***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: In the Physicians ' Health Study , a r and omized , placebo-controlled , double-blind trial of aspirin in the reduction of cardiovascular mortality and beta-carotene in decreasing cancer incidence , 33,223 subjects were eligible and willing to enter the trial . Instead of r and omizing this group immediately , all participants received identical calendar packs that contained active aspirin and beta-carotene placebo . Following an 18-week run-in , only 22,071 subjects who remained eligible and willing and had taken at least 2/3 of their pills were r and omized . We estimated the effect of the run-in as follows : pill taking compliance increased 20 - 41 per cent ; sample size decreased 34 per cent ; duration of follow-up decreased 7 per cent which result ed in a 7 per cent decrease in the expected event rate for the placebo group . To estimate these changes , we made assumptions about compliance and outcome risk for those excluded by the run-in . Our conclusion , however , about the net effect of the run-in on the power of the study remains constant across variations in a number of those assumptions . The power with the run-in , with 22,071 good compliers was typically higher , and never more than negligibly lower , than the power without the run-in , with 33,223 good and poor compliers . In addition , savings from enrolling 11,152 fewer subjects in the trial result ed from the use of the run-in BACKGROUND Among apparently healthy men , elevated levels of C-reactive protein ( CRP ) , a marker for systemic inflammation , predict risk of myocardial infa rct ion and thromboembolic stroke . Whether increased levels of CRP are also associated with the development of symptomatic peripheral arterial disease ( PAD ) is unknown . METHODS AND RESULTS Using a prospect i ve , nested , case-control design , we measured baseline levels of CRP in 144 apparently healthy men participating in the Physicians ' Health Study who subsequently developed symptomatic PAD ( intermittent claudication or need for revascularization ) and in an equal number of control subjects matched on the basis of age and smoking habit who remained free of vascular disease during a follow-up period of 60 months .  Median CRP levels at baseline were significantly higher among those who subsequently developed PAD ( 1.34 versus 0.99 mg/L ; P=.04 ) . Furthermore , the risks of developing PAD increased significantly with each increasing quartile of baseline CRP concentration such that relative risks of PAD from lowest ( referent ) to highest quartile of CRP were 1.0 , 1.3 , 2.0 , and 2.1 ( Ptrend=.02 ) . Compared with those with no clinical evidence of disease , the subgroup of case patients who required revascularization had the highest baseline CRP levels ( median= 1.75 mg/L ; P= .04 ) ; relative risks from lowest to highest quartile of CRP for this end point were 1.0 , 1.8 , 3.8 , and 4.1 ( Ptrend=.02 ) . Risk estimates were similar after additional control for body mass index , hypercholesterolemia , hypertension , diabetes , and a family history of premature atherosclerosis . CONCLUSIONS These prospect i ve data indicate that among apparently healthy men , baseline levels of CRP predict future risk of developing symptomatic PAD and thus provide further support for the hypothesis that chronic inflammation is important in the pathogenesis of atherothrombosis We showed previously that natural killer ( NK ) cell activity is significantly greater in elderly men supplemented with beta-carotene  than in those taking placebo . In an attempt to determine the mechanism of beta-carotene 's effect , we analyzed the production of NK cell-enhancing cytokines ( interferon alpha , interferon gamma , and interleukin 12 ) . Boston-area participants in the Physicians ' Health Study ( men aged 65 - 88 y ; mean age , 73 y ) who had been supplemented with beta-carotene ( 50 mg on alternate days ) for an average of 12 y were enrolled in a r and omized , placebo-controlled , double-blind study . Elderly subjects taking beta-carotene supplements  had significantly greater plasma beta-carotene concentrations than those taking placebo . Beta-carotene-supplemented elderly men had significantly greater NK cell activity than did elderly men receiving placebo .  Percentages of NK cells ( CD16+CD56 + ) were not significantly different between the beta-carotene and placebo groups . Production of interleukin 12 , interferon alpha , or concanavalin A-stimulated interferon gamma by cultured peripheral blood mononuclear cells was not significantly different between beta-carotene-supplemented elderly and those taking placebo . Our results indicate that beta-carotene-induced enhancement of NK cell activity is not mediated by changes in percentages of CD16+CD56 + NK cells nor through up-regulation of interleukin 12 or interferon alpha BACKGROUND AND PURPOSE From a physiological perspective , physical activity might be expected to decrease the risk of developing stroke . However , epidemiological studies of physical activity and stroke risk have yielded divergent findings . We therefore sought to examine the association between exercise and stroke risk . METHODS This was a prospect i ve cohort study of 21 823 men , followed up for an average of 11.1 years . Participants were from the Physicians ' Health Study , a r and omized trial of low-dose aspirin and beta carotene . Men , aged 40 to 84 years at baseline , were free of self-reported myocardial infa rct ion , stroke , transient ischemic attack , and cancer . At baseline , they reported on the frequency of exercise vigorous enough to work up a sweat . Stroke occurrence was reported by participants and confirmed after medical record review ( n=533 ) . We used Cox proportional hazards regression to analyze the data . RESULTS With adjustment for age , treatment assignment , smoking , alcohol intake , history of angina , and parental history of myocardial infa rct ion , the relative risks of total stroke associated with vigorous exercise < 1 time , 1 time , 2 to 4 times , and > /=5 times per week at baseline were 1.00 ( referent ) , 0.79 ( 95 % confidence interval [ CI ] , 0.61 to 1 . 03 ) , 0.80 ( 95 % CI , 0.65 to 0.99 ) , and 0.79 ( 95 % CI , 0.61 to 1.03 ) , respectively ; P for trend=0.04 . In subgroup analyses , the inverse association appeared stronger with hemorrhagic than ischemic stroke . When we additionally adjusted for body mass index , history of hypertension , high cholesterol , and diabetes mellitus , corresponding relative risks for total stroke were 1.00 ( referent ) , 0.81 ( 95 % CI , 0.61 to 1.07 ) , 0.88 ( 95 % CI , 0.70 to 1.10 ) , and 0.86 ( 95 % CI , 0.65 to 1.13 ) , respectively ; P for trend=0.25 . CONCLUSIONS Exercise vigorous enough to work up a sweat is associated with decreased  stroke risk in men . In the present study , the inverse association with physical activity appeared to be mediated through beneficial effects on body weight , blood pressure , serum cholesterol , and glucose tolerance . Apart from its favorable influences on these variables , physical activity had no significant residual association with stroke incidence Supplementation of healthy elderly persons with beta-carotene  has been considered a way to enhance immune responses . In study 1 the short-term effect of beta-carotene ( 90 mg/d for 3 wk ) on immunity was assessed in a r and omized , double-blind , placebo-controlled longitudinal comparison of healthy elderly women . In study 2 the long-term effect of beta-carotene ( 50 mg every other day for 10 - 12 y ) on immunity was assessed in a r and omized , double-blind , placebo-controlled longitudinal comparison of men enrolled in the Physicians ' Health Study . Subjects from both studies taking active supplements  had significantly greater plasma beta-carotene concentrations than did subjects taking placebo .  The pre- to postintervention change in delayed-type hypersensitivity skin test responses between beta-carotene and placebo groups in the short-term study was not significantly different , nor was the response between treatment groups in the long-term study . There were no significant effects due to beta-carotene supplementation on in vitro lymphocyte proliferation , production of interleukin 2 , or production of prostagl and in E2 as a result of short- or long-term beta-carotene supplementation . In addition , there were no differences in the profiles of lymphocyte subsets [ total T cells ( CD3 + ) , T helper cells ( CD4 + ) , T cytotoxic-suppressor cells ( CD8 + ) , and B cells ( CD19 + ) ] due to short- or long-term beta-carotene supplementation , nor were there differences in percentages of CD16 + natural killer cells or activated lymphocytes ( cells expressing interleukin 2 transferrin receptor ) due to long-term beta-carotene supplementation . Consistent results from these two trials show that beta-carotene supplementation did not have an enhancing or suppressive effect on T cell-mediated immunity of healthy elderly To determine the effects of long-term beta-carotene supplementation on concentrations of carotenoids and tocopherols in plasma and in blood cells , fasting blood was collected from 73 r and omly selected physicians from the Boston area who are participating in the Physicians Health Study ( PHS ) . The PHS is a r and omized , placebo-controlled , double-blind study . In 1982 , 22,071 male physicians were assigned to one of four treatments ( 325 mg aspirin alone , 50 mg beta-carotene alone , both , or neither ) every other day . Plasma , peripheral blood mononuclear cells ( P BMC s ) , and red blood cells ( RBCs ) from physicians who have participated in the study for approximately 12 y were analyzed for carotenoids and tocopherols . Compared with the placebo group , the supplemented group had higher beta-carotene concentrations in plasma ( 1.73+/-0.16 compared with 0.54+/-0.06 micromol/L0 , RBCs ( 91.5+/-9.7 compared with 31.2+/-4.2 pmol/g hemoglobin ) , and P BMC s ( 61.6+/-10.3 compared with 15.5+/-2.5 pmol/10(7 ) cells ) . There were no differences in other carotenoids or tocopherols in plasma , RBCs , and P BMC s between these two groups . The beta-carotene concentrations . Plasma cryptoxanthin correlated with both RBC and P BMC cryptoxanthin concentrations but plasma lycopene correlated only with P BMC lycopene concentrations . These data suggest that plasma may not be the best indicator of carotenoid status . Furthermore , long-term beta-carotene supplementation in men results in higher beta-carotene concentrations in plasma , RBCs and P BMC s without lowering concentrations of other carotenoids or tocopherols Natural killer ( NK ) cell activity has been postulated to be an immunologic link between beta-carotene and cancer prevention . In a cross-sectional , placebo-controlled , double-blind study we examined the effect of 10 - 12 y of beta-carotene supplementation ( 50 mg on alternate days ) on NK cell activity in 59 ( 38 middle-aged men , 51 - 64 y ; 21 elderly men , 65 - 86 y ) Boston area participants in the Physicians ' Health Study . No significant difference was seen in NK cell activity due to beta-carotene supplementation in the middle-aged group . The elderly men had significantly lower NK cell activity than the middle-aged men ; however , there was no age-associated difference in NK cell activity in men supplemented with beta-carotene . beta-carotene-supplemented elderly men had significantly greater NK cell activity than elderly men receiving placebo . The reason for this is unknown ; however , it was not due to an increase in the percentage of NK cells , nor to an increase in interleukin 2 ( IL-2 ) receptor expression , nor to IL-2 production . beta-carotene may be acting directly on one or more of the lytic stages of NK cell cytotoxicity , or on NK cell activity-enhancing cytokines other than IL-2 , such as IL-12 . Our results show that long-term beta-carotene supplementation enhances NK cell activity in elderly men , which may be beneficial for viral and tumoral surveillance The Physicians ' Health Study is a r and omized , double-blind , placebo-controlled trial using a 2 x 2 factorial design to test the effects of low-dose aspirin on risk of cardiovascular disease and beta-carotene supplementation on the incidence of cancer . To evaluate self-reported compliance with assigned treatment , we measured serum thromboxane B2 , which is decreased after aspirin use , and plasma beta-carotene in sample s of study participants drawn from three geographic locations in three different time periods .  Thromboxane B2 levels were markedly lower in those assigned to aspirin ( median = 63.5 pg/mL ) than in those given aspirin placebo ( median = 3,600 pg/mL , P less than .0001 ) . Similarly , those assigned to beta-carotene had significantly higher levels ( median = 1, 
    Output:
    
There was no evidence that antioxidant vitamin supplementation prevented or delayed the onset of AMD .
Similar results were seen when the analyses were restricted to beta-carotene and alpha-tocopherol .
There is no evidence to date that the general population should take antioxidant vitamin and mineral supplements to prevent or delay the onset of AMD .