A longitudinal study of pre-pregnancy antioxidant levels and subsequent perinatal outcomes in black and white women: The CARDIA Study.

BACKGROUND: Although protective associations between dietary antioxidants and pregnancy outcomes have been reported, randomized controlled trials of supplementation have been almost uniformly negative. A possible explanation is that supplementation during pregnancy may be too late to have a beneficial effect. Therefore, we examined the relationship between antioxidant levels prior to pregnancy and birth outcomes. METHODS AND FINDINGS: Serum carotenoids and tocopherols were assayed in fasting specimens at 1985-86 (baseline) and 1992-1993 (year 7) from 1,215 participants in Coronary Artery Risk Development in Young Adults (CARDIA) study. An interviewer-administered quantitative food-frequency questionnaire assessed dietary intake of antioxidants. Pregnancy outcome was self-reported at exams every 2 to 5 years. Linear and logistic regression modeling was used to assess relationships of low birthweight (LBW; <2,500 g), continuous infant birthweight, preterm birth (PTB; <37 weeks) and length of gestation with antioxidant levels adjusted for confounders, as well as interactions with age and race. RESULTS: In adjusted models, lycopene was associated with higher odds of LBW (adjusted odds ratio for top quartile, 2.15, 95% confidence interval 1.14, 3.92) and shorter gestational age (adjusted beta coefficient -0.50 weeks). Dietary intake of antioxidants was associated with lower birthweight, while supplement use of vitamin C was associated with higher gestational age (0.41 weeks, 0.01, 0.81). CONCLUSIONS: Higher preconception antioxidant levels are not associated with better birth outcomes.

Plasma Ascorbic Acid, A Priori Diet Quality Score, and Incident Hypertension: A Prospective Cohort Study.

Vitamin C may reduce risk of hypertension, either in itself or by marking a healthy diet pattern. We assessed whether plasma ascorbic acid and the a priori diet quality score relate to incident hypertension and whether they explain each other's predictive abilities. Data were from 2884 black and white adults (43% black, mean age 35 years) initially hypertension-free in the Coronary Artery Risk Development in Young Adults Study (study year 10, 1995-1996). Plasma ascorbic acid was assessed at year 10 and the diet quality score at year 7. Eight-hundred-and-forty cases of hypertension were documented between years 10 and 25. After multiple adjustments, each 12-point (1 SD) higher diet quality score at year 7 related to mean 3.7 µmol/L (95% CI 2.9 to 4.6) higher plasma ascorbic acid at year 10. In separate multiple-adjusted Cox regression models, the hazard ratio of hypertension per 19.6-µmol/L (1 SD) higher ascorbic acid was 0.85 (95% CI 0.79-0.92) and per 12-points higher diet score 0.86 (95% CI 0.79-0.94). These hazard ratios changed little with mutual adjustment of ascorbic acid and diet quality score for each other, or when adjusted for anthropometric variables, diabetes, and systolic blood pressure at year 10. Intake of dietary vitamin C and several food groups high in vitamin C content were inversely related to hypertension, whereas supplemental vitamin C was not. In conclusion, plasma ascorbic acid and the a priori diet quality score independently predict hypertension. This suggests that hypertension risk is reduced by improving overall diet quality and/or vitamin C status. The inverse association seen for dietary but not for supplemental vitamin C suggests that vitamin C status is preferably improved by eating foods rich in vitamin C, in addition to not smoking and other dietary habits that prevent ascorbic acid from depletion.

Effects of calcium supplementation on biomarkers of inflammation and oxidative stress in colorectal adenoma patients: a randomized controlled trial.

Inflammation and oxidative stress play important roles in colorectal carcinogenesis. There is strong evidence that calcium reduces risk for colorectal neoplasms, possibly through its ability to bind bile acids and prevent their colonic toxicity (which occurs via an oxidative mechanism and results in an inflammatory response). In a previously reported pilot, randomized, controlled trial among sporadic colorectal adenoma patients we found that those on 2.0 g/day of calcium, relative to those on placebo, had an estimated drop in a combined cytokine z-score of 48% (P = 0.18) over 6 months. To follow-up these promising preliminary findings, we tested the efficacy of two doses of supplemental calcium (1.0 or 2.0 g/day) relative to placebo on modulating circulating biomarkers of inflammation [C-reactive protein (CRP) and 10 cytokines] and oxidative stress (F2-isoprostanes) over a 4-month treatment period among 193 patients with previous sporadic, colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. The inflammation markers were measured in plasma using electrochemiluminescence detection-based immunoassays, and F2-isoprostanes were measured in plasma using gas chromatography-mass spectrometry. Over a 4-month treatment period, we found no appreciable effects of calcium on CRP, cytokines, or F2-isoprostanes (P > 0.4), overall or within strata of several major risk factors for colorectal carcinogenesis, such as body mass index and regular use of nonsteroidal anti-inflammatory drugs. Overall, our results provide no evidence that calcium supplementation favorably modulates concentrations of circulating biomarkers of inflammation or oxidative stress over 4 months among patients with a previous colorectal adenoma.

The Minnesota Green Tea Trial (MGTT), a randomized controlled trial of the efficacy of green tea extract on biomarkers of breast cancer risk: study rationale, design, methods, and participant characteristics.

PURPOSE: The Minnesota Green Tea Trial (MGTT) was a randomized, placebo-controlled, double-blinded trial investigating the effect of daily green tea extract consumption for 12 months on biomarkers of breast cancer risk. METHODS: Participants were healthy postmenopausal women at high risk of breast cancer due to dense breast tissue with differing catechol-O-methyltransferase (COMT) genotypes. The intervention was a green tea catechin extract containing 843.0 ± 44.0 mg/day epigallocatechin gallate or placebo capsules for 1 year. Annual digital screening mammograms were obtained at baseline and month 12, and fasting blood and 24-h urine samples were provided at baseline and at months 6 and 12. Primary endpoints included changes in percent mammographic density, circulating endogenous sex hormones, and insulin-like growth factor axis proteins; secondary endpoints were changes in urinary estrogens and estrogen metabolites and circulating F2-isoprostanes, a biomarker of oxidative stress. RESULTS: The MGTT screened more than 100,000 mammograms and randomized 1,075 participants based on treatment (green tea extract vs. placebo), stratified by COMT genotype activity (high COMT vs. low/intermediate COMT genotype activity). A total of 937 women successfully completed the study and 138 dropped out (overall dropout rate = 12.8 %). CONCLUSIONS: In this paper we report the rationale, design, recruitment, participant characteristics, and methods for biomarker and statistical analyses.

Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study.

BACKGROUND: The role of omega-3 (n-3) fatty acids (FAs) in the development of type 2 diabetes is uncertain, especially with regard to any differential influence of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). OBJECTIVE: The objective was to examine the association between total omega-3 FAs, marine omega-3 (EPA, DHA), nonmarine omega-3 (ALA), and omega-6 (n-6) FAs and omega-6:omega-3 ratio and risk of type 2 diabetes in a Chinese population in Singapore. DESIGN: The analysis included 43,176 Chinese men and women free of chronic disease, aged 45-74 y, in the Singapore Chinese Health Study. Baseline data collection occurred between 1993 and 1998, with follow-up interviews between 1999 and 2004. Cox regression models were used to examine the associations between FA intakes at baseline and risk of developing diabetes. RESULTS: Increased intakes of total omega-3 FAs were inversely associated with diabetes incidence [hazard ratio (HR) for the fifth compared with the first quintile: 0.78; 95% CI: 0.65, 0.94; P for trend = 0.02]. Omega-3 FAs from marine sources were not associated with diabetes risk, whereas nonmarine omega-3 FA intake was strongly associated (HR for the fifth compared with the first quintile: 0.79; 95% CI: 0.67, 0.93; P for trend = 0.004). Omega-6 and omega-6:omega-3 ratio were not associated with incidence of type 2 diabetes. CONCLUSION: Consumption of nonmarine sources (ALA) of omega-3 FAs is associated with a decreased risk of type 2 diabetes in Chinese Singaporeans.

Food synergy: an operational concept for understanding nutrition.

Research and practice in nutrition relate to food and its constituents, often as supplements. In food, however, the biological constituents are coordinated. We propose that "thinking food first"' results in more effective nutrition research and policy. The concept of food synergy provides the necessary theoretical underpinning. The evidence for health benefit appears stronger when put together in a synergistic dietary pattern than for individual foods or food constituents. A review of dietary supplementation suggests that although supplements may be beneficial in states of insufficiency, the safe middle ground for consumption likely is food. Also, food provides a buffer during absorption. Constituents delivered by foods taken directly from their biological environment may have different effects from those formulated through technologic processing, but either way health benefits are likely to be determined by the total diet. The concept of food synergy is based on the proposition that the interrelations between constituents in foods are significant. This significance is dependent on the balance between constituents within the food, how well the constituents survive digestion, and the extent to which they appear biologically active at the cellular level. Many examples are provided of superior effects of whole foods over their isolated constituents. The food synergy concept supports the idea of dietary variety and of selecting nutrient-rich foods. The more we understand about our own biology and that of plants and animals, the better we will be able to discern the combinations of foods, rather than supplements, which best promote health.

The relationship between dose of vitamin E and suppression of oxidative stress in humans.

The oxidation hypothesis of atherogenesis has been the focus of much research over the past 2 decades. However, randomized placebo-controlled trials evaluating the efficacy of vitamin E in preventing cardiovascular events in aggregate have failed to show a beneficial effect. Implicit in these trials is that the dose of vitamin E tested effectively suppressed oxidative stress status but this was never determined. We defined the dose-dependent effects of vitamin E (RRR-alpha-tocopherol) to suppress plasma concentrations of F2-isoprostanes, a biomarker of free radical-mediated lipid peroxidation, in participants with polygenic hypercholesterolemia and enhanced oxidative stress, a population at risk for cardiovascular events. A time-course study was first performed in participants supplemented with 3200 IU/day of vitamin E for 20 weeks. A dose-ranging study was then performed in participants supplemented with 0, 100, 200, 400, 800, 1600, or 3200 IU/day of vitamin E for 16 weeks. In the time-course study, maximum suppression of plasma F2-isoprostane concentrations did not occur until 16 weeks of supplementation. In the dose-ranging study there was a linear trend between the dosage of vitamin E and percentage reduction in plasma F2-isoprostane concentrations which reached significance at doses of 1600 IU (35+/-2%, p<0.035) and 3200 IU (49+/-10%, p<0.005). This study provides information on the dosage of vitamin E that decreases systemic oxidant stress in vivo in humans and informs the planning and evaluation of clinical studies that assess the efficacy of vitamin E to mitigate disease.

Longitudinal associations between body mass index and serum carotenoids: the CARDIA study.

Cross-sectional studies report an inverse association between BMI and serum carotenoid concentration. The present study examined the prospective association between BMI and the serum concentration of five carotenoids in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Serum carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, zeaxanthin/lutein, lycopene), BMI, dietary intake, physical activity and dietary supplement use were measured at years 0 and 7 in 3071 black and white male and female participants, who were either persistent smokers or non-smokers. Among non-smokers, year 0 BMI predicted year 7 serum carotenoid levels: obese subjects (BMI > or =30 kg/m2) had an average concentration of the sum of four carotenoids (alpha-carotene +beta-carotene + zeaxanthin/lutein+beta-cryptoxanthin) that was 22 % lower than the concentration among subjects with a BMI of less than 22 kg/m2. In contrast, the sum of carotenoids among smokers was only 6 % lower. Relationships between BMI and serum lycopene were weak. The change from year 0 to year 7 in serum carotenoids, except for lycopene, was inversely associated with the change in BMI among non-smokers but not among smokers. Parallel findings were observed for BMI and serum gamma-glutamyl transferase level. In summary, the observation that BMI predicted the evolution of serum carotenoids during a 7-year follow-up among young non-smoking adults is consistent with the hypothesis that carotenoids are decreased in protecting against oxidative stress generated by adipose tissue, while smokers maintain a minimal level of serum carotenoids independent of adiposity. The results for lycopene were, however, discordant from those of the other carotenoids.

Relation of ascorbic acid to coronary artery calcium: the Coronary Artery Risk Development in Young Adults Study.

Ascorbic acid is an antioxidant nutrient possibly related to the development of atherosclerosis. To examine the relation between ascorbic acid and coronary artery calcium, an indicator of subclinical coronary disease, the authors analyzed data from 2,637 African-American and White men and women aged 18-30 years at baseline who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (1985-2001). Participants completed diet histories at enrollment and year 7, and plasma ascorbic acid levels were obtained at year 10. Coronary artery computed tomography was performed at year 15. The authors calculated odds ratios in four biologically relevant plasma ascorbic acid categories, adjusting for possible confounding variables. When compared with men with high plasma ascorbic acid levels, men with low levels to marginally low levels had an increased prevalence of coronary artery calcium (multivariate odds ratio = 2.68, 95% confidence interval: 1.31, 5.48). Among women, the association was attenuated and nonsignificant (multivariate odds ratio = 1.50, 95% confidence interval: 0.58, 3.85). Ascorbic acid intakes from diet alone and diet plus supplements were not associated with coronary artery calcium. Low to marginally low plasma ascorbic acid levels were associated with a higher prevalence of coronary artery calcium among men but not among women.