsets and natural killer cells , enhanced proliferation response to mitogen , increased interleukin-2 production , and higher antibody response and natural killer cell activity . These subjects were less likely than those in the placebo group to have illness due to infections ( mean [ SD ] 23 [ 5 ] vs 48 [ 7 ] days per year , p = 0.002 ) . Supplementation with a modest physiological amount of micronutrients improves immunity and decreases the risk of infection in old age BACKGROUND There is conflicting evidence on the benefits of foods rich in vitamin E ( alpha-tocopherol ) , n-3 polyunsaturated fatty acids ( PUFA ) , and their pharmacological substitutes . We investigated the effects of these substances as supplements in patients who had myocardial infa rct ion . METHODS From October , 1993 , to September , 1995 , 11,324 patients surviving recent ( < or = 3 months ) myocardial infa rct ion were r and omly assigned supplements of n-3 PUFA ( 1 g daily , n=2836 ) , vitamin E ( 300 mg daily , n=2830 ) , both ( n=2830 ) , or none ( control , n=2828 ) for 3.5 years . The primary combined efficacy endpoint was death , non-fatal myocardial infa rct ion , and stroke . Intention-to-treat analyses were done according to a factorial design ( two-way ) and by treatment group ( four-way ) . FINDINGS Treatment with n-3 PUFA , but not vitamin E , significantly lowered the risk of the primary endpoint ( relative-risk decrease 10 % [ 95 % CI 1 - 18 ] by two-way analysis , 15 % [ 2 - 26 ] by four-way analysis ) . Benefit was attributable to a decrease in the risk of death ( 14 % [ 3 - 24 ] two-way , 20 % [ 6 - 33 ] four-way ) and cardiovascular death ( 17 % [ 3 - 29 ] two-way , 30 % [ 13 - 44 ] four-way ) . The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint ( 14 % [ 1 - 26 ] ) and for fatal events ( 20 % [ 5 - 33 ] ) . INTERPRETATION Dietary supplementation with n-3 PUFA led to a clinical ly important and statistically significant benefit . Vitamin E had no benefit . Its effects on fatal cardiovascular events require further exploration Tobacco/betel nut chewers ( Kerala , India ) with well-developed oral leukoplakias were chosen for a short-term intervention trial of vitamin A therapy .  Participants were r and omly distributed into two groups , one receiving 200,000 IU vitamin A per week ( 0.14 mg/kg body wt/per day ) for 6 months , and the other receiving placebo capsules . Their cancer-causing habit , which can be quantitated ( an average of 13.1 betel quids/day , 26.1 min/quid ) , did not change during the trial period . The 6-month oral administration of vitamin A caused complete remission in 57.1 % of participants , and a total suppression of the development of new leukoplakias in all chewers receiving vitamin A ( n = 21 ) , as compared to 3 % and 21 % , respectively , in the placebo group ( n = 33 ) . The results were substantiated by examining the histological and cytological changes on small biopsies which were taken at the onset and at the completion of the trial period . Over the 6-month period of vitamin A administration , the number of layers of spinous cells decreased in 85 % of the participants , the loss of polarity of basal cells was reduced from 72.2 % to 22.2 % of chewers , subepidermal lymphocytic infiltration was greatly diminished from 66.7 % to 5.5 % of chewers , and nuclei with condensed chromatin disappeared from the epidermal layer ( 72.2 % before to 0 % at the end of the trial ) National Institutes of Health ( NIH ) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1 ) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality ( AHRQ ) , 2 ) presentations by investigators working in areas relevant to the conference questions during a 2-day public session , 3 ) questions and statements from conference attendees during open discussion periods that are part of the public session , and 4 ) closed deliberations by the panel during the remainder of the second day and the morning of the third . This statement is an independent report of the panel and is not a policy statement of the NIH or the federal government . The statement reflects the panel 's assessment of medical knowledge available at the time the statement was written . Thus , it provides a snapshot in time of the state of knowledge on the conference topic . When reading the statement , keep in mind that new knowledge is inevitably accumulating through medical research . At least half of American adults take a dietary supplement , the majority of which are multivitamin/multimineral ( MVM ) supplements . As more and more Americans seek strategies for maintaining good health and preventing disease , and as the marketplace offers an increasing number of products to fulfill that desire , it is important that consumers have the best possible information to make their choices . Assessing the available scientific evidence on the benefits of MVM supplement use for chronic disease prevention , identifying the gaps in the evidence , and recommending an appropriate research agenda to meet the shortfalls are subjects considered in this report . The word vitamine was coined in 1912 , as an abbreviated term meant to capture the notion of important factors in the diet , or vital amines . This was preceded more than 150 years earlier by British navy physician James Lind 's discoveryin the first recorded controlled trialthat citrus juice , a good source of what was found 2 centuries later to be vitamin C , could prevent scurvy in sailors . In 1913 , the first vitamin was isolated : thiamin , the deficiency of which caused beriberi . Thirteen vitamins and 15 essential minerals have now been identified as important to human nutrition . Large-scale fortification of diets began in the United States with the addition of iodine to table salt in 1924 to prevent goiter , followed by the addition of vitamin D to milk in 1933 to prevent rickets and the addition of thiamin , riboflavin , niacin , and iron to flour in 1941 . Multivitamin/multimineral products providing more than vitamins A and D became available in pharmacies and grocery stores in the mid-1930s . In the early 1940s , the first MVM tablet was introduced . Although clinical deficiency of vitamins or minerals , other than iron , is now uncommon in the United States , growth in supplement use has accelerated rapidly with marketing spurred by cl aims some based on scientific studies that chronic conditions could be prevented or treated by supplement use . Annual sales of supplements to Americans are now reported at about $ 23 billion , a substantial share of which is spent on vitamins and minerals . Because of such widespread use of MVM , increasing public and medical confusion over apparently contradictory results from studies , and reports of possible adverse effects from overuse in certain circumstances , the Office of Dietary Supplements and the Office of Medical Applications of Research of the NIH convened a State-of-the-Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention , held on 1517 May 2006 , in Bethesda , Maryl and . The goal of the conference was to assess the evidence available on MVM use and outcomes for chronic disease prevention in the generally healthy population of adults and to make recommendations for future research . The conference focused on vitamins and minerals and did not deal with botanicals , hormones , or other supplements . It also did not address the treatment of vitamin or mineral deficiencies . Except for considerations of safety , the conference also did not review issues of primary relevance to pregnant women or children . Specifically , the conference explored the following key questions : 1 ) What are the current patterns and prevalence of the public 's use of MVM supplements ? 2 ) What is known about the dietary nutrient intake of MVM users versus nonusers ? 3 ) What is the efficacy of single vitamin/mineral supplement use in chronic disease prevention ? 4 ) What is the efficacy of MVM  in chronic disease prevention in the general population of adults ? 5 ) What is known about the safety of MVM  for the generally healthy population ? and 6 ) What are the major knowledge gaps and research opportunities regarding MVM use ? During the first 2 days of the conference , experts presented information on each of the key questions . After weighing the scientific evidence , including the data presented by the speakers and a formal evidence report commissioned through AHRQ , an independent panel prepared and presented a draft of this state-of-the-science statement addressing the conference questions . The evidence report prepared for the conference is available at www.ahrq.gov/clinic/tp/multivittp.htm . For the purpose of this statement , the term MVM refers to any supplement containing 3 or more vitamins and minerals but no herbs , hormones , or drugs , with each component at a dose less than the tolerable upper level determined by the Food and Nutrition Boardthe maximum daily intake likely to pose no risk for adverse health effects . Our review also included studies of the relationship of single-nutrient supplements and 2-nutrient supplements to certain disease outcomes . The term primary prevention refers to preventing the development of disease in a person who does not have the disease in question . The chronic conditions assessed include cancer ; age-related sensory loss ; and cardiovascular , endocrine , neurologic , musculoskeletal , gastroenterologic , renal , and pulmonary diseases . A word is warranted about the nature of the evidence base considered by the panel . The range of vitamins and minerals of possible interest was so broad that the conference planning committee chose to focus the evidence report on nutrients for which the potential for impact had been most strongly suggested and on conditions for which supplements were thought to have the most potential influence . The planning committee also limited the scope of the evidence report to consideration of r and omized , controlled trials ( RCTs ) , which are generally considered the gold st and ard for evidence -based decision making . These are studies in which participants are allocated by chance alone to receive or not to receive 1 of 2 or more clinical interventions . For example , while folate supplementation was initially shown to decrease the risk for neural tube defects in animal studies , outcome data in nonhuman models were not considered sufficient evidence on which to base policy recommendations . At the next level of evidence , observational studies in humans suggested efficacy of folate supplementation to prevent such defects . However , these were criticized because they were not r and omized and were potentially subject to bias . Not until these findings were confirmed by RCTs in humans was public policy implemented , including fortification of cereal grains with folate . An observational study is one in which the exposure or treatment of interest is not assigned to the participant by the investigator . Such studies suggested that -carotene intake might protect against the development of some types of cancer . However , RCTs of -carotene supplementation not only showed no benefit , they also found an increased risk for lung cancer in persons who smoked cigarettes or who were exposed to asbestos . These examples illustrate both the risk of relying only on observational studies and the advantage of RCTs in identifying both benefits and risks of MVM supplementation . Limiting the focus of our statement to RCTs has some inherent limitations , given the potential of other types of studies to provide important insights . Observational studies , for example , are particularly useful for generating hypotheses , defining adverse effects , and documenting long-term treatment consequences . They are often essential precursors to the well-conducted RCTs important for policy formation . Our principal recommendations focus on the compelling research activities that must be supported to better inform the decisions that millions of Americans are making each day to use or not to use MVM supplements to prevent chronic disease . At the same time , mindful of the constraints of the available evidence base , we have also taken care not to make premature recommendations about whether generally healthy Americans should or should not take MVM supplements . Because of the need for more reliable information on MVMs , we have made strong recommendations for research and for increased U.S. Food and Drug Administration ( FDA ) oversight of the MVM industry . 1 . What Are the Current Patterns and Prevalence of the Public 's Use of MVM Supplements ? More than half of American adults take dietary supplements in the belief that they will make them feel better , give them greater energy , improve their health , and prevent and treat disease . The use of supplements has been steadily increasing , and growth appears likely to continue . Currently , users spend more than $ 23 billion per year on supplements , and among this supplement-using population , MVM is the major category of supplements , used by about one third of Americans . Uncertainty remains in estimating prevalence of use because of problems defining these products ; increasing complexity in the formulation of supplements , including more non-MVM components and specialized formulas ; and varying frequency of use . It appears that use is higher BACKGROUND The Beta-Carotene and Retinol Efficacy Trial ( CARET ) tested the effect of daily beta-carotene ( 30 mg ) and retinyl palmitate ( 25,000 IU ) on the incidence of lung cancer , other cancers , and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure . CARET was stopped ahead of schedule in January 1996 because participants who were r and omly assigned to receive the active intervention were found to have a 28 % increase in incidence of lung cancer , a 17 % increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group . METHODS After the intervention ended , CARET participants returned the study vitamins to their study center and provided a final blood sample . They continue to be followed annually by telephone and mail self-report .  Self-reported cancer endpoints were confirmed by review of pathology reports , and death endpoints were confirmed by review of death certificates . All statistical tests were two-sided . RESULTS With follow-up through December 31 , 2001 , the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 ( 95 % confidence interval [ CI ] = 0.97 to 1.31 ) and 1.08 ( 95 % CI = 0.99 to 1.17 ) , respectively . Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up . By contrast , the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped . During the post-intervention phase , females had larger relative risks of lung cancer mortality ( 1.33 versus 1.14 ; P = .36 ) , cardiovascular disease mortality ( 1.44 versus 0.93 ; P = .03 ) , and all-cause mortality ( 1.37 versus 0.98 ; P = .001 ) than males . CONCLUSIONS The previously reported adverse effects of beta-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant . Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females , and cardiovascular disease mortality primarily to females and to former smokers CONTEXT Immune response in elderly individuals has been reported to improve after micronutrient supplementation . However , efficacy trials evaluating infectious diseases as outcomes are scarce and inconclusive . OBJECTIVE To investigate the effect of daily multivitamin-mineral and vitamin E supplementation on incidence and severity of acute respiratory tract infections in elderly individuals . DESIGN A r and omized , double blind , placebo-controlled , 2 x 2 factorial trial . SETTING AND PARTICIPANTS A total of 652 noninstitutionalized individuals aged 60 years or older enrolled from 2 community-based sampling strategies in the Wageningen area of the Netherl and s , conducted from 1998 to 2000 . At baseline , 6 % of participants had suboptimal ascorbic acid and 1.3 % had suboptimal alpha-tocopherol plasma concentration . INTERVENTION Physiological doses of multivitamin-minerals , 200 mg of vitamin E , both , or placebo . MAIN OUTCOME MEASURES Incidence and severity of self-reported acute respiratory tract infections at 15 months , as assessed by a nurse ( telephone contact ) , home visits , and microbiological and serological testing in subsets of patients . RESULTS During a median observation period of 441 days , 443 ( 68 % ) of 652 participants recorded 1024 respiratory tract infection episodes . The incidence rate ratio of acute respiratory tract infection for multivitamin-mineral supplementation was 0.95 ( 95 % confidence interval , 0.75 - 1.15 ; P = .58 ) and for vitamin E supplementation , 1.12 ( 95 % confidence interval , 0.88 - 1.25 ; P = .21 ) . Severity of infections was not influenced by multivitamin-mineral supplementation . For vitamin E vs no vitamin E , severity was worse : median ( interquartile range ) for illness- duration was 19 ( 9 - 37 ) vs 14 ( 6 - 29 ) days , P = .02 ; number of symptoms , 6 ( 3 - 8 ) vs 4 ( 3 - 8 ) , P = .03 ; presence of fever , 36.7 % vs 25.2 % , P = .009 ; and restriction of activity , 52.3 % vs 41.1 % , P = .02 . CONCLUSIONS Neither daily multivitamin-mineral supplementation at physiological dose nor 200 mg of vitamin E showed a favorable effect on incidence and severity of acute respiratory tract infections in well-nourished noninstitutionalized elderly individuals . Instead we observed adverse effects of vitamin E on illness severity Patients with chronic hepatitis C virus ( HCV ) infection often develop liver cirrhosis and hepatocellular carcinoma ( HCC ) . The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection . Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at r and om into two groups . Forty-four patients were treated with alpha-tocopherol ( Vit E group ) while the other 39 were followed as controls . The clinical background ( gender , age , and laboratory data ) was similar in the two groups . Serum levels of alpha-tocopherol , albumin , alanine aminotransferase ( ALT ) , and total cholesterol and platelet count were measured serially over a period of five years . The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment . Platelet count , serum albumin , ALT , and total cholesterol were not different between the two groups during the five-year period . Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls , albeit statistically insignificant . The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV . Although the administration of alpha-tocopherol normalized the level one month later , it could neither improve liver function , suppress hepatocarcinogenesis , nor improve cumulative survival . Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant OBJECTIVE To evaluate the effect of a multivitamin/mineral supplement on development or progression of  age-related lens opacities .  DESIGN R and omized , double-masked , single center , placebo-controlled clinical trial . PARTICIPANTS One thous and twenty participants , 55 to 75 years old and with early or no cataract , were r and omly assigned to a daily tablet of a multivitamin/mineral formulation or a placebo . METHODS Baseline and annual lens photographs were grade d for severity of lens opacities according to a modification of the Age-Related Eye Disease Study system for classifying cataracts . MAIN OUTCOME MEASURES The primary outcome was a prespecified increase from baseline in nuclear , cortical , or posterior subcapsular cataract ( PSC ) opacity grade s or cataract surgery . Secondary outcomes included an increase in type-specific opacity grade s , cataract surgery , and visual acuity ( VA ) loss from baseline > or = 15 letters . RESULTS Participants were observed for an average of 9.0+/-2.4 years . There was a decrease in total lens events in participants assigned to the multivitamin/mineral formulation compared with those assigned to the placebo ( hazard ratio [ HR ] , 0.82 ; 95 % confidence interval [ CI ] , 0.68 - 0.98 ; P = 0.03 ) . Nuclear events were significantly less common ( HR , 0.66 ; 95 % CI , 0.50 - 0.88 ; P = 0.004 ) and PSC events significantly more common ( HR , 2.00 ; 95 % CI , 1.35 - 2.98 ; P<0.001 ) in participants taking the multivitamin/mineral formulation than in those assigned to the placebo . No statistically significant treatment effects were seen for cortical opacities , moderate VA loss , or cataract surgery . CONCLUSIONS Lens events were less common in participants who took the multivitamin/mineral formulation , but treatment had opposite effects on the development or progression of nuclear and PSC opacities , the 2 most visually important opacity subtypes Data Safety Monitoring Committees ( DSMB ) for large , long-term r and omized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects . The DSMB for the Women 's Health Initiative Clinical Trials , on observing early indication of a surprising  adverse cardiovascular effect of post-menopausal hormones , spent several years deliberating what recommendations it should make . This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence . The paper concludes with some recommendations for other DSMBs Background —Epidemiological studies have demonstrated an inverse relationship between vitamin E intake and cardiovascular disease ( CVD ) risk . In contrast , r and omized controlled trials have reported conflicting results as to whether vitamin E supplementation reduces atherosclerosis progression and CVD events . Methods and Results —The study population consisted of men and women ≥40 years old with an LDL cholesterol level ≥3.37 mmol/L ( 130 mg/dL ) and no clinical signs or symptoms of CVD . Eligible participants were r and omized to DL-&agr;-tocopherol 400 IU per day or placebo and followed every 3 months for an average of 3 years . The primary trial end point was the rate of change in the common carotid artery far-wall intima-media thickness ( IMT ) assessed by computer image-processed B-mode ultrasonograms . A mixed effects model using all determinations of IMT was used to test the hypothesis of treatment differences in IMT change rates . Compared with placebo , & agr;-tocopherol supplementation significantly raised plasma vitamin E levels ( P < 0.0001 ) , reduced circulating oxidized LDL ( P = 0.03 ) , and reduced LDL oxidative susceptibility ( P < 0.01 ) . However , vitamin E supplementation did not reduce the progression of IMT over a 3-year period compared with subjects r and omized to placebo . Conclusions —The results are consistent with previous r and omized controlled trials and extend the null results of vitamin E supplementation to the progression of IMT in healthy men and women at low risk for CVD Objective — Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events . However , these studies did not address possible benefit to subgroups with increased oxidative stress . Haptoglobin ( Hp ) , a major antioxidant protein , is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus ( DM ) . The Hp gene is polymorphic with 2 common alleles , 1 and 2 . The Hp 2 allelic protein product provides inferior antioxidant protection compared with the Hp 1 allelic product . We sought to test the hypothesis that vitamin E could reduce cardiovascular events in DM individuals with the Hp 2 - 2 genotype , a subgroup that comprises 2 % to 3 % of the general population . Methods and Results —1434 DM individuals ≥55 years of age with the Hp 2 - 2 genotype were r and omized to vitamin E ( 400 U/d ) or placebo . The primary composite outcome was myocardial infa rct ion , stroke , and cardiovascular death . At the first evaluation of events , 18 months after initiating the study , the primary outcome was significantly reduced in individuals receiving vitamin E ( 2.2 % ) compared with placebo ( 4.7 % ; P=0.01 ) and led to early termination of the study . Conclusions —Vitamin E supplementation appears to reduce cardiovascular events in individuals with DM and the Hp 2 - 2 genotype ( Clinical Trials.gov NCT00220831 ) 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 We hypothesize that smokers with the null genotype for GSTM1 ( GSTM1 - 0 ) , who thus lack the detoxification enzyme glutathione S-transferase mu-1 , develop atherosclerosis at an increased rate compared to smokers with the positive genotype ( GSTM1 - 1 ) . We used data from a 2-year r and omized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers .  Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness ( CCA-IMT ) as measured by B-mode ultrasonography . The frequency of GSTM1 - 0 genotype was 0.5 in both the placebo and the vitamin E group . Smokers with GSTM1 - 0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1 - 1 ( 0.97 versus 0.92 mm , P=0.09 ) . Within the placebo group , more CCA-IMT progression was found for smokers with the GSTM1 - 0 than for smokers with the GSTM1 - 1 genotype after adjustment for baseline IMT and major CVD risk factors ( 0.050 versus -0.002 mm , P=0.046 ) . In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found . Overall , smokers with GSTM1 - 0 genotype had a higher mean 2-year progression compared to those with GSTM1 - 1 as shown by a difference in increase of 0.042 mm ( 95 % CI 0.006 ; 0.078 , P=0.02 ) . In conclusion , our data suggest that smokers lacking the detoxifying enzyme GST mu-1 develop progression of atherosclerosis at an increased rate OBJECTIVE To determine whether supplementation with vitamins and trace elements in modest amounts influences cognitive function in apparently healthy , elderly subjects . METHODS The study was design ed as a r and omized , double-blind , placebo-controlled trial . Ninety-six , apparently healthy , independent men and women older than 65 y of age were recruited and r and omized to receive a supplement of trace elements and vitamins or a placebo daily for 12 mo . Blood-nutrient levels were estimated at baseline and at the end of the study . The major outcome measure assessed was cognitive function consisting of immediate and long-term memory , abstract thinking , problem-solving ability , and attention . RESULTS Eighty-six subjects completed the 1-y trial . The supplemented group showed a significant improvement in all cognitive tests ( P < 0.001 to 0.05 ) except long-term memory recall ( P > 0.1 ) . Those whose blood-nutrient levels were below the reference st and ard showed lower responses on cognitive tests . There was no significant correlation between individual nutrient levels and performance on various cognitive function tests . CONCLUSIONS Cognitive functions improved after oral supplementation with modest amounts of vitamins and trace elements . This has considerable clinical and public health significance . We recommend that such a supplement be provided to all elderly subjects because it should significantly improve cognition and thus quality of life and the ability to perform activities of daily living . Such a nutritional approach may delay the onset of Alzheimer 's disease CONTEXT Secondary analyses of 2 r and omized controlled trials and supportive epidemiologic and pre clinical data indicated the potential of selenium and vitamin E for preventing prostate cancer . OBJECTIVE To determine whether selenium , vitamin E , or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men . DESIGN , SETTING , AND PARTICIPANTS A r and omized , placebo-controlled trial ( Selenium and Vitamin E Cancer Prevention Trial [ SELECT ] ) of 35,533 men from 427 participating sites in the United States , Canada , and Puerto Rico r and omly assigned to 4 groups ( selenium , vitamin E , selenium + vitamin E , and placebo ) in a double-blind fashion between August 22 , 2001 , and June 24 , 2004 . Baseline eligibility included age 50 years or older ( African American men ) or 55 years or older ( all other men ) , a serum prostate-specific antigen level of 4 ng/mL or less , and a digital rectal examination not suspicious for prostate cancer . INTERVENTIONS Oral selenium ( 200 microg/d from L-selenomethionine ) and matched vitamin E placebo , vitamin E ( 400 IU/d of all rac-alpha-tocopheryl acetate ) and matched selenium placebo , selenium + vitamin E , or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years . MAIN OUTCOME MEASURES Prostate cancer and prespecified secondary outcomes , including lung , colorectal , and overall primary cancer . RESULTS As of October 23 , 2008 , median overall follow-up was 5.46 years ( range , 4.17 - 7.33 years ) . Hazard ratios ( 99 % confidence intervals [ CIs ] ) for prostate cancer were 1.13 ( 99 % CI , 0.95 - 1.35 ; n = 473 ) for vitamin E , 1.04 ( 99 % CI , 0.87 - 1.24 ; n = 432 ) for selenium , and 1.05 ( 99 % CI , 0.88 - 1.25 ; n = 437 ) for selenium + vitamin E vs 1.00 ( n = 416 ) for placebo . There were no significant differences ( all P>.15 ) in any other prespecified cancer end points . There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group ( P = .06 ) and type 2 diabetes mellitus in the selenium group ( relative risk , 1.07 ; 99 % CI , 0.94 - 1.22 ; P = .16 ) but not in the selenium + vitamin E group . CONCLUSION Selenium or vitamin E , alone or in combination at the doses and formulations used , did not prevent prostate cancer in this population of relatively healthy men . TRIAL REGISTRATION clinical trials.gov identifier : NCT00006392 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 OBJECTIVES To evaluate the effect of vitamin and mineral supplementation on infections in an elderly institutionalized population . DESIGN Eighteen-month , r and omized , placebo-controlled trial . SETTING Twenty-one long-term care facilities . PARTICIPANTS Seven hundred sixty-three subjects from 21 long-term care facilities . INTERVENTION Participants were r and omized to receive one multivitamin and mineral supplementation daily or placebo . MEASUREMENTS The primary outcome was number of infections per subject . Secondary outcomes were antibiotic use and hospitalization rates . Infection control surveillance was conducted over 18 months using st and ardized criteria . RESULTS Outcome data from 748 subjects , mean age 85 , were included in the intention-to-treat analysis . Using univariate analyses , there was no difference in infectious episodes between the supplemented and placebo groups ( 3.5 infections per 1,000 resident-days vs 3.8 infections per 1,000 resident-days , odds ratio (OR)=0.92 , 95 % confidence interval (CI)=0.82 - 1.03 , P=.12 ) . There was a reduction in antibiotic usage in the supplementation group , but this was not significant in the multivariate model . There was no difference in the number of hospital visits . In the multivariate analysis , the effect of multivitamin use on total number of infections was not significant ( OR=0.77 , 95 % CI=0.54 - 1.1 ) . Subjects without dementia had a greater rate of infections than those with dementia ( OR=1.44 , 95 % CI=1.19 - 1.76 ) . In post hoc subgroup analysis , subjects without dementia who received supplementation had a significantly lower rate of infections than those who received placebo ( relative risk=0.81 , 95 % CI=0.66 - 0.99 ) . CONCLUSION Overall , multivitamin and mineral supplementation does not have a significant effect on the incidence of infections in institutionalized seniors , although the subgroup of residents in long-term care without dementia may benefit from supplementation . Further research is needed to determine its effect in high-risk subgroups within the nursing home population BACKGROUND Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer 's disease . METHODS In a double-blind study , we evaluated subjects with the amnestic subtype of mild cognitive impairment . Subjects were r and omly assigned to receive 2000 IU of vitamin E daily , 10 mg of donepezil daily , or placebo for three years . The primary outcome was clinical ly possible or probable Alzheimer 's disease ; secondary outcomes were cognition and function . RESULTS A total of 769 subjects were enrolled , and possible or probable Alzheimer 's disease developed in 212 . The overall rate of progression from mild cognitive impairment to Alzheimer 's disease was 16 percent per year . As compared with the placebo group , there were no significant differences in the probability of progression to Alzheimer 's disease in the vitamin E group ( hazard ratio , 1.02 ; 95 percent confidence interval , 0.74 to 1.41 ; P=0.91 ) or the donepezil group ( hazard ratio , 0.80 ; 95 percent confidence interval , 0.57 to 1.13 ; P=0.42 ) during the three years of treatment . Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group , the donepezil group had a reduced likelihood of progression to Alzheimer 's disease during the first 12 months of the study ( P=0.04 ) , a finding supported by the secondary outcome measures . Among carriers of one or more apolipoprotein E epsilon4 alleles , the benefit of donepezil was evident throughout the three-year follow-up . There were no significant differences in the rate of progression to Alzheimer 's disease between the vitamin E and placebo groups at any point , either among all patients or among apolipoprotein E epsilon4 carriers . CONCLUSIONS Vitamin E had no benefit in patients with mild  cognitive impairment . Although donepezil therapy was associated with a lower rate of progression to Alzheimer 's disease during the first 12 months of treatment , the rate of progression to Alzheimer 's disease after three years was not lower among patients treated with donepezil than among those given placebo Free radicals and reactive species produced in vivo can trigger cell damage and DNA modifications result ing in carcinogenesis . Dietary antioxidants trap these species limiting their damage . The present study evaluated the role of vitamins C and E in the prevention of potentially premalignant modifications to DNA in the human stomach by supplementing  patients  who , because of hypochlorhydria and possible depletion of gastric antioxidants , could be at increased risk of gastric cancer . Patients undergoing surveillance for Barrett 's oesophagus ( n 100 ) , on long-term proton pump inhibitors  were r and omized into two groups : vitamin C ( 500 mg twice/d ) and vitamin E ( 100 mg twice/d ) for 12 weeks ( the supplemented group ) or placebo . Those attending for subsequent endoscopy had gastric juice , plasma and mucosal measurements of vitamin levels and markers of DNA damage . Seventy-two patients completed the study .  Plasma ascorbic acid , total vitamin C and vitamin E were elevated in the supplemented group consistent with compliance . Gastric juice ascorbic acid and total vitamin C levels were raised significantly in the supplemented group ( P=0.01 ) but supplementation had no effect on the mucosal level of this vitamin . However , gastric juice ascorbic acid and total vitamin C were within normal ranges in the unsupplemented group . Mucosal malondialdehyde , chemiluminescence and DNA damage levels in the comet assay were unaffected by vitamin supplementation . In conclusion , supplementation does not affect DNA damage in this group of patients . This is probably because long-term inhibition of the gastric proton pump alone does not affect gastric juice ascorbate and therefore does not increase the theoretical risk of gastric cancer because of antioxidant depletion Background —Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression , but the evidence from clinical trials is controversial . In the first 3 years of the ASAP trial , the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women . This article examines the 6-year effect of supplementation on common carotid artery ( CCA ) intima-media thickness ( IMT ) . Methods and Results —The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol ≥5.0 mmol/L ( 193 mg/dL ) , 440 ( 84.6 % ) of whom completed the study . Atherosclerotic progression was assessed ultrasonographically . In covariance analysis in both sexes , supplementation reduced the main study outcome , the slope of mean CCA-IMT , by 26 % ( 95 % CI , 5 to 46 , P = 0.014 ) , in men by 33 % ( 95 % CI , 4 to 62 , P = 0.024 ) and in women by 14 % ( not significant ) . In both sexes combined , the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group ( 25 % treatment effect , 95 % CI , 2 to 49 , P = 0.034 ) . In men , this treatment effect was 37 % ( 95 CI , 4 to 69 , P = 0.028 ) . The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques . Vitamin E had no effect on HDL cholesterol . Conclusions —These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C  slows down atherosclerotic progression in hypercholesterolemic persons BACKGROUND Gastric cancer is one of the most common malignancies worldwide . Histopathologic studies have identified a sequence of changes in the gastric mucosa that mark the slow progression from normal tissue to carcinoma . Epidemiologic evidence suggests that a diet rich in fresh fruit and vegetables could be a protective factor against this disease . This effect may be mediated through antioxidant vitamins . METHODS A r and omized , double-blind chemoprevention trial was conducted among 1980 subjects in Tachira State , Venezuela ( whose population is at high risk for gastric cancer ) , to determine the effect of dietary supplementation with vitamin C , vitamin E , and beta-carotene on the progression and regression of precancerous gastric lesions . Subjects were r and omly assigned to receive either a combination of vitamin C ( 750 mg/day ) , vitamin E ( 600 mg/day ) , and beta-carotene ( 18 mg/day ) or placebo for 3 years . Changes in the gastric mucosa were determined by histologic diagnosis based on five biopsies taken from prespecified areas of the stomach at baseline and annually for 3 years . All biopsies were review ed by a single expert pathologist . Progression rates ( and regression rates ) were calculated by comparing the first and last available gastroscopies for each subject and dividing the number of subjects whose diagnoses increased ( decreased ) in severity by the total follow-up time . Overall rate ratios were calculated by Poisson regression , controlling for baseline diagnosis . All statistical tests were two-sided . RESULTS Median plasma vitamin levels were increased in the treatment group between baseline and 1 year after r and omization from 0.43 micromol/L ( interquartile range [ IQR ] = 0.26 - 0.69 ) to 2.89 micromol/L ( IQR = 1.76 - 4.22 ) for beta-carotene , from 26.7 micromol/L ( IQR = 23.1 - 31.2 ) to 54.9 micromol/L ( IQR = 42.8 - 67.6 ) for alpha-tocopherol , and from 47.70 micromol/L ( IQR = 36.9 - 58.5 ) to 61.9 micromol/L ( IQR = 52.2 - 72.7 ) for vitamin C. Overall progression rates per 100 person-years were 74.3 in the placebo group and 67.8 in the group r and omly assigned to vitamins . Overall regression rates were 109.4 in the placebo group and 116.5 in the group r and omly assigned to vitamins . There was no statistically significant difference in progression rate ( rate ratio = 0.92 , 95 % confidence interval [ CI ] = 0.74 to 1.15 ) or regression rate ( rate ratio = 1.09 , 95 % CI = 0.90 to 1.33 ) between vitamin and placebo groups . CONCLUSION Supplementation with antioxidant micronutrients is not an effective tool for gastric cancer control in this high-risk population . The results of this trial are consistent with previous findings on the lack of effect of nutritional supplementation on precancerous gastric lesions BACKGROUND Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease , and earlier basic research suggested plausible mechanisms . Because large r and omized trials of long duration were necessary to test this hypothesis directly , we conducted a trial of beta carotene supplementation . METHODS In a r and omized , double-blind , placebo-controlled trial of beta carotene ( 50 mg on alternate days ) , we enrolled 22,071 male physicians , 40 to 84 years of age , in the United States ; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982 . By December 31 , 1995 , the scheduled end of the study , fewer than 1 percent had been lost to follow-up , and compliance was 78 percent in the group that received beta carotene . RESULTS Among 11,036 physicians r and omly assigned to receive beta carotene  and 11,035 assigned to receive placebo , there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease , or in overall mortality . In the beta carotene group , 1273 men had any malignant neoplasm  ( except nonmelanoma skin cancer ) , as compared with 1293 in the placebo group ( relative risk , 0.98 ; 95 percent confidence interval , 0.91 to 1.06 ) . There were also no significant differences in the number of cases of lung cancer ( 82 in the beta carotene group vs. 88 in the placebo group ) ; the number of deaths from cancer ( 386 vs. 380 ) , deaths from any cause ( 979 vs. 968 ) , or deaths from cardiovascular disease ( 338 vs. 313 ) ; the number of men with myocardial infa rct ion ( 468 vs. 489 ) ; the number with stroke ( 367 vs. 382 ) ; or the number with any one of the previous three end points ( 967 vs. 972 ) . Among current and former smokers , there were also no significant early or late differences in any of these end points . CONCLUSIONS In this trial among healthy men , 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms , cardiovascular disease , or death from all causes BACKGROUND R and omized trials have yielded mixed results on the effects of treatment for Helicobacter pylori and little information on the effects of vitamins or garlic supplements on precancerous gastric lesions . We conducted a r and omized trial to test the effects of one-time H. pylori treatment and long-term vitamin or garlic supplements in reducing the prevalence of  advanced precancerous gastric lesions . METHODS Most of the adults aged 35 - 64 years in 13 r and omly selected villages in Linqu County , Sh and ong Province , China , were identified and given baseline endoscopies in 1994 . In 1995 , 3365 eligible subjects were r and omly assigned in a factorial design to three interventions or placebos : amoxicillin and omeprazole for 2 weeks in 1995 ( H. pylori treatment ) ; vitamin C , vitamin E , and selenium for 7.3 years ( vitamin supplement ) ; and aged garlic extract and steam-distilled garlic oil for 7.3 years ( garlic supplement ) . Subjects underwent endoscopies with biopsies in 1999 and 2003 , and the prevalence of precancerous gastric lesions was determined by histopathologic examination of seven st and ard biopsy sites . The 3365 eligible r and omized subjects represented 93.5 % of those with baseline endoscopy and included all baseline histologic categories except gastric cancer . Only 0.18 % had normal gastric mucosa . Logistic regression was used to estimate the intervention effects on the odds of advanced precancerous gastric lesions , and t-tests were used to assess effects on histologic severity . All statistical tests were two-sided . RESULTS H. pylori treatment result ed in statistically significant decreases in the combined prevalence of severe chronic atrophic gastritis , intestinal metaplasia , dysplasia , or gastric cancer in 1999 ( odds ratio [ OR ] = 0.77 ; 95 % confidence interval [ CI ] = 0.62 to 0.95 ) and in 2003 ( OR = 0.60 ; 95 % CI = 0.47 to 0.75 ) , and had favorable effects on the average histopathologic severity and on progression and regression of precancerous gastric lesions in 2003 . H. pylori treatment did not reduce the combined prevalence of dysplasia or gastric cancer . However , fewer subjects receiving H. pylori treatment ( 19/1130 ; 1.7 % ) than receiving placebo ( 27/1128 ; 2.4 % ) developed gastric cancer ( adjusted P = .14 ) . No statistically significant favorable effects were seen for garlic or vitamin supplements . CONCLUSION H. pylori treatment reduces the prevalence of precancerous gastric lesions and may reduce gastric cancer incidence , but further data are needed to prove the latter point . Long-term vitamin or garlic supplementation had no beneficial effects on the prevalence of precancerous gastric lesions or on gastric cancer incidence The objective of this study was to assess the effects of ascorbic acid supplementation , 500 mg twice daily in the treatment of pressure ulcers as an adjunct to st and ardized treatment . The design consisted of a multicenter blinded r and omized trial . The control group received 10 mg of ascorbic acid twice daily . Patients from 11 nursing homes and 1 hospital participated . Main outcome measures included wound survival , healing rates of wound surfaces , and clinimetric changes over 12 weeks . Eighty-eight patients were r and omized . Intention-to-treat analysis showed that the wound closure probability per unit time ( i.e. , the closure rate ) was not higher in the intervention group than in the control group ( Cox hazard ratio of 0.78 [ 90 % precision interval , 0.44 - 1.39 ] ) . Mean absolute healing rates were 0.21 and 0.27 cm2/week in the intervention and control group , respectively ( PI of the adjusted difference : -0.17 to 0.13 ) . Relative healing rates and healing velocities did not show favorable results of ascorbic acid supplementation , either . A panel scored slides of the ulcers with a report mark between 1 ( bad ) and 10 ( excellent ) . The improvement was 0.45 and 0.72 points per week in the intervention and control group , respectively ( PI of the adjusted difference : -0.50 to 0.20 ) . With another clinimetric index we could not show any differences , either . These data do not support the idea that ascorbic acid supplementation ( 500 vs. 10 mg twice daily ) speeds up the healing of pressure ulcers Thirty elderly long-stay patients were r and omly allocated to receive either placebo or dietary supplementation with vitamins A , C and E for 28 days . Nutritional status and cell-mediated immune function were assessed before and after the period of supplementation . Following vitamin supplementation , cell-mediated immune function improved as indicated by a significant increase in the absolute number of T cells ( p less than 0.05 ) , T4 subsets ( p less than 0.05 ) , T4 to T8 ratio ( p less than 0.01 ) and the proliferation of lymphocytes in response to phytohaemagglutinin ( p less than 0.01 ) . In contrast , no significant changes were noted in the immune function of the placebo group . We conclude that supplementation with the dietary antioxidants vitamins A , C and E can improve aspects of cell-mediated immune function in elderly long-stay patients CONTEXT Hormone replacement therapy ( HRT ) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease , but no clinical trials have demonstrated benefit to support their use . OBJECTIVE To determine whether HRT or antioxidant vitamin supplements , alone or in combination , influence the progression of coronary artery disease in postmenopausal women , as measured by serial quantitative coronary angiography . DESIGN , SETTING , AND PATIENTS The Women 's Angiographic Vitamin and Estrogen ( WAVE ) Trial , a r and omized , double-blind trial of 423 postmenopausal women with at least one 15 % to 75 % coronary stenosis at baseline coronary angiography . The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada . INTERVENTIONS Patients were r and omly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen ( plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy  ) , or matching placebo , and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily , or placebo . MAIN OUTCOME MEASURE Annualized mean ( SD ) change in minimum lumen diameter ( MLD ) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient . Patients with intercurrent death or myocardial infa rct ion ( MI ) were imputed the worst rank of angiographic outcome . RESULTS The mean ( SD ) interval between angiograms was 2.8 ( 0.9 ) years . Coronary progression , measured in mean ( SD ) change , worsened with HRT by 0.047 ( 0.15 ) mm/y and by 0.024 ( 0.15 ) mm/y with HRT placebo ( P = .17 ) ; and for antioxidant vitamins by 0.044 ( 0.15 ) mm/y and with vitamin placebo by 0.028 ( 0.15 ) mm/y ( P = .32 ) . When patients with intercurrent death or MI were included , the primary outcome showed an increased risk for women in the active HRT group ( P = .045 ) , and suggested an increased risk in the active vitamin group ( P = .09 ) . Fourteen patients died in the HRT group and 8 in the HRT placebo group ( hazard ratio [ HR ] , 1.8 ; 95 % confidence interval [ CI ] , 0.75 - 4.3 ) , and 16 in the vitamin group and 6 in the vitamin placebo group ( HR , 2.8 ; 95 % CI , 1.1 - 7.2 ) . Death , nonfatal MI , or stroke occurred in 26 HRT patients vs 15 HRT controls ( HR , 1.9 ; 95 % CI , 0.97 - 3.6 ) and in 26 vitamin patients and 18 vitamin controls ( HR , 1.5 ; 95 % CI , 0.80 - 2.9 ) . There was no interaction between the 2 treatment interventions . CONCLUSION In postmenopausal women with coronary disease , neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit . Instead , a potential for harm was suggested with each treatment OBJECTIVE Patients with systemic lupus erythematosus ( SLE ) experience excess morbidity and mortality due to coronary artery disease ( CAD ) that can not be fully explained by the classical CAD risk factors . Among emerging CAD risk factors , oxidative stress is currently being emphasized . We evaluated the effects of longterm antioxidant vitamins on markers of oxidative stress and antioxidant defense and endothelial function in 39 patients with SLE . METHODS Patients were r and omized to receive either placebo or vitamins ( 500 mg vitamin C and 800 IU vitamin E daily ) for 12 weeks . Markers of oxidative stress included malondialdehyde ( MDA ) and allantoin . Antioxidants measured included erythrocyte superoxide dismutase and glutathione peroxidase , plasma total antioxidant power ( as FRAP value ) , and ascorbic acid and vitamin E concentrations . Endothelial function was assessed by flow-mediated dilatation ( FMD ) of the brachial artery and plasma concentration of von Willebr and factor ( vWF ) and plasminogen activator inhibitor type 1 ( PAI-1 ) . Primary outcome of the study included the change in lipid peroxidation as revealed by MDA levels . Secondary outcomes included changes in allantoin and antioxidant levels and change in endothelial function . RESULTS After treatment , plasma ascorbic acid and alpha-tocopherol concentrations were significantly ( p < 0.05 ) increased only in the vitamin-treated group , associated with a significant decrease ( p < 0.05 ) in plasma MDA . Other oxidative stress markers and antioxidant levels remained unchanged in both groups . FMD and vWF and PAI-1 levels remained unchanged in both groups . CONCLUSION Combined administration of vitamins C and E was associated with decreased lipid peroxidation , but did not affect endothelial function in patients with SLE after 3 months of therapy We conducted a r and omized , double-blind , controlled trial to examine the efficacy of retinol supplementation on the incidence of  first new nonmelanoma skin cancer in moderate-risk subjects . A total of 2297 free-living subjects were enrolled ; subjects resided in Arizona ( median age , 63 years ) and had a history of more than 10 actinic keratoses and at most 2 squamous cell carcinoma ( SCC ) or basal cell carcinoma ( BCC ) skin cancers . Subjects were r and omly assigned to receive oral retinol ( 25,000 IU ) or placebo supplementation daily for up to 5 years . The primary end points for the trial were time to first new SCC or BCC . During a median follow-up time of 3.8 years , we found that 526 subjects had a first new skin cancer . Comparing retinol-supplemented subjects with placebo-supplemented subjects showed a hazard ratio for first new SCC of 0.74 ( 95 % confidence interval , 0.56 - 0.99 ; P = 0.04 ) . The hazard ratio of first new BCC for the retinol-supplemented subjects compared with those receiving placebo was 1.06 ( 95 % confidence interval , 0.86 - 1.32 ; P = 0.36 ) . Potentially adverse symptoms that were judged to be associated with retinol were rare ( approximately 1 % higher in the retinol group than in the control group ) . Therefore , we concluded that daily supplementation with 25,000 IU of retinol was effective in preventing SCC , although it did not prevent BCC AIMS Chronic heart failure ( CHF ) is a common and leading cause of death in industrialized countries . The potential benefits of micronutrient supplementation in CHF are extensive . Therefore , we examined the influence of long-term multiple micronutrient supplementation on left ventricular ( LV ) function , levels of pro-inflammatory cytokines , and quality -of-life ( QoL ) in elderly patients with CHF . METHODS AND RESULTS Thirty CHF patients [ age 75.4 ( 0.7 ) , mean ( SEM ) , LV ejection fraction ( LVEF ) < or = 35 % ] were r and omized to receive capsules containing a combination of high-dose micronutrients ( calcium , magnesium , zinc , copper , selenium , vitamin A , thiamine , riboflavin , vitamin B(6 ) , folate , vitamin B(12 ) , vitamin C , vitamin E , vitamin D , and Coenzyme Q10 ) or placebo for 9 months in a double-blind fashion . All subjects were on stable optimal medical therapy for at least 3 months before enrolment . At r and omization and at study end , tumour necrosis factor-alpha and its soluble receptors TNFR-1 and TNFR-2 were measured and six-minute walk test and QoL were assessed . Cardiac magnetic resonance scanning was performed to evaluate cardiac dimensions and LVEF . Two patients died during follow-up . The remaining patients ( 14 r and omized to placebo and 14 to micronutrients ) were well matched for LV function , symptoms , and exercise capacity . At the end of the follow-up period , LV volumes were reduced in the intervention group with no change in the placebo group [ -13.1 (17.1)% vs. + 3.8 (10.0)% ; P<0.05 ] . LVEF increased by 5.3+/-1.4 % in the intervention group and was unchanged in the placebo group ( P<0.05 ) . Patients taking micronutrients also had a significant improvement in QoL score between enrolment and study end [ + 9.5 (1.6)% ; P<0.05 ] , whereas those taking placebo had a slight deterioration [ -1.1 (0.8)% ; P=0.12 ] . Six-minute walk test and inflammatory cytokine levels remained unchanged in both groups . CONCLUSION Long-term multiple micronutrient supplementation can improve LV volumes and LVEF and QoL scores in elderly patients with heart failure due to LV systolic dysfunction BACKGROUND Antioxidant supplementation is thought to improve immunity and thereby reduce infectious morbidity . However , few large trials in elderly people have been conducted that include end points for clinical variables . OBJECTIVE To determine the effects of long-term daily supplementation with trace elements ( zinc sulfate and selenium sulfide ) or vitamins ( beta carotene , ascorbic acid , and vitamin E ) on immunity and the incidence of infections in institutionalized elderly people . METHODS This r and omized , double-blind , placebo-controlled intervention study included 725 institutionalized elderly patients ( > 65 years ) from 25 geriatric centers in France . Patients received an oral daily supplement of nutritional doses of trace elements ( zinc and selenium sulfide ) or vitamins ( beta carotene , ascorbic acid , and vitamin E ) or a placebo within a 2 x 2 factorial design for 2 years . MAIN OUTCOME MEASURES Delayed-type hypersensitivity skin response , humoral response to influenza vaccine , and infectious morbidity and mortality . RESULTS Correction of specific nutrient deficiencies was observed after 6 months of supplementation and was maintained for the first year , during which there was no effect of any treatment on delayed-type hypersensitivity skin response . Antibody titers after influenza vaccine were higher in groups that received trace elements alone or associated with vitamins , whereas the vitamin group had significantly lower antibody titers ( P<.05 ) . The number of patients without respiratory tract infections during the study was higher in groups that received trace elements ( P = .06 ) . Supplementation with neither trace elements nor vitamins significantly reduced the incidence of urogenital infections . Survival analysis for the 2 years did not show any differences between the 4 groups . CONCLUSIONS Low-dose supplementation of zinc and selenium provides significant improvement in elderly patients by increasing the humoral response after vaccination and could have considerable public health importance by reducing morbidity from respiratory tract infections INTRODUCTION Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis ( ALS ) . The antioxidant vitamin E ( alpha-tocopherol ) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS . The current study was design ed to determine whether alpha-tocopherol ( 500 mg b.i.d . ) may be efficacious in the treatment of ALS . METHODS Two hundred and eighty-nine patients with ALS of less than 5 years duration , treated with riluzole , were enrolled in this study , and were r and omly assigned to receive either alpha-tocopherol or placebo daily for one year . The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale . Patients were assessed at entry , and every 3 months thereafter during the study period . Survival was also recorded . Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment . RESULTS After 12 months of treatment , alpha-tocopherol had no effect on the primary outcome measure . Survival was not influenced by treatment . Among secondary outcome measures , patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B ( P=0.046 ) of the ALS Health State scale . After 3 months treatment , analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma ( P = 0.0389 ) and a decrease in plasma levels of thiobarbituric acid reactive species ( P = 0.0055 ) in the group of patients given alpha-tocopherol in combination with riluzole . CONCLUSION Although alpha-tocopherol did not appear to affect the survival and motor function in ALS , patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed , after 3 months , changes in biochemical markers of oxidative stress . Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints BACKGROUND There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer 's disease . METHODS We conducted a double-blind , placebo-controlled , r and omized , multicenter trial in patients with Alzheimer 's disease of moderate severity . A total of 341 patients received the selective monoamine oxidase inhibitor selegiline ( 10 mg a day ) , alpha-tocopherol ( vitamin E , 2000 IU a day ) , both selegiline and alpha-tocopherol , or placebo for two years . The primary outcome was the time to the occurrence of any of the following : death , institutionalization , loss of the ability to perform basic activities of daily living , or severe dementia ( defined as a Clinical Dementia Rating of 3 ) . RESULTS Despite r and om assignment , the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups , and this variable was highly predictive of the primary outcome ( P<0.001 ) . In the unadjusted analyses , there was no statistically significant difference in the outcomes among the four groups . In analyses that included the base-line score on the Mini-Mental State Examination as a covariate , there were significant delays in the time to the primary outcome for the patients treated with selegiline ( median time , 655 days ; P=0.012 ) , alpha-tocopherol ( 670 days , P=0.001 ) or combination therapy ( 585 days , P=0.049 ) , as compared with the placebo group ( 440 days ) . CONCLUSIONS In patients with moderately severe impairment from Alzheimer 's disease , treatment with selegiline or alpha-tocopherol slows the progression of disease Because supplements of vitamins C and E had been associated with reduction of fecal mutagen levels , a double-blind r and omized trial was design ed to examine the effects of these vitamins on the rate of recurrence of colorectal polyps , presumed precursors for colorectal cancer . Two hundred patients believed to be free of polyps after removal of at least one colorectal polyp were r and omized to receive a supplement of 400 mg each of ascorbic acid and alpha-tocopherol , or a placebo .  Fifteen patients had to be excluded because a review of pathology indicated that their polyps were not adenomatous . A second colonoscopic examination was planned after 2 yr of supplementation .  One hundred thirty-seven people ( 75 % of eligible subjects ) completed the study ;  polyps were observed in the second colonoscopy in 41.4 % of 70 subjects on vitamin supplements and in 50.7 % of 67 subjects on placebos . After adjustment for differences between groups in demographic and dietary factors before study entry , the relative risk of polyp occurrence was 0.86 , with 95 % confidence limits from 0.51 to 1.45 , in an analysis of 129 subjects with complete information on demographic and dietary factors who had completed the trial . Of the 48 patients who had not completed the study , 7 had died , 33 had not returned to their physician for an examination , and 8 had had a follow-up colonoscopy or sigmoidoscopy . Inclusion of the three polyps found in these eight examinations led to an estimate of relative risk of 0.86 ( 95 % confidence limits , 0.51 to 1.43 ) . The findings of this investigation suggest that any reduction in the rate of polyp recurrence associated with vitamin supplementation is small , and a larger study would be required to ensure that an effect of this size was not a chance finding BACKGROUND Elevated benzo(a)pyrene [B(a)P]-DNA adducts have been associated with 3-fold increased risk of lung cancer in current smokers . We assessed the chemopreventive effects of antioxidant supplementation using B(a)P-DNA adducts in leukocytes as an intermediate cancer risk marker . METHODS Subjects were r and omized to a double-blinded placebo-controlled clinical trial of antioxidant vitamin supplementation [ 500 mg vitamin C and 400 IU vitamin E ( dl-alpha-tocopherol ) daily ] or placebo .  Smokers with > or = 10 cigarettes per day and serum cotinine > or = 25 ng/mL were eligible for the study .  B(a)P-DNA adduct level was the outcome . The r and omization was stratified by gender and cigarettes per day ( < or = 20 or > 20 ) . Smoking habits and blood sample s were collected every 3 months during the 15-month treatment period . Sample s were analyzed for B(a)P-DNA adducts ( high-performance liquid chromatography ) , plasma cotinine , vitamin levels , and GSTM1 genotype . The intent-to-treat model adjusted for B(a)P-DNA and cotinine at r and omization . RESULTS Overall and among men , there was no effect of treatment on B(a)P-DNA adduct levels . Among treated women , B(a)P-DNA adducts decreased by 31 % compared with women on placebo ( P = 0.03 ) . Among treated women with the GSTM1 genotype , there was a 43 % decrease in adducts ( P = 0.04 ) . CONCLUSION Our primary hypothesis that the mean level of smoking-related B(a)P-DNA adducts would be lower in all subjects in the vitamin treatment group compared with all placebo-treated subjects was not substantiated . However , our secondary gender-specific analysis found a significant reduction in B(a)P-DNA adducts in women with vitamin treatment , suggesting that antioxidant supplementation maymitigate some of the procarcinogenic effects of exposuretoB(a)P. The effect in GSTM1-null women suggeststhat certain subgroups may derive more benefit fromsupplementation . Although the results of this trial showthe potential chemopreventive role of antioxidants , thebest way for smokers to reduce their cancer risk remains smoking cessation OBJECTIVE Alcohol ingestion promotes lipoperoxidation and alters cellular antioxidant mechanisms . Alpha-tocopherol levels decrease in alcoholics as severity of liver damage increases . The aim of this protocol was to study the effects of a long-term oral 500 mg vitamin E daily supplementation in decompensated ambulatory alcoholic cirrhotics . PATIENTS AND METHODS 67 subjects were included in this double blind trial ; 33 patients received vitamin E and 34 patients received placebo tablets of identical appearance during 1 year . Each month , the patients were seen by a nurse practitioner who was in charge of detecting alcohol ingestion and checking adherence to treatment . Every 3 months , the patients underwent a medical examination , and blood sample s were taken for clinical laboratory analysis and serum vitamin E measurement . RESULTS Alpha-tocopherol levels were significantly lower in patients with more severe liver disease . This difference was not significant when vitamin E levels were corrected by cholesterol . Oral supplementation significantly increased serum vitamin E levels in the experimental group . Alcohol ingestion and hospitalization rates were similar in both groups . Life table analysis did not show significant differences in mortality between the two groups . DISCUSSION Vitamin E supplementation with adequate doses of an alpha-tocopheryl acetate formulation during 1 year did not influence hepatic laboratory parameters , mortality or hospitalization rates of decompensated alcoholic cirrhotics , although serum levels of the vitamin significantly increased Aging is associated with a progressive decline in the immune system and a greater susceptibility to infection . This double-blind , placebo-controlled study , examined the effect of a vitamin and trace element supplement on immune responses of healthy , noninstitutionalized elderly subjects . Forty-seven subjects aged 61 - 79 years were r and omly assigned to receive placebo or micronutrient supplementation for one year . Thirty-five individuals completed the one-year study .  Immune function was assessed before and after the period of supplementation . Cell-mediated immune function assessed by the number of T cells and subsets remained constant in the supplemented group and there was a significant increase in CD57 natural killer cells . In contrast , a significant decrease in T cells , CD4 cells , and CD4 : CD8 ratio was noted in the placebo group . Supplementation with micronutrients can play a crucial role in the maintenance of normal immune function in the elderly We conducted a population ‐based , double‐blind , r and omized controlled trial to examine the effect of vitamin C supplementation on serum pepsinogen ( PG ) level , Helicobacter pylori ( H. pylori ) infection , and cytotoxin‐associated gene A ( Cag A ) status .  Subjects aged 40 to 69 years living in one village in Akita prefecture , a high‐risk area for gastric cancer in Japan , were recruited through annual health check‐up programs . Among 635 subjects diagnosed as having chronic gastritis on the basis of serum PG levels , after excluding ineligible cases , 439 subjects were assigned to one of four groups using a 2 × 2 factorial design ( 0 or 15 mg/day β‐carotene and 50 or 500 mg/day vitamin C ) . However , based on the results from two β‐carotene trials in the United States , we discontinued β‐carotene ( vitamin C supplementation was continued ) . Finally , 120 subjects in the low‐dose group ( vitamin C 50 mg ) , and 124 subjects in the high‐dose group ( vitamin C 500 mg ) completed the 5‐year supplementation . The difference in the change of PGI/II ratio between baseline and after 5‐year follow up was statistically significant between the intervention groups among those who completed the supplementation : ‐0.25 for the low‐dose group and ‐0.13 for the high‐dose group ( P=0.046 ) . To conclude , vitamin C supplementation may protect against progression of gastric mucosal atrophy . ( Cancer Sci 2003 ; 94 : 378–382 OBJECTIVE To investigate the impact of Vitamin E on lipids and peroxidation during statin treatment . RESEARCH DESIGN AND METHODS T1DM patients with high cholesterol received  Atorvastatin 20 mg with either placebo ( group AP , n = 11 ) or d-alpha-tocopherol 750 IU ( group AE , n = 11 ) daily . They were monitored for blood biochemistry , low-density lipoprotein ( LDL ) subfractions and lipid peroxidation at inclusion and after 3 and 6 months . RESULTS Serum cholesterol and triglycerides decreased to the same extent ( 29 and 21 % respectively ) in both groups . Serum tocopherol decreased by 18 % in AP and increased by 50 % in AE ( P < 0.0001 , between-group comparison by repeated measures ANOVA ) but relative to lipids it increased by 15 % in AP and by 100 % in AE . Copper-induced production of thiobarbituric reactive substances in the LDL + VLDL fraction increased by 18 % in AP and did not change in AE ( P = 0.02 ) . The lagtime for the production of fluorescent products was prolonged by 13 min only in group AE ( P = 0.028 ) . Plasma malondialdehyde decreased by 35 % in both groups ( P = 0.002 ) but not when adjusted for lipids . CONCLUSIONS In T1DM Vitamin E supplements do not affect the lowering of lipids and plasma malondialdehyde achieved by Atorvastatin . They reverse the increase of in vitro peroxidation caused by Atorvastatin but do not achieve the decreases observed in patients not receiving lipid-lowering drugs . These results indicate that the antioxidant effect of Vitamin E is attenuated when given in conjunction with this statin The objective of this study was to determine the effects of a year of Zn supplementation on Zn concentrations in circulating cells and on cellular immune functions in the elderly . Subjects , aged 60 - 89 , were given a placebo , 15 mg Zn , or 100 mg Zn daily for 12 months . All subjects also received a multivitamin/mineral supplement that contained no additional Zn . Blood sample s were drawn and immune functions assessed prior to and at 3 , 6 , 12 , and 16 months after beginning Zn supplementation . Subject diets were also assessed at each visit . Dietary folate , pyridoxine , alpha-tocopherol , copper , zinc , and magnesium were consistently below recommended intakes . Although plasma Zn increased significantly in the 100 mg Zn treatment group , concentrations of Zn in erythrocytes , mononuclear cells , polymorphonuclear leukocytes , and platelets were not significantly increased by zinc supplementation . Natural killer cell activity was transiently enhanced by the 100 mg/day dose of Zn . There was a progressive improvement in delayed dermal hypersensitivity ( DDH ) and in lymphocyte proliferative responses to two mitogens ; this may have been due to one or more components of the multivitamin/mineral supplement administered to all study subjects . The enhancement of DDH was significantly greater in the placebo group than in either zinc treatment group . Thus , zinc had a beneficial effect on one measure of cellular immune function while simultaneously having an adverse effect on another measure of cellular immunity Background : We have previously reported , in an uncontrolled trial , an improvement in fatigue scores in patients with primary biliary cirrhosis given oral antioxidant supplementation . We now present data from a controlled trial BACKGROUND The use of sunscreens on the skin can prevent sunburn but whether long-term use can prevent skin cancer is not known . Also , there is evidence that oral betacarotene supplementation lowers skin-cancer rates in animals , but there is limited evidence of its effect in human beings . METHODS In a community-based r and omised trial with a 2 by 2 factorial design , individuals were assigned to four treatment groups : daily application of a sun protection factor 15-plus sunscreen to the head , neck , arms , and h and s , and betacarotene supplementation ( 30 mg per day ) ; sunscreen plus placebo tablets ; betacarotene only ; or placebo only .  Participants were 1621 residents of Nambour in southeast Queensl and , Australia . The endpoints after 4.5 years of follow-up were the incidence of basal-cell and squamous-cell carcinomas both in terms of people treated for newly diagnosed disease and in terms of the numbers of tumours that occurred . Analysis of the effect of sunscreen was based only on skin cancers that developed on sites of daily application . All analyses were by intention to treat . FINDINGS 1383 participants underwent full skin examination by a dermatologist in the follow-up period . 250 of them developed 758 new skin cancers during the follow-up period . There were no significant differences in the incidence of first new skin cancers between groups r and omly assigned daily sunscreen and no daily sunscreen ( basal-cell carcinoma 2588 vs 2509 per 100,000 ; rate ratio 1.03 [ 95 % CI 0.73 - 1.46 ] ; squamous-cell carcinoma 876 vs 996 per 100,000 ; rate ratio 0.88 [ 0.50 - 1.56 ] ) . Similarly , there was no significant difference between the betacarotene and placebo groups in incidence of either cancer ( basal-cell carcinoma 3954 vs 3806 per 100,000 ; 1.04 [ 0.73 - 1.27 ] ; squamous-cell carcinoma 1508 vs 1146 per 100,000 ; 1.35 [ 0.84 - 2.19 ] ) . In terms of the number of tumours , there was no effect on incidence of basal-cell carcinoma by sunscreen use or by betacarotene but the incidence of squamous-cell carcinoma was significantly lower in the sunscreen group than in the no daily sunscreen group ( 1115 vs 1832 per 100,000 ; 0.61 [ 0.46 - 0.81 ] ) . INTERPRETATION There was no harmful effect of daily use of sunscreen in this medium-term study . Cutaneous squamous-cell carcinoma , but not basal-cell carcinoma seems to be amenable to prevention through the routine use of sunscreen by adults for 4.5 years . There was no beneficial or harmful effect on the rates of either type of skin cancer , as a result of betacarotene supplementation BACKGROUND Both lipid-modifying therapy and antioxidant vitamins are thought to have benefit in patients with coronary disease . We studied simvastatin-niacin and antioxidant-vitamin therapy , alone and together , for cardiovascular protection in patients with coronary disease and low plasma levels of HDL . METHODS In a three-year , double-blind trial , 160 patients with coronary disease , low HDL cholesterol levels and normal LDL cholesterol levels were r and omly assigned to receive one of four regimens : simvastatin plus niacin , vitamins , simvastatin-niacin plus antioxidants ; or placebos . The end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event ( death , myocardial infa rct ion , stroke , or revascularization ) . RESULTS The mean levels of LDL and HDL cholesterol were unaltered in the antioxidant group and the placebo group ; these levels changed substantially ( by -42 percent and + 26 percent , respectively ) in the simvastatin-niacin group . The protective increase in HDL2 with simvastatin plus niacin was attenuated by concurrent therapy with antioxidants . The average stenosis progressed by 3.9 percent with placebos , 1.8 percent with antioxidants ( P=0.16 for the comparison with the placebo group ) , and 0.7 percent with simvastatin-niacin plus antioxidants ( P=0.004 ) and regressed by 0.4 percent with simvastatin-niacin alone ( P<0.001 ) . The frequency of the clinical end point was 24 percent with placebos ; 3 percent with simvastatin-niacin alone ; 21 percent in the antioxidant-therapy group ; and 14 percent in the simvastatin-niacin-plus-antioxidants group . CONCLUSIONS Simvastatin plus niacin provides marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels . The use of antioxidant vitamins in this setting must be question ed Colonic adenomas represent the natural precursor lesions of most colorectal cancers . The treatment of choice is endoscopic polypectomy . However , after endoscopic removal , polyps recur in a large fraction of cases . Thus , we evaluated the effect of antioxidant vitamins or lactulose on the recurrence rate of adenomatous polyps . After polypectomy , 255 individuals were r and omized into three groups . Group 1 was given vitamin A ( 30,000 IU/ day ) , vitamin C ( 1 g/day ) , and vitamin E ( 70 mg/day ) ; Group 2 was given lactulose ( 20 g/day ) ; Group 3 received no treatment .  Forty-six subjects had to be excluded because the histologic diagnosis was not consistent with adenoma . The remaining 209 individuals were included in the analysis according to the “ intention to treat ” criterion , though 34 did not adhere to the scheduled treatment or were lost during the follow-up . Subjects were followed at regular intervals for an average of 18 months . Polyps recurring before one year from index colonoscopy were considered missed by the endoscopist . In the 209 evaluable subjects , the percentages of recurrence of adenomas were 5.7 percent , 14.7 percent , and 35.9 percent in the vitamins , lactulose , and untreated groups , respectively . The fraction of subjects remaining free of adenomas , estimated by Kaplan-Meier survival curves , was significantly different among the three groups ( log-rank chisquared = 17.138;P < 0.001 ) . Using Cox 's regression analysis , treatment was the only variable that significantly contributed to the model ( regression coefficient=0.905;P<0.001 ) . In conclusion , either antioxidant vitamins or , to a lesser extent , lactulose lower the recurrence rate of adenomas of the large bowel and can be proposed as chemopreventive agents , at least in high-risk individuals OBJECTIVES To test the hypothesis that a micronutrient supplement can improve seroconversion after influenza immunization in older institutionalized people . DESIGN : R and omized , double-blind , placebo-controlled study . SETTING Nursing and residential homes in Liverpool , United Kingdom . PARTICIPANTS One hundred sixty-four residents aged 60 and older from 31 homes were initially r and omized ; of these , 119 ( 72.6 % ) completed the study . INTERVENTION Participants were r and omized to receive a micronutrient supplement providing the reference nutrient intake for all vitamins and trace elements or identical placebo . Tablets were taken over an 8-week period during September and October 2000 ; influenza vaccine was administered 4 weeks after their commencement . MEASUREMENTS The hemagglutination-inhibiting antibody response as defined by a fourfold or greater titer rise over 4 weeks and assessed separately for each of the three antigens contained in the 2000/2001 influenza vaccine ( A/New Caledonia/20/99 ( H1N1 ) , A/Moscow/10/99 ( H3N2 ) , B/Beijing/184/93 ( B ) ) . RESULTS Despite a significant increase in serum concentrations of vitamins A , C , D3 , E , folate , and selenium in the supplemented group , there was no significant difference between groups ( supplemented vs placebo , respectively ) in the proportion of participants seroconverting to H1N1 ( 41 % vs 49 % , P=.374 ) , H3N2 ( 49 % vs 58 % , P=.343 ) , or B ( 41 % vs 40 % , P=.944 ) . CONCLUSION A micronutrient supplement providing the reference nutrient intake administered over 8 weeks had no beneficial effect on antibody response to influenza vaccine in older people living in long-term care BACKGROUND R and omized trials have largely failed to support an effect of antioxidant vitamins on the risk of cardiovascular disease ( CVD ) . Few trials have examined interactions among antioxidants , and , to our knowledge , no previous trial has examined the individual effect of ascorbic acid ( vitamin C ) on CVD . METHODS The Women 's Antioxidant Cardiovascular Study tested the effects of ascorbic acid ( 500 mg/d ) , vitamin E ( 600 IU every other day ) , and beta carotene ( 50 mg every other day ) on the combined outcome of myocardial infa rct ion , stroke , coronary revascularization , or CVD death among 8171 female health professionals at increased risk in a 2 x 2 x 2 factorial design . Participants were 40 years or older with a history of CVD or 3 or more CVD risk factors and were followed up for a mean duration of 9.4 years , from 1995 - 1996 to 2005 . RESULTS A total of 1450 women experienced 1 or more CVD outcomes . There was no overall effect of ascorbic acid ( relative risk [ RR ] , 1.02 ; 95 % CI , 0.92 - 1.13 [ P = .71 ] ) , vitamin E ( RR , 0.94 ; 95 % CI , 0.85 - 1.04 [ P = .23 ] ) , or beta carotene ( RR , 1.02 ; 95 % CI , 0.92 - 1.13 [ P = .71 ] ) on the primary combined end point or on the individual secondary outcomes of myocardial infa rct ion , stroke , coronary revascularization , or CVD death . A marginally significant reduction in the primary outcome with active vitamin E was observed among the prespecified subgroup of women with prior CVD ( RR , 0.89 ; 95 % CI , 0.79 - 1.00 [ P = .04 ] ; P value for interaction , .07 ) . There were no significant interactions between agents for the primary end point , but those r and omized to both active ascorbic acid and vitamin E experienced fewer strokes ( P value for interaction , .03 ) . CONCLUSION There were no overall effects of ascorbic acid , vitamin E , or beta carotene on cardiovascular events among women at high risk for CVD CONTEXT Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events . Clinical trials have generally failed to confirm benefits , possibly due to their relatively short duration . OBJECTIVE To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer , cancer death , and major cardiovascular events .  DESIGN , SETTING , AND PATIENTS A r and omized , double-blind , placebo-controlled international trial ( the initial Heart Outcomes Prevention Evaluation [ HOPE ] trial conducted between December 21 , 1993 , and April 15 , 1999 ) of patients at least 55 years old with vascular disease or diabetes mellitus was extended ( HOPE-The Ongoing Outcomes [ HOPE-TOO ] ) between April 16 , 1999 , and May 26 , 2003 . Of the initial 267 HOPE centers that had enrolled 9541 patients , 174 centers participated in the HOPE-TOO trial . Of 7030 patients enrolled at these centers , 916 were deceased at the beginning of the extension , 1382 refused participation , 3994 continued to take the study intervention , and 738 agreed to passive follow-up . Median duration of follow-up was 7.0 years . INTERVENTION Daily dose of natural source vitamin E ( 400 IU ) or matching placebo . MAIN OUTCOME MEASURES Primary outcomes included cancer incidence , cancer deaths , and major cardiovascular events ( myocardial infa rct ion , stroke , and cardiovascular death ) . Secondary outcomes included heart failure , unstable angina , and revascularizations . RESULTS Among all HOPE patients , there were no significant differences in the primary analysis : for cancer incidence , there were 552 patients ( 11.6 % ) in the vitamin E group vs 586 ( 12.3 % ) in the placebo group ( relative risk [ RR ] , 0.94 ; 95 % confidence interval [ CI ] , 0.84 - 1.06 ; P = .30 ) ; for cancer deaths , 156 ( 3.3 % ) vs 178 ( 3.7 % ) , respectively ( RR , 0.88 ; 95 % CI , 0.71 - 1.09 ; P = .24 ) ; and for major cardiovascular events , 1022 ( 21.5 % ) vs 985 ( 20.6 % ) , respectively ( RR , 1.04 ; 95 % CI , 0.96 - 1.14 ; P = .34 ) . Patients in the vitamin E group had a higher risk of heart failure ( RR , 1.13 ; 95 % CI , 1.01 - 1.26 ; P = .03 ) and hospitalization for heart failure ( RR , 1.21 ; 95 % CI , 1.00 - 1.47 ; P = .045 ) . Similarly , among patients enrolled at the centers participating in the HOPE-TOO trial , there were no differences in cancer incidence , cancer deaths , and major cardiovascular events , but higher rates of heart failure and hospitalizations for heart failure . CONCLUSION In patients with vascular disease or diabetes mellitus , long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure OBJECTIVES We sought to determine whether lipid-lowering therapy and antioxidants retard the progression of coronary calcification and prevent atherosclerotic cardiovascular disease ( ASCVD ) events . BACKGROUND The electron beam computed tomography-derived coronary calcium score predicts coronary disease events . Small , uncontrolled studies suggest that vigorous lipid-lowering therapy slows progression of coronary calcification and prevents coronary artery disease events , but controlled , scientific demonstration of these effects is lacking . METHODS We conducted a double-blind , placebo-controlled r and omized clinical trial of atorvastatin 20 mg daily , vitamin C 1 g daily , and vitamin E ( alpha-tocopherol ) 1,000 U daily , versus matching placebos in 1,005 asymptomatic , apparently healthy men and women age 50 to 70 years with coronary calcium scores at or above the 80th percentile for age and gender . All study participants also received aspirin 81 mg daily . Mean duration of treatment was 4.3 years . RESULTS Treatment reduced total cholesterol by 26.5 % to 30.4 % ( p < 0.0001 ) , low-density lipoprotein cholesterol by 39.1 % to 43.4 % ( p < 0.0001 ) , and triglycerides by 11.2 % to 17.0 % ( p < or = 0.02 ) but had no effect ( p = 0.80 ) on progression of coronary calcium score ( Agatston method ) . Treatment also failed to significantly reduce the primary end point , a composite of all ASCVD events ( 6.9 % vs. 9.9 % , p = 0.08 ) . Event rates were related to baseline calcium score ( pre-specified analysis ) and may have been reduced in a subgroup of participants with baseline calcium score > 400 ( 8.7 % vs. 15.0 % , p = 0.046 [ not a pre-specified analysis ] ) . CONCLUSIONS Treatment with alpha-tocopherol , vitamin C , and low doses of atorvastatin ( 20 mg once daily ) did not affect the progression of coronary calcification . Treatment may have reduced ASCVD events , especially in subjects with calcium scores > 400 , but these effects did not achieve conventional levels of statistical significance context Funding surgery worldwide for age-related cataract ( ARC ) , a leading cause of blindness , is a huge economic burden . Non-surgical means of slowing ARC progression could benefit patients and reduce this burden . objective To determine if a mixture of oral antioxidant micronutrients [ mg/day ] ( ß-carotene [ 18 ] , vitamin C [ 750 ] , and vitamin E [ 600 ] ) would modify progression of ARC . design REACT was a multi-centered , prospect i ve , double-masked , r and omized , placebo-controlled , 3-year trial . setting Consecutive adult American and English out patients with early ARC were recruited . patients Four-hundred- and -forty-five patients were eligible ; 297 were r and omized ; 231 ( 78 % ) were followed for two years ; 158 ( 53 % ) were followed for three years ; 36 ( 12 % ) were followed for four years . Twelve patients  died during the trial ( 9 on vitamins ; 3 on placebo ( p = 0.07 ) ) . There were no serious safety issues . intervention After a three-month placebo run-in , patients were r and omized by clinical center to the vitamin or placebo groups and followed every four months . main outcome measure Cataract severity was documented with serial digital retroillumination imagery of the lens ; progression was quantified by image analysis assessing increased area of opacity . This measure of area , ‘ increase % pixels opaque ’ ( IPO ) , was the main outcome measure . results There were no statistically significant differences between the treatment groups at baseline . The characteristics of dropouts and the mean follow-up times by treatment group were the same . After two years of treatment , there was a small positive treatment effect in U.S. patients ( p = 0.0001 ) ; after three years a positive effect was apparent ( p = 0.048 ) in both the U.S. and the U.K. groups . The positive effect in the U.S. group was even greater after three years : ( IPO = 0.389 ( vitamin ) vs. IPO = 2.517 ( placebo ) ; p = 0.0001 ) . There was no statistically significant benefit of treatment in the U.K. group . In spite of nearly perfect r and omization into treatment groups , the U.S. and U.K. cohorts differed significantly . conclusion Daily use of the afore-mentioned micronutrients for three years produced a small deceleration in progression of ARC Objective Our aim was to evaluate whether vitamin E ( 500IU ) slowed the progression of  carotid atherosclerosis  in a population of chronic smokers over 4 years as measured by ultrasound determination of carotid intima-media thickness ( IMT ) and systemic arterial compliance ( SAC ) . Methods The Melbourne Atherosclerosis Vitamin E Trial ( MAVET ) was a r and omized , double-blind , placebo-controlled trial in which 409 male and female smokers aged 55 years and over were r and omized to receive 500IU per day of natural vitamin E or placebo . The primary endpoint was progression of carotid atherosclerosis determined by intima-media thickness of the right common carotid artery . Secondary outcomes were change in systemic arterial compliance and low-density lipoprotein ( LDL ) oxidative susceptibility over time . Results The mean increase in intima-media thickness over time in the vitamin E group was 0.0041 mm/year faster than placebo ( 95 % confidence interval −0.0021 to 0.0102 mm/year , P=0.20 ) . Similarly , a non-significant difference between vitamin E and placebo was found for rate of change in systemic arterial compliance ( P=0.11 ) . Vitamin E supplementation did , however , significantly reduce LDL oxidative susceptibility ( P>0.001 ) . Conclusion Vitamin E supplementation is ineffective in reducing the progression of carotid atherosclerosis as measured by intima-media thickness in chronic smokers . This finding extends our knowledge of lack of effectiveness of vitamin E supplementation in population s with high oxidant stress . Eur J Cardiovasc Prev Rehabil 13:341 - 347 © 2006 The European Society of BACKGROUND Beta carotene has been associated with a decreased risk of human cancer in many studies employing dietary question naires or blood measurements , and it has had protective effects in some animal models of carcinogenesis . METHODS We tested the possible cancer-preventing effects of beta carotene by r and omly assigning 1805 patients who had had a recent nonmelanoma skin cancer to receive either 50 mg of beta carotene or placebo per day and by conducting annual skin examinations to determine the occurrence of new nonmelanoma skin cancer . RESULTS Adherence to the prescribed treatment was good , and after one year the actively treated group 's median plasma beta carotene level ( 3021 nmol per liter ) was much higher than that of the control group ( 354 nmol per liter ) . After five years of follow-up , however , there was no difference between the groups in the rate of occurrence of the first new nonmelanoma skin cancer ( relative rate , 1.05 ; 95 percent confidence interval , 0.91 to 1.22 ) . In subgroup analyses , active treatment showed no efficacy either in the patients whose initial plasma beta carotene level was in the lowest quartile or in those who currently smoked . There was also no significant difference between treated and control groups in the mean number of new nonmelanoma skin cancers per patient-year . CONCLUSIONS In persons with a previous nonmelanoma skin cancer , treatment with beta carotene does not reduce the occurrence of new skin cancers over a five-year period of treatment and observation Summary .Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis ( ALS ) . The antioxidant vitamin E ( alpha-tocopherol ) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS . The current study , a double blind , placebo-controlled , r and omised , stratified , parallel-group clinical trial , was design ed to determine whether vitamin E ( 5000 mg per day ) may be efficacious in slowing down disease progression when added to riluzole . Methods . 160 patients in 6 German centres with either probable or definite ALS ( according to the El Escorial Criteria ) and a disease duration of less than 5 years , treated with riluzole , were included in this study and were r and omly assigned to receive either alpha-tocopherol ( 5000 mg per day ) or placebo for 18 months . The Primary outcome measure was survival , calculating time to death , tracheostomy or permanent assisted ventilation , according to the WFN- Criteria of clinical trials . Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales , manual muscle testing ( BMRC ) , spasticity scale , ventilatory function and the Sickness Impact Profile ( SIP ALS/19 ) . Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18 . Vitamin E sample s were taken for compliance check and Quality Control of the trial . For Safety , a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18 . Height and weight were recorded at baseline and weight alone at the follow-up visits . A neurological examination as well as vital signs ( heart rate and blood pressure ) , an ECG and VEP ’s were recorded at each visit . Furthermore , spontaneously reported adverse experiences and serious adverse events were documented and st and ard laboratory tests including liver function tests performed . For Statistical Analysis , the population to be considered for the primary outcome measure was an “ intent-to-treat ” ( ITT ) population which included all r and omised patients who had received at least one treatment dose ( n = 160 patients ) . For the secondary outcome measures , a two way analysis of variance was performed on a patient population that included all r and omised patients who had at least one assessment after inclusion . Results . Concerning the primary endpoint , no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test . The functional assessment s showed a marginal trend in favour of vitamin E , without reaching significance . Conclusion . Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol . Larger or longer studies might be needed . However , administration of this megadose does not seem to have any significant side effects in this patient population The aim of this study was to determine if vitamin A supplementation reduces the incidence of bacterial infections among elderly nursing-home residents . One hundred and nine patients were enrolled into a double-masked , placebo-controlled  trial at an academically affiliated nursing home . Fifty-six patients received a single capsule containing 1,000 IU of vitamin A ( placebo ) and 53 received a single capsule containing 200,000 IU of vitamin A.  Antibiotic-treated infections were enumerated for 90 days after dosing and infection rates were expressed per 1000 days of follow-up . There were 42 antibiotic-treated infections altogether , 21 in each group . The infection rates in the vitamin A and placebo groups were 4.7 and 4.3 per 1,000 days of follow-up , respectively ( relative risk 1.1 ; 95 % CI 0.6 , 2.0 ) . The findings of this study do not support a role for vitamin A supplements for the prevention of infections among frail elderly nursing-home patients Because their formation is associated with tumor development in specific tissues , DNA adducts have potential usefulness as intermediate end points in chemoprevention studies . To determine the efficacy of a combination of antioxidant vitamins ( vitamins C and E and beta-carotene ) , a r and omized clinical trial was conducted among heavy smokers using DNA damage as the end point . Immunological methods were used to measure polycyclic aromatic hydrocarbon-DNA adducts and oxidative DNA damage ( 8-oxo or hydroxydeoxyguanosine ) in mononuclear and oral cells . A total of 121 subjects were r and omized to the 6-month intervention and received either vitamins or placebo .  Dropout rates were higher in the placebo than in the vitamin group ; 65 % of subjects in the vitamin group , but only 47 % in the placebo group , provided specimens at 6 months . Plasma levels of all three antioxidants rose significantly in the vitamin group but not in the placebo group . All four measures of DNA damage decreased in both groups ; the between-group differences were not statistically significant . These data do not provide clear evidence that antioxidant vitamin intake prevents DNA damage . However , the study demonstrates that DNA damage is a useful end point in chemoprevention trials The possibility of pharmacological control of large bowel adenomas has been suggested by effectiveness of antioxidants in experimental tumor models and by the results of a limited clinical study using ascorbic acid . Over a two year period we tested this hypothesis in a r and omized , double‐blind study of 49 patients with polyposis coli . Of 36 patients who were evaluable at completion , 19 had received ascorbic acid , 3g/day , and 17 had received a placebo . We found a reduction in polyp area in the ascorbic acid‐treated group at nine months of follow‐up ( P < 0.03 ) and trends toward reduction in both number and area of rectal polyps during the middle of the trial . A labeling study of rectal epithelium with tritiated thymidine also hinted at a treatment effect . Our data suggest that ascorbic acid temporarily influenced polyp growth or turnover . Although these results have no current therapeutic value , our findings support continued studies of chemoprevention in this and other high risk setting Context Vitamin E supplements ( 400 IU or more daily ) have no clear clinical benefits and may be harmful . Contribution Self-reported data from 4609 adults who participated in the 19992000 National Health and Nutrition Examination Survey showed that about 11 % consumed at least 400 IU of vitamin E daily . Use was highest among older white adults who also consumed other antioxidant supplements .  Caution s We do not know the form of vitamin E that adults consumed , but -tocopherol is the form most commonly found in supplements . Implication s Many adults may be taking vitamin E supplements that have no proven clinical benefits and might be harmful . The Editors In a recent meta- analysis of r and omized clinical trials , Miller and colleagues reported that the intake of vitamin E of at least 400 IU per day from supplements was associated with a small increase in mortality from all causes ( 1 ) . The recent findings of the Women 's Health Study , in which participants consumed 600 IU of vitamin E every other day , were consistent with the results from this meta- analysis ( 2 , 3 ) . Furthermore , the Heart Outcomes Prevention Evaluation research ers linked the use of 400 IU of vitamin E per day to an increased risk for congestive heart failure ( 4 ) . Vitamin E intake of 400 IU per day or greater can practicably be achieved only through supplementation . Among adults older than 20 years of age who participated in the U.S. Department of Agriculture 's 19941996 Continuing Surveys of Food Intake by Individuals , the median intake of vitamin E was 5.6 mg of -tocopherol equivalents per day ( 6.7 IU ) for men and 4.0 ( 4.8 IU ) for women ( 5 ) . Supplemental use of vitamins and minerals has increased in the United States , and supplemental use of vitamin E increased rapidly between 1987 and 2000 ( 6 , 7 ) . The extent to which supplements containing high doses of vitamin E are used in the United States remains incompletely documented , however . Therefore , our objectives were to estimate the percentage of U.S. adults who use supplements leading to intake of vitamin E of 400 IU or greater per day and to examine the social and demographic variations in these estimates . Methods We used data from the National Health and Nutrition Examination Survey ( NHANES ) conducted from 1999 to 2000 ( 8) . This survey included a representative sample of the civilian , noninstitutionalized U.S. population selected through stratified , multistage sampling . Trained interviewers , using a computer-assisted personal interview system , interviewed participants at home . Subsequently , participants completed additional question naires ( including a single 24-hour dietary recall ) ; underwent basic neurosensory , anthropometric , fitness , and oral health evaluations ; and provided a blood sample at the mobile examination center . The response rate was 81.9 % for those interviewed and 76.3 % for those examined . An Institutional Review Board at the Centers for Disease Control and Prevention approved the survey . Participants provided informed consent . Participants who responded affirmatively to the question Have you used or taken any vitamins , minerals , or other dietary supplements in the past month ? were asked to provide additional details about the dose , frequency , and duration of use . The interviewer also asked to see the containers of the supplements to record information about the name and manufacturer of the supplements . If participants could not produce the containers , interviewers asked them to recall this information . We estimated the dietary intake of vitamin E from a single 24-hour recall . Laboratory personnel measured serum concentrations of - and -tocopherol using a Waters Alliance high-performance liquid chromatography system ( Waters Corp. , Milford , Massachusetts ) . A detailed description of laboratory quality control procedures used in the survey can be accessed at the Centers for Disease Control and Prevention Web site ( 9 ) . Among participants age 20 years or older , we estimated the percentage ( 95 % CI ) who 1 ) did not use supplements or used supplements that did not contain vitamin E , 2 ) consumed less than 400 IU per day from the use of supplements , and 3 ) used supplements providing at least 400 IU per day . We examined the variation in the intake of vitamin E , 400 IU or greater per day , by the following characteristics of participants : age ; sex ; race or ethnicity ; educational status ; presence of chronic conditions ( coronary heart disease , angina pectoris , stroke , and diabetes ) ; smoking behavior ; strata of blood pressure ; serum total cholesterol concentration ; and body mass index . We present results only for the 3 major racial or ethnic groups ( white , African-American , and Mexican-American ) because the sample sizes for the other groups were small . Other results are based on all available data . For 2- sample tests of proportions , we used a t-test . For characteristics with 3 levels , we tested the differences in the intake of vitamin E  from supplements with a test for linear trend . We used SUDAAN statistical analysis software ( Research Triangle Institute , Research Triangle Park , North Carolina ) to account for the complex sampling design of the survey and to produce proper estimates of the st and ard errors ( 10 ) . Results Figure 1 shows the numbers of participants who were included in the analyses . The participants who did not have a serum determination of -tocopherol were an average of 2.2 years older ( P= 0.017 ) than the other participants , but the percentages who were male , were white , and who had at least a high school education did not significantly differ . Figure 1 . Sample -size flow for 19992000 National Health and Nutrition Examination Survey . Overall , 11.3 % ( CI , 9.7 % to 13.1 % ) of adults used supplements that led to a daily intake of 400 IU or greater , and 25.7 % ( CI , 24.0 % to 27.5 % ) consumed less than 400 IU per day from such supplements . As illustrated in the Table , such intake increased with increasing age ( P < 0.001 for linear trend ) , was about equal for men and women ( P > 0.2 ) , and was more common among white persons than African-American ( P < 0.001 ) or Mexican-American persons ( P < 0.001 ) . Participants who had a history of coronary heart disease , angina pectoris , stroke , or diabetes were more likely to use high doses of vitamin E  than participants without these conditions ( P < 0.001 for all age-adjusted differences ) . Table . Unadjusted Percentages of Adults Aged 20 Years or Older Who Consume  400 IU of Vitamin E per Day from the Use of Vitamin , Mineral , or Dietary Supplements ( 19992000 National Health and Nutrition Examination Survey ) The distribution of concentrations of serum -tocopherol for 3875 participants reflected the intake of vitamin E ( Figure 2 ) . For participants who did not use supplements or did not use supplements containing vitamin E , the median serum concentration of -tocopherol was 22.85 mol/L ( n= 2506 ) ; in comparison , participants using supplements had median concentrations of 30.22 mol/L ( intake of < 400 IU per day ; n= 953 ) and 49.03 mol/L ( intake of 400 IU per day ; n= 409 ) . The ratios of concentrations of -tocopherol to total cholesterol for the 3 groups were , respectively , 4.47 mol/mmol ( n= 2494 ) , 5.85 mol/mmol ( n= 947 ) , and 9.04 mol/mmol ( n= 408 ) . Serum -tocopherol concentrations were 6.01 mol/L ( no supplementation ; n= 2172 ) , 4.40 mol/L ( < 400 IU per day ; n= 827 ) , and 2.08 mol/L ( 400 IU per day ; n= 377 ) ; the respective ratios of concentrations of - to -tocopherol were 3.61 mol/mol ( n= 2161 ) , 6.81 mol/mol ( n= 824 ) , and 24.22 mol/mol ( n= 358 ) . Figure 2 . Concentrations of serum -tocopherol ( top ) and -tocopherol ( bottom ) among U.S. adults age 20 years or older by intake of vitamin E from the  use of vitamin , mineral , or dietary supplements ( 19992000 National Health and Nutrition Examination Survey ) . To examine the Pearson correlation coefficients between log-transformed concentrations of the 2 tocopherols , we used a smaller set of participants ( n= 1474 ) who attended the mobile examination center in the morning , had fasted at least 8 hours , and had concentrations of triglycerides measured using a reference method that was performed only among morning attendees . After adjustment for age and concentrations of total cholesterol and triglycerides , the Pearson correlation coefficient was 0.62 . The adjusted correlations were 0.48 for participants who consumed at least 400 IU of vitamin E per day from supplements , 0.56 for participants who consumed less than 400 IU per day from such supplements , and 0.30 for participants who did not use supplements or did not consume vitamin E from supplements . Participants who used supplements containing vitamin E commonly used other antioxidants , such as vitamin C or -carotene . The percentages of participants who used  supplements containing vitamin C  were 84.9 % ( CI , 80.8 % to 89.1 % ) among participants who consumed 400 IU per day of vitamin E from supplements , 97.9 % ( CI , 96.7 % to 99.2 % ) among participants who consumed less than 400 IU per day from such supplements , and 6.4 % ( CI , 5.1 % to 7.8 % ) among participants who did not use supplements or did not consume vitamin E from supplements . For -carotene , these percentages were 50.4 % ( CI , 42.8 % to 58.1 % ) , 66.0 % ( CI , 61.8 % to 70.2 % ) , and less than 1.0 % , respectively . For the self-reported use of cholesterol-lowering medications , these percentages were 19.7 % ( CI , 14.8 % to 24.6 % ) , 7.1 % ( CI , 5.2 % to 9.0 % ) , and 6.3 % ( CI , 4.9 % to 7.8 % ) . Among 4239 participants who attended the mobile examination center  and completed the 24-hour dietary recall , the median intake of vitamin E  from diet was 7.40 mg of -tocopherol equivalents per day ( 8.8 IU ) and ranged from 0.03 to 153.26 mg of -tocopherol equivalents per day ( 0.04 to 182.7 IU ) . Among participants who consumed at least 400 IU per day from supplements , 1 participant 's total intake of vitamin E  from diet and supplements exceeded 400 IU per day . Discussion In this representative sample of U.S. adults , about 11.3 % used supplements leading to an intake of vitamin E 400 IU per CONTEXT Respiratory tract infections are prevalent in elderly individuals , result ing in increased morbidity , mortality , and use of health care services . Vitamin E supplementation has been shown to improve immune response in elderly persons . However , the clinical importance of these findings has not been determined . OBJECTIVE To determine the effect of 1 year of vitamin E supplementation on respiratory tract infections in elderly nursing home residents . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled trial was conducted from April 1998 to August 2001 at 33 long-term care facilities in the Boston , Mass , area . A total of 617 persons aged at least 65 years and who met the study 's eligibility criteria were enrolled ; 451 ( 73 % ) completed the study . INTERVENTION Vitamin E ( 200 IU ) or placebo capsule administered daily ; all participants received a capsule containing half the recommended daily allowance of essential vitamins and minerals . MAIN OUTCOME MEASURES Incidence of respiratory tract infections , number of persons and number of days with respiratory tract infections ( upper and lower ) , and number of new antibiotic prescriptions for respiratory tract infections among all participants r and omized and those who completed the study . RESULTS Vitamin E had no significant effect on incidence or number of days with infection for all , upper , or lower respiratory tract infections . However , fewer participants receiving vitamin E acquired 1 or more respiratory tract infections ( 60 % vs 68 % ; risk ratio [ RR ] , 0.88 ; 95 % confidence interval [ CI ] , 0.76 - 1.00 ; P = .048 for all participants ; and 65 % vs 74 % ; RR , 0.88 ; 95 % CI , 0.75 - 0.99 ; P = .04 for completing participants ) , or upper respiratory tract infections ( 44 % vs 52 % ; RR , 0.84 ; 95 % CI , 0.69 - 1.00 ; P = .05 for all participants ; and 50 % vs 62 % ; RR , 0.81 ; 95 % CI , 0.66 - 0.96 ; P = .01 for completing participants ) . When common colds were analyzed in a post hoc subgroup analysis , the vitamin E group had a lower incidence of common cold ( 0.67 vs 0.81 per person-year ; RR , 0.83 ; 95 % CI , 0.68 - 1.01 ; P = .06 for all participants ; and 0.66 vs 0.83 per person-year ; RR , 0.80 ; 95 % CI , 0.64 - 0.98 ; P = .04 for completing participants ) and fewer participants in the vitamin E group acquired 1 or more colds ( 40 % vs 48 % ; RR , 0.83 ; 95 % CI , 0.67 - 1.00 ; P = .05 for all participants ; and 46 % vs 57 % ; RR , 0.80 ; 95 % CI , 0.64 - 0.96 ; P = .02 for completing participants ) . Vitamin E had no significant effect on antibiotic use . CONCLUSIONS Supplementation with 200 IU per day of vitamin E did not have a statistically significant effect on lower respiratory tract infections in elderly nursing home residents . However , we observed a protective effect of vitamin E supplementation on upper respiratory tract infections , particularly the common cold , that merits further investigation 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 OBJECTIVE To determine whether treatment with vitamin E ( 500 IU daily ) reduces either the incidence or rate of progression of age-related cataracts .  DESIGN A prospect i ve , r and omized , double-masked , placebo-controlled clinical trial entitled the Vitamin E , Cataract and Age-Related Maculopathy Trial . PARTICIPANTS Of 1906 screened volunteers , 1193 eligible subjects with early or no cataract , aged 55 to 80 years , were enrolled and followed up for 4 years . INTERVENTION Subjects were assigned r and omly to receive either 500 IU of natural vitamin E in soybean oil encapsulated in gelatin or a placebo with an identical appearance . MAIN OUTCOME MEASURES The incidence and progression rates of age-related cataract were assessed annually with both clinical lens opacity gradings and computerized analysis of Scheimpflug and retroillumination digital lens images obtained with a Nidek EAS-1000 lens camera . The analysis was undertaken using data from the eye with the more advanced opacity for each type of cataract separately and for any cataract changes in each individual . RESULTS Overall , 87 % of the study population completed the 4 years of follow-up , with 74 % of the vitamin E group and 76 % of the placebo group continuing on their r and omized treatment allocation throughout this time . For cortical cataract , the 4-year cumulative incidence rate was 4.5 % among those r and omized to vitamin E and 4.8 % among those r and omized to placebo ( P = 0.87 ) . For nuclear cataract , the corresponding rates were 12.9 % and 12.1 % ( P = 0.77 ) . For posterior subcapsular cataract , the rates were 1.7 % and 3.5 % ( P = 0.08 ) , whereas for any of these forms of cataract , they were 17.1 % and 16.7 % , respectively . Progression of cortical cataract was seen in 16.7 % of the vitamin E group and 18.4 % of the placebo group ( P = 0.76 ) . Corresponding rates for nuclear cataract were 11.4 % and 11.9 % ( P = 0.84 ) , whereas those of any cataract were 16.5 % and 16.7 % , respectively . There was no difference in the rate of cataract extraction between the 2 groups ( P = 0.87 ) . Lens characteristics of the participants withdrawn from the r and omized medications were not different from those who continued . CONCLUSIONS Vitamin E given for 4 years at a dose of 500 IU daily did not reduce the incidence of or progression of nuclear , cortical , or posterior subcapsular cataracts . These findings do not support the use of vitamin E to prevent the development or to slow the progression of age-related cataracts BACKGROUND Excess cardiovascular mortality has been documented in chronic haemodialysis patients . Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without , suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis . We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease . METHODS Haemodialysis patients with pre-existing cardiovascular disease ( n=196 ) aged 40 - 75 years at baseline from six dialysis centres were enrolled and r and omised to receive  800 IU/day vitamin E or matching placebo . Patients were followed for a median 519 days . The primary endpoint was a composite variable consisting of : myocardial infa rct ion ( fatal and non-fatal ) , ischaemic stroke , peripheral vascular disease ( excluding the arteriovenous fistula ) , and unstable angina . Secondary outcomes included each of the component outcomes , total mortality , and cardiovascular-disease mortality . FINDINGS A total of 15 ( 16 % ) of the 97 patients assigned to vitamin E and 33 ( 33 % ) of the 99 patients assigned to placebo had a primary endpoint ( relative risk 0.46 [ 95 % CI 0.27 - 0.78 ] , p=0.014 ) . Five ( 5.1 % ) patients assigned to vitamin E and 17 ( 17.2 % ) patients assigned to placebo had myocardial infa rct ion ( 0.3 [ 0.11 - 0.78 ] , p=0.016 ) . No significant differences in other secondary endpoints , cardiovascular disease , or total mortality were detected . INTERPRETATION In haemodialysis patients with prevalent cardiovascular disease , supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infa rct ion BACKGROUND People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel . Antioxidant vitamins , which are present in vegetables and fruits , have been associated with a diminished risk of cancers at various anatomical sites . We conducted a r and omized , controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma , a precursor of invasive cancer . METHODS We r and omly assigned 864 patients , using a two-by-two factorial design , to four treatment groups , which received placebo ; beta carotene ( 25 mg daily ) ; vitamin C ( 1 g daily ) and vitamin E ( 400 mg daily ) ; or the beta carotene plus vitamins C and E. In order to identify new adenomas , we performed complete colonoscopic examinations in the patients one year and four years after they entered the study . The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations . RESULTS Patients adhered well to the prescribed regimen , and 751 completed the four-year clinical trial . There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas ; the relative risk for beta carotene was 1.01 ( 95 percent confidence interval , 0.85 to 1.20 ) ; for vitamins C and E , it was 1.08 ( 95 percent confidence interval , 0.91 to 1.29 ) . Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location . CONCLUSIONS The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer . Although our data do not prove definitively that these antioxidants have no anticancer effect , other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits BACKGROUND A number of vitamins and minerals have been shown to influence carcinogenesis in experimental animals . In humans , epidemiologic evidence suggests that intake of fruits and vegetables may reduce risk of esophageal and other cancers . Vitamins and minerals in these foods may contribute to the reduced cancer risk . The people of Linxian , China , have persistently low intake of multiple nutrients and exhibit one of the world 's highest rates of esophageal/gastric cardia cancer , with an exceptionally high risk of esophageal dysplasia . PURPOSE To determine whether supplementation with multiple vitamins and minerals may reduce esophageal/gastric cardia cancer among persons with esophageal dysplasia , we conducted a 6-year prospect i ve intervention trial in Linxian . METHODS Mortality and cancer incidence were ascertained from May 1985 through May 1991 for 3318 persons with cytologic evidence of esophageal dysplasia who were r and omly assigned to receive , throughout that period , daily supplementation with 14 vitamins and 12 minerals or placebo . Doses were typically two to three times U.S. Recommended Daily Allowances . Compliance was assessed by counting unused pills monthly for all trial participants and by assaying nutrient levels in blood collected from sample s of individuals r and omly selected without replacement every 3 months throughout the trial . Cancers were identified through routine surveillance and by special cytology and endoscopy screenings after 2 1/2 years and 6 years . RESULTS A total of 324 deaths occurred during the 6-year intervention period ; 167 occurred in the control ( placebo ) group and 157 occurred in the  supplement  group . Cancer was the leading cause of death ( 54 % of all deaths ) ; 18 % were due to cerebrovascular diseases and 29 % to other causes . Cumulative esophageal/gastric cardia death rates were 8 % lower ( relative risk [ RR ] = 0.92 ; 95 % confidence interval [ CI ] = 0.67 - 1.28 ) among individuals receiving supplements rather than placebo , a nonsignificant ( P > .10 ) difference . Risk of total mortality was 7 % lower ( RR = 0.93 ; 95 % CI = 0.75 - 1.16 ; P > .10 ) , total cancer 4 % lower ( RR = 0.96 ; 95 % CI = 0.71 - 1.29 ; P > .10 ) , cerebrovascular disease 38 % lower ( RR = 0.62 ; 95 % CI = 0.37 - 1.06 ; P = .08 ) , and other diseases 12 % higher ( RR = 1.12 ; 95 % CI = 0.74 - 1.69 ; P > .10 ) among the treated group . Cumulative cancer incidence rates were nearly the same in the two groups . CONCLUSIONS No substantial short-term beneficial effect on incidence or mortality for this type of cancer occurred following daily supplementation with multiple vitamins and minerals among adults with precancerous lesions of the esophagus . IMPLICATION S Although no statistically significant short-term benefits were observed , longer follow-up should be more informative about the effectiveness of this 6-year supplementation on cancer and other diseases among individuals with esophageal dysplasia BACKGROUND Age-related macular degeneration ( ARMD ) is the leading cause of vision loss in aging Westem societies . The objective of the lutein antioxidant supplementation trial ( LAST ) is to determine whether nutritional supplementation with lutein or lutein together with antioxidants , vitamins , and minerals , improves visual function and symptoms in atrophic ARMD . METHODS The study was a prospect i ve , 12-month , r and omized , double-masked , placebo-controlled trial conducted at an urban midwestern Veterans Administration Hospital from August 1999 to May 2001 . Ninety patients with atrophic ARMD were referred by ophthalmologists at two Chicago-area veterans medical facilities . Patients in Group 1 received lutein 10 mg ( L ) ; in Group 2 , a lutein 10 mg/antioxidants/vitamins and minerals broad spectrum supplementation formula ( L/A ) ; and in Group 3 , a maltodextrin placebo ( P ) over 12 months . RESULTS In Groups 1 L and 2 L/A , mean eye macular pigment optical density increased approximately 0.09 log units from baseline , Snellen equivalent visual acuity improved 5.4 letters for Group 1 L and 3.5 letters for Group 2 L/A , and contrast sensitivity improved . There was a net subjective improvement in Amsler grid in Group 1 L. VFO-14 question naires conceming subjective glare recovery were nearly significant at 4 months for Group 2 L/A. Patients who received the placebo ( Group 3 ) had no significant changes in any of the measured findings . CONCLUSION In this study , visual function is improved with lutein alone or lutein together with other nutrients . Further studies are needed with more patients , of both genders , and for longer periods of time to assess long-term effects of lutein or lutein together with a broad spectrum of antioxidants , vitamins , and minerals in the treatment of atrophic age-related macular degeneration BACKGROUND Epidemiologic evidence of associations between the high intake of fat and low intake of dietary fiber , beta carotene , and other dietary constituents and the risk of colorectal neoplasia has been inconsistent and has not provided a sufficient basis for recommendations concerning the dietary prevention of large-bowel cancer in humans . PURPOSE We conducted a clinical trial to assess the effects on the incidence of adenomas of reducing dietary fat to 25 % of total calories and supplementing the diet with 25 g of wheat bran daily and a capsule of beta carotene ( 20 mg daily ) . METHODS We performed a r and omized , partially double-blinded , placebo-controlled factorial trial in which half the patients were assigned to each intervention , result ing in seven  intervention  groups and one control group . Eligibility criteria included histologic confirmation of at least one colorectal adenoma and confidence expressed by the colonoscopist that all polyps had been removed . Dietary changes were individually initiated and monitored by dietitians and research nurses . At surveillance colonoscopy , the size and location of all polyps were recorded , and their histology was later central ly review ed . Among 424 patients who were r and omly assigned in the trial , 13 were found to be ineligible upon histologic review . Among the remaining 411 , complete outcome data were collected from 390 at 24 months and from 306 at 48 months . All P values are from two-sided tests of statistical significance . RESULTS There was no statistically significant prevention of total new adenomas with any of the interventions . We found a statistically non-significant reduced risk of large adenomas ( > or = 10 mm ) with the low-fat intervention : At 24 months , the odds ratio ( OR ) adjusted for potential confounders = 0.4 and 95 % confidence interval ( CI ) = 0.1 - 1.1 ; at 48 months , OR = 0.3 and 95 % CI = 0.1 - 1.0 . Less and statistically nonsignificant reductions in the risk of large adenomas were found with wheat bran : At 24 months , OR = 0.8 and 95 % CI = 0.3 - 2.2 ; at 48 months , OR = 0.8 and 95 % CI = 0.3 - 2.5 . Patients on the combined intervention of low fat and added wheat bran had zero large adenomas at both 24 and 48 months , a statistically significant finding ( P = .03 ) . CONCLUSIONS Because only small numbers of patients were studied , our finding that the combination of fat reduction and a supplement of wheat bran reduced the incidence of large adenomas in this r and omized , controlled trial must be treated with caution . The results do suggest , however , that these interventions may reduce the transition from smaller to larger adenomas , a step that may critically define those adenomas most likely to progress to malignancy BACKGROUND Previous research has identified a high risk of gastric carcinoma as well as a high prevalence of cancer precursor lesions in rural population s living in the province of Nariño , Colombia , in the And es Mountains . METHODS A r and omized , controlled chemoprevention trial was conducted in subjects with confirmed histologic diagnoses of multifocal nonmetaplastic atrophy and /or intestinal metaplasia , two precancerous lesions . Individuals were assigned to receive anti-Helicobacter pylori triple therapy and /or dietary supplementation with ascorbic acid , beta-carotene , or their corresponding placebos . Gastric biopsy specimens taken at baseline were compared with those taken at 72 months . Relative risks of progression , no change , and regression from multifocal nonmetaplastic atrophy and intestinal metaplasia were analyzed with multivariate polytomous logistic regression models to estimate treatment effects . All statistical tests were two-sided . RESULTS All three basic interventions result ed in statistically significant increases in the rates of regression : Relative risks were 4.8 ( 95 % confidence interval [ CI ] = 1.6 - 14.2 ) for anti-H. pylori treatment , 5 . 1 ( 95 % CI = 1.7 - 15.0 ) for beta-carotene treatment , and 5.0 ( 95 % CI = 1.7 - 14.4 ) for ascorbic acid treatment in subjects with atrophy . Corresponding relative risks of regression in subjects with intestinal metaplasia were 3.1 ( 95 % CI = 1.0 - 9.3 ) , 3.4 ( 95 % CI = 1.1 - 9.8 ) , and 3.3 ( 95 % CI = 1.1 - 9.5 ) . Combinations of treatments did not statistically significantly increase the regression rates . Curing the H. pylori infection ( which occurred in 74 % of the treated subjects ) produced a marked and statistically significant increase in the rate of regression of the precursor lesions ( relative risks = 8.7 [ 95 % CI = 2.7 - 28.2 ] for subjects with atrophy and 5.4 [ 95 % CI = 1.7 - 17.6 ] for subjects with intestinal metaplasia ) . CONCLUSIONS In the very high-risk population studied , effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process , mostly by increasing the rate of regression of cancer precursor lesions , and may be an effective strategy to prevent gastric carcinoma To evaluate the clinical antioxidant effects of vitamin E , 161 healthy volunteers aged 39 to 56 years , were given 100 or 3 mg of d-α-tocopheryl acetate orally daily for 6 years using a r and omized , double-blind design . Among the 147 volunteers who qualified for the analysis , seven of the 73 volunteers receiving 3 mg d-α-tocopheryl acetate daily and none of the 74 volunteers receiving 100 mg had coronary disorders including myocardial damage ( P < 0.02 ) . ST or T wave abnormalities on electrocardiograms were considered to indicate coronary disorders ( four volunteers ) . The mean serum total tocopherol ( TOC ) concentration in the 100-mg group was significantly higher than that in the 3-mg group 6 months after the start of the study , and this raised value was maintained throughout the study ; the level in the 3-mg group did not change significantly from the baseline value . The low-density lipoprotein cholesterol/total TOC ratio , a parameter of the inhibition of peroxidation of low-density lipoprotein cholesterol , was the only serum lipid parameter that was significantly different , at baseline , in the volunteers with coronary disorders compared with the others . These findings indicate that long-term supplementation with 100 mg tocopheryl acetate daily may prevent the early stages of coronary atherosclerosis by decreasing peroxidation of low-density lipoprotein cholesterol BACKGROUND It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease , cancer , and other adverse outcomes . METHODS 20,536 UK adults ( aged 40 - 80 ) with coronary disease , other occlusive arterial disease , or diabetes were r and omly allocated to receive antioxidant vitamin supplementation ( 600 mg vitamin E , 250 mg vitamin C , and 20 mg beta-carotene daily ) or matching placebo . Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants . An average of 83 % of participants in each treatment group remained compliant during the scheduled 5-year treatment period . Allocation to this vitamin regimen approximately doubled the plasma concentration of alpha-tocopherol , increased that of vitamin C by one-third , and quadrupled that of beta-carotene . Primary outcomes were major coronary events ( for overall analyses ) and fatal or non-fatal vascular events ( for subcategory analyses ) , with subsidiary assessment s of cancer and of other major morbidity . FINDINGS There were no significant differences in all-cause mortality ( 1446 [ 14.1 % ] vitamin-allocated vs 1389 [ 13.5 % ] placebo-allocated ) , or in deaths due to vascular ( 878 [ 8.6 % ] vs 840 [ 8.2 % ] ) or non-vascular ( 568 [ 5.5 % ] vs 549 [ 5.3 % ] ) causes . Nor were there any significant differences in the numbers of participants having non-fatal myocardial infa rct ion or coronary death ( 1063 [ 10.4 % ] vs 1047 [ 10.2 % ] ) , non-fatal or fatal stroke ( 511 [ 5.0 % ] vs 518 [ 5.0 % ] ) , or coronary or non-coronary revascularisation ( 1058 [ 10.3 % ] vs 1086 [ 10.6 % ] ) . For the first occurrence of any of these " major vascular events " , there were no material differences either overall ( 2306 [ 22.5 % ] vs 2312 [ 22.5 % ] ; event rate ratio 1.00 [ 95 % CI 0.94 - 1.06 ] ) or in any of the various subcategories considered . There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause . INTERPRETATION Among the high-risk individuals that were studied , these antioxidant vitamins appeared to be safe . But , although this regimen increased blood vitamin concentrations substantially , it did not produce any significant reductions in the 5-year mortality from , or incidence of , any type of vascular disease , cancer , or other major outcome The aim of this study was to assess the effect of vitamin and /or glucose energy supplementation in elderly medical patients on an intention-to-treat basis . One hundred and six elderly medical in- patients were entered into a double-bind placebo-controlled factorial trial of glucose energy and vitamin supplementation . Supplementation was given for 1 month . This trial was design ed to detect a > 2 kg increase in weight and > 3 g/l increase in serum albumin between active and placebo supplementation in 100 patients with 90 % power ( p < 0.05 ) . Other outcome measures included changes in Barthel activities of daily living , length of stay , and mental test score ( MTS ) . No interaction between vitamin and glucose supplementation was demonstrated . Active energy supplementation with glucose alone was associated with a + 0.6 kg change in weight and + 0.7 g/l change in albumin [ 95 % confidence interval ( CI ) -0.8 , + 2.0 and -1.3 , + 2.8 , respectively ] . The respective changes for active vitamin supplementation were -0.6 kg for weight and + 0.5 g/l for albumin ( 95 % CI -2.1 , + 0.8 and -1.5 , + 2.6 , respectively ) . There were no significant differences in mental test score , Barthel score , or length of stay between the two groups . Compliance with the  glucose energy supplementation  was poor with only one-third of patients consuming more than 50 % of the offered drink . We conclude that the giving of glucose alone and /or vitamin supplementation in elderly patient is of no benefit on an intention-to-treat basis BACKGROUND The experimental design , subjects , procedures and baseline data for the prospect i ve double blind dry ARMD-antioxidant intervention study have been described in Part 1 . METHODS At eight DVA medical centers , 32 patients ( group one ) were assigned a placebo and 39 patients ( group two ) a " broad spectrum " antioxidant capsule .  Data was collected in five areas : demographic ; ophthalmic ; dietary analysis of daily food intake ; serum analysis ; and adverse gastrointestinal symptoms . Data was serially acquired at baseline , 6 months , 12 months and 18 months , and was analyzed by univariate repeated factors ANOVA , p = 0.05 . RESULTS Group two ( antioxidant po BID ) maintained their distance LogMAR visual acuity ( p = 0.03 ) , while there was a trend toward both stabilized near M print ( p = 0.07 ) and 6 cycle/degree contrast sensitivity ( p approximately 0.10 ) , in left eyes . However , group two ( antioxidant ) also had increased cortical opacification of the right lens ( p = 0.04 ) , compared to group one ( placebo ) . Self perceived stabilization of vision was reported by subjects in group two and supported the objective data ( Pearson chi square ; p = 0.05 ) . CONCLUSIONS A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years . The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance . Decreased intake of cardioprotective nutrients ( vitamin E , zinc , magnesium , B6 and folate ) in ARMD patients remained constant over the course of the trial 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 A r and omised double-blind intervention trial was carried out in Huixian , Henan Province , People 's Republic of China , to determine whether combined treatment with retinol , riboflavine , and zinc could lower the prevalence of precancerous lesions of the oesophagus .  610 subjects in the age group 35 - 64 were r and omised to receive once a week the active treatment ( 15 mg [ 50 000 IU ] retinol , 200 mg riboflavine , and 50 mg zinc ) or placebo . Both at entry to the study and at the end of the treatment , 13.5 months later , the subjects were examined , with an emphasis on signs of  vitamin A and riboflavine deficiences , and  riboflavine , retinol , beta-carotene , and zinc levels were measured . Compliance was excellent . The final examination , on 567 ( 93 % ) subjects , included oesophagoscopy and at least two biopsies . The intervention did not affect the prevalence of oesophageal lesions : after one year , the prevalence of oesophagitis with or without atrophy or dysplasia was 45.3 % in the placebo group and 48.9 % in the vitamin/zinc treated group Because of previous reports of the beneficial effect of vitamin E in angina pectoris patients , 48 patients , with both stable angina and positive ( chest pain plus ishemic ST depression ) maximal exercise treadmill tests , participated in a double-blind cross-over study of 6 months of vitamin E and 6 months of placebo therapy , separated by a 2 month no treatment period . All 48 patients had positive selective coronary arteriograms ( 75 per cent obstruction of at least a major coronary artery ) and /or Q wave ECG evidence of previous myocardial infa rct ion ( Minnesota criteria ) . Evaluation of drug effectiveness was based on performance of serial maximal exercise treadmill tests , serial systolic time interval measurements , and daily angina diaries . No statistically significant differences between the two treatment studied . It is concluded that a large dose of vitamin E ( 1,600 I.U. of d-alpha-tocopherol succinate daily ) for 6 months in patients with stable angina pectoris fails to increase the exercise capacity , improve left ventricular function , or reduce the frequency of chest pain To determine the impact of a trace element and vitamin supplementation on infectious morbidity , a double-blind controlled trial was performed on 81 elderly subjects in a geriatric center during a 2-year period . Subjects were r and omly assigned to one of four treatment groups , and received daily : placebo ; trace elements/zinc 20 mg ; selenium 100 micrograms ) ; vitamins ( vitamin C 120 mg ; beta-carotene 6 mg ; alpha-tocopherol 15 mg ) ; or a combination of trace elements and vitamins at equal doses . ( 1 ) Before supplementation , low serum values in vitamin C , folate , zinc and selenium were observed in more than two thirds of the patients . ( 2 ) After 6 months of supplementation , a significant increase in vitamin and trace element serum levels was obtained in the corresponding treatment groups : a plateau was then observed for the whole study . ( 3 ) Subjects who received trace elements ( zinc and selenium ) alone or associated with vitamins had significantly less infectious events during the 2 years of supplementation . These results indicate that supplementation with low doses of vitamins and trace elements is able to rapidly correct corresponding deficiencies in the institutionalized elderly . Moreover , zinc and selenium reduced infectious events Published evidence suggests that aspects of trial design lead to biased intervention effect estimates , but findings from different studies are inconsistent . This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials . Outcome measures were classified as " mortality , " " other objective , " " or subjective , " and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity . Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear ( vs. adequate ) r and om-sequence generation ( ratio of odds ratios , 0.89 [ 95 % credible interval { CrI } , 0.82 to 0.96 ] ) and with inadequate or unclear ( vs. adequate ) allocation concealment ( ratio of odds ratios , 0.93 [ CrI , 0.87 to 0.99 ] ) . Lack of or unclear double-blinding ( vs. double-blinding ) was associated with an average of 13 % exaggeration of intervention effects ( ratio of odds ratios , 0.87 [ CrI , 0.79 to 0.96 ] ) , and between-trial heterogeneity was increased for such studies ( SD increase in heterogeneity , 0.14 [ CrI , 0.02 to 0.30 ] ) . For each characteristic , average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes , with little evidence of bias in trials with objective and mortality outcomes . This study is limited by incomplete trial reporting , and findings may be confounded by other study design characteristics . Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes
BACKGROUND AND AIMS Evidence shows that antioxidant supplements may increase  mortality .
Our aims were to assess whether different doses of beta-carotene , vitamin A , and vitamin E affect mortality in primary and secondary prevention r and omized clinical trials with low risk of bias .
BACKGROUND All essential compounds to stay healthy can not be synthesized in our body .
Therefore , these compounds must be taken through our diet or obtained in other ways [ 1 ] .
Oxidative stress has been suggested to cause a variety of diseases [ 2 ] .
Therefore , it is speculated that antioxidant supplements could have a potential role in preventing diseases and death .
Despite the fact that a normal diet in high-income countries may provide sufficient amounts of antioxidants [ 3,4 ] , more than one third of adults regularly take antioxidant supplements [ 5,6 ]