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1.  Weight loss and calcium intake influence calcium absorption in overweight postmenopausal women12–3 
Background
Weight loss (WL) reduces bone mass and increases fracture risk. Mechanisms regulating calcium metabolism during WL are unclear.
Objective
The objective was to assess the effect of 6 wk of WL at 2 different amounts of calcium intake [normal (NlCa): 1 g/d; high (HiCa): 1.8 g/d] on true fractional calcium absorption (TFCA), bone turnover, and bone-regulating hormones in overweight postmenopausal women.
Design
Seventy-three women (body mass index, 26.9 ± 1.9 kg/m2) were recruited either to consume a moderately energy-restricted diet (WL group) or to maintain their body weight [weight-maintenance (WM) group] and were randomly assigned to either the HiCa or the NlCa group in a double-blind manner. Subjects underwent weekly diet counseling, and measurements were taken at baseline and after 6 wk.
Results
Fifty-seven women completed the study and had a baseline TFCA of 24.9 ± 7.4%. Energy restriction significantly decreased the total calcium absorbed (P < 0.05) in the WL group (n = 32) compared with the WM group (n = 25; analysis of covariance). Regression analysis showed that a greater rate of weight loss suppressed TFCA and the total calcium absorbed (P < 0.05) in the HiCa group. The women in the NlCa WL group absorbed inadequate amounts of calcium (195 ± 49 mg/d), whereas the women in the HiCa WL group absorbed adequate amounts (348 ± 118 mg/d). Parathyroid hormone explained 22% of the variance in calcium absorbed in the NlCa group only.
Conclusions
We suggest that WL is associated with elevated calcium requirements that, if not met, could activate the calcium-parathyroid hormone axis to absorb more calcium. Normal intakes of calcium during energy restriction result in inadequate total calcium absorption and could ultimately compromise calcium balance and bone mass.
PMCID: PMC4016237  PMID: 15213038
Calcium absorption; bone turnover; diet; postmenopausal status; weight loss
2.  Premenopausal overweight women do not lose bone during moderate weight loss with adequate or higher calcium intake123 
Background
Weight loss is associated with bone loss, but this has not been examined in overweight premenopausal women.
Objective
The aim of this study was to assess whether overweight premenopausal women lose bone with moderate weight loss at recommended or higher than recommended calcium intakes.
Design
Overweight premenopausal women [n = 44; x‒ (±SD) age: 38 ± 6.4 y; body mass index (BMI): 27.7 ± 2.1 kg/m2] were randomly assigned to either a normal (1 g/d) or high (1.8 g/d) calcium intake during 6 mo of energy restriction [weight loss (WL) groups] or were recruited for weight maintenance at 1 g Ca/d intake. Regional bone mineral density and content were measured by dual-energy X-ray absorptiometry, and markers of bone turnover were measured before and after weight loss. True fractional calcium absorption (TFCA) was measured at baseline and during caloric restriction by using a dual-stable calcium isotope method.
Results
The WL groups lost 7.2±3.3% of initial body weight. No significant decrease in BMD or rise in bone turnover was observed with weight loss at normal or high calcium intake. The group that consumed high calcium showed a strong relation (r = 0.71) between increased femoral neck bone mineral density and increased serum 25-hydroxyvitamin D. No significant effect of weight loss on TFCA was observed, and the total calcium absorbed was adequate at 238±81 and 310±91 mg/d for the normal- and high-calcium WL groups, respectively.
Conclusion
Overweight premenopausal women do not lose bone during weight loss at the recommended calcium intake, which may be explained by sufficient amounts of absorbed calcium.
PMCID: PMC4008879  PMID: 17413095
Bone; calcium absorption; hormones; premenopausal women; weight loss
3.  A PROSPECTIVE STUDY OF DIETARY ENERGY DENSITY AND WEIGHT GAIN IN WOMEN 
Background
Little is known about the long-term effects of dietary energy density (ED) on weight gain.
Methods
We conducted a prospective study of 50,026 women (mean age: 36.5; SD: 4.6) in the Nurses' Health Study II followed from 1991 to 1999. Dietary ED and body weight were ascertained in 1991, 1995, and 1999. Total dietary ED was calculated by dividing each subject's daily energy intake (kcal) by the reported weight (g) of all foods consumed.
Results
Dietary ED was positively correlated with saturated fat (r=0.16), trans fat (r=0.15), and the glycemic index (r=0.16), but inversely correlated with vegetable protein (r=−0.30), vegetables (r=−0.27), and fruits (r=−0.17). ED was not significantly correlated with total fat intake (r=0.08). Women who increased their dietary ED during follow-up the most (5th quintile) had a statistical significant greater multivariate-adjusted weight gain as compared with those who decreased their dietary ED most (1st quintile) (in the 8-y time period: 6.42 kg versus 4.57 kg; p for trend < 0.001). However, the amount of weight change over time varied considerably according to the ED of individual foods and beverages.
Conclusion
Increases in total dietary ED were associated with long-term weight gain among younger and middle-aged women. However, public health recommendations cannot be made simply based on ED values of individual foods and beverages only. Reducing consumption of foods high in saturated and trans fats and refined carbohydrates and increasing consumption of fruits and vegetables may help to reduce dietary ED and prevent weight gain.
PMCID: PMC3977032  PMID: 18779295
4.  Dietary flavonoid intake and non-Hodgkin lymphoma risk 
Background
The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects.
Objective
We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk.
Design
During 1998–2000, we identified incident NHL cases aged 20–74 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequency-matched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake.
Results
Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes—diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146).
Conclusion
A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.
PMCID: PMC3971470  PMID: 18469269
5.  Abdominal obesity and hyperglycemia mask the effect of a common APOC3 haplotype on the risk of myocardial infarction123 
Background
Plasma apolipoprotein (apo) C-III strongly predicts myocardial infarction (MI) and directly activates atherogenic processes invascularcells.Geneticvariationintheinsulinresponseelementofthe APOC3 promoter is associated with an increased risk of MI.
Objective
The objective was to determine whether the APOC3 promoter variation affects plasma apo C-III concentrations and MI only when insulin sensitivity is normal.
Design
TheAPOC3*222haplotype,definedbytheminorallelesofthe single nucleotide polymorphisms 3238C→G, –455T→C, and –482C→T, was studied in 1703 matched nonfatal case-control pairs with MI in the Central Valley of Costa Rica. We used fasting hyper-glycemia and abdominal obesity as surrogates for insulin sensitivity.
Results
The APOC3*222 haplotype was associated with higher apo C-III concentrations only in those with the lowest waist circumference or fasting glucose concentration. The association between the APOC3*222 haplotype and nonfatal MI, previously reported in this population, was strongly influenced by fasting hyperglycemia and abdominal obesity. The odds ratios for MI for the APOC3*222 haplotype were 1.72 (95% CI: 1.16, 2.54) and 1.84 (1.31, 2.59) in subjects in the lowest quintiles of abdominal obesity and fasting hyperglycemia, respectively, and were 0.75 (0.54, 1.05) and 1.16 (0.85, 1.59) in subjects in the highest quintiles, respectively (P for interaction <0.05).
Conclusion
The results support the concept that mutations in the APOC3 promoter inhibit the down-regulation of APOC3 expression by insulin. This cardioprotective system becomes dysfunctional in abdominal obesity and hyperglycemia.
PMCID: PMC3861874  PMID: 18541587
6.  Neighborhood socioeconomic status and fruit and vegetable intake among Whites, Blacks, and Mexican-Americans in the United States 
Background
Socioeconomic and racial/ethnic disparities in health status across the United States are large and persistent. Obesity rates are rising faster in Black and Hispanic populations than in Whites and foreshadow even greater disparities in chronic diseases such as diabetes and cardiovascular disease in years to come. Factors that influence dietary intake of fruits and vegetables in these populations are only partly understood.
Objective
We examined associations between fruit and vegetable intake and neighborhood socioeconomic status (NSES), analyzed whether NSES explains racial differences in intake, and explored the extent to which NSES has differential effects by race/ethnicity of United States (U.S.) adults.
Design
Using geocoded residential addresses from the Third National Health and Nutrition Examination Survey (NHANES III), we merged individual-level data with county and census-tract level U.S. Census data. We estimated three-level hierarchical models predicting fruit and vegetable intake with individual characteristics and an index of neighborhood SES as explanatory variables.
Results
Neighborhood SES was positively associated with fruit and vegetable intake: a one standard deviation increase in the neighborhood SES index was associated with consumption of nearly 2 additional servings of fruit and vegetables per week. Neighborhood SES explained some of the Black-White disparity in fruit and vegetable intake and was differentially associated with fruit and vegetable intake among Whites, Blacks, and Mexican-Americans.
Conclusions
The positive association of neighborhood SES with fruit and vegetable intake is one important pathway through which the social environment of neighborhoods affects population health and nutrition for Whites, Blacks and Hispanics in the United States.
PMCID: PMC3829689  PMID: 18541581
Neighborhood Socioeconomic Status; Race/Ethnicity; Fruit and Vegetable Consumption
7.  Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults2 
The American journal of clinical nutrition  2009;89(6):10.3945/ajcn.2009.27465.
Background
Rodent studies show that oligofructose promotes weight loss, stimulates satiety hormone secretion, reduces energy intake, and improves lipid profiles.
Objective
Our objective was to examine the effects of oligofructose supplementation on body weight and satiety hormone concentrations in overweight and obese adults.
Design
This study was a randomized, double-blind, placebo-controlled trial. Forty-eight otherwise healthy adults with a body mass index (in kg/m2) > 25 were randomly assigned to receive 21 g oligo-fructose/d or a placebo (maltodextrin) for 12 wk. Body composition (by dual-energy X-ray absorptiometry); meal tolerance tests, including satiety hormone response; food intake; and subjective appetite ratings were determined.
Results
There was a reduction in body weight of 1.03 ±0.43 kg with oligofructose supplementation, whereas the control group experienced an increase in body weight of 0.45 ± 0.31 kg over 12 wk (P = 0.01). A lower area under the curve (AUC) for ghrelin (P = 0.004) and a higher AUC for peptide YY (PYY) with oligofructose (P = 0.03) coincided with a reduction in self-reported caloric intake (P ≤ 0.05). Glucose decreased in the oligofructose group and increased in the control group between initial and final tests (P ≤ 0.05). Insulin concentrations mirrored this pattern (P ≤ 0.05). Oligofructose supplementation did not affect plasma active glucagon-like peptide 1 secretion. According to a visual analog scale designed to assess side effects, oligofructose was well tolerated.
Conclusions
Independent of other lifestyle changes, oligofructose supplementation has the potential to promote weight loss and improve glucose regulation in overweight adults. Suppressed ghrelin and enhanced PYY may contribute in part to the reduction in energy intake. The trial was registered at clinicaltrials.gov as NCT00522353.
doi:10.3945/ajcn.2009.27465
PMCID: PMC3827013  PMID: 19386741 CAMSID: cams3657
8.  Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib1,2,3 
Background
Type I glycogen storage disease (GSD) is caused by a deficiency of glucose-6-phosphatase resulting in severe fasting hypoglycemia.
Objective
We compared the efficacy of a new modified starch with the currently used cornstarch therapy in patients with type Ia and Ib GSD.
Design
This was a randomized, 2-d, double-blinded, crossover pilot study comparing the commonly used uncooked cornstarch with the experimental starch in 12 subjects (6 GSDIa, 6 GSDIb) aged ≥13 y. At 2200, the subjects were given 100 g of digestible starch, and glucose and lactate were measured hourly until the subject's plasma glucose concentration reached 60 mg/dL or until the subject had fasted for 10 h. The order in which the products were tested was randomized in a blinded fashion.
Results
The matched-pair Gehan rank test for censored survival was used to compare the therapies. The experimental starch maintained blood glucose concentrations significantly longer than did the traditional therapy (P = 0.013) in the 2-sided analysis. Most of the benefit was found to be after glucose concentrations fell below 70 mg/dL. The currently used cornstarch resulted in higher peak glucose concentrations and a more rapid rate of fall than did the new starch.
Conclusions
The experimental starch was superior to standard therapy in preventing hypoglycemia (≤60 mg/dL). This therapy may allow patients with GSD to sleep through the night without awakening for therapy while enhancing safety. Additional studies are warranted to determine whether alternative dosing will further improve control in the therapeutic blood glucose range.
PMCID: PMC3808112  PMID: 18996862
9.  How can the Developmental Origins of Health and Disease (DOHaD) hypothesis contribute to improving health in developing countries?23 
The American journal of clinical nutrition  2011;94(6 0):10.3945/ajcn.110.000562.
The relevance of nutrition during pregnancy and early infancy in defining short-term health and survival has been well established. However, the Developmental Origins of Health and Disease (DOHaD) paradigm provides a framework to assess the effect of early nutrition and growth on long-term health. This body of literature shows that early nutrition has significant consequences on later health and well-being. In this article, we briefly present the main consequences of malnutrition that affect human growth and development and consider how the DOHaD paradigm, with its evolutionary implications, might contribute to better addressing the challenge of improving nutrition. We examine how this paradigm is particularly appropriate in understanding the health and nutrition transition in countries that face the double burden of nutrition-related diseases (acute malnutrition coexisting with obesity and other chronic diseases). We focus on stunting (low height-for-age) to examine the short- as well as long-term consequences of early malnutrition with a life-course, transgenerational, and multidisciplinary perspective. We present current global and regional prevalence of stunting and discuss the need to reposition maternal and infant nutrition not only in health and nutrition intervention programs but also in consideration of the emerging research questions that should be resolved to better orient program and policy decisions.
doi:10.3945/ajcn.110.000562
PMCID: PMC3808270  PMID: 21543534
10.  Physical activity intensity, sedentary time, and body composition in preschoolers123 
Background
Detailed associations between physical activity (PA) subcomponents, sedentary time, and body composition in preschoolers remain unclear.
Objective
We examined the magnitude of associations between objectively measured PA subcomponents and sedentary time with body composition in 4-y-old children.
Design
We conducted a cross-sectional study in 398 preschool children recruited from the Southampton Women’s Survey. PA was measured by using accelerometry, and body composition was measured by using dual-energy X-ray absorptiometry. Associations between light physical activity, moderate physical activity (MPA), vigorous physical activity (VPA), and moderate-to-vigorous physical activity (MVPA) intensity; sedentary time; and body composition were analyzed by using repeated-measures linear regression with adjustment for age, sex, birth weight, maternal education, maternal BMI, smoking during pregnancy, and sleep duration. Sedentary time and PA were also mutually adjusted for one another to determine whether they were independently related to adiposity.
Results
VPA was the only intensity of PA to exhibit strong inverse associations with both total adiposity [P < 0.001 for percentage of body fat and fat mass index (FMI)] and abdominal adiposity (P = 0.002 for trunk FMI). MVPA was inversely associated with total adiposity (P = 0.018 for percentage of body fat; P = 0.022 for FMI) but only because of the contribution of VPA, because MPA was unrelated to fatness (P ≥ 0.077). No associations were shown between the time spent sedentary and body composition (P ≥ 0.11).
Conclusions
In preschoolers, the time spent in VPA is strongly and independently associated with lower adiposity. In contrast, the time spent sedentary and in low-to-moderate–intensity PA was unrelated to adiposity. These results indicate that efforts to challenge pediatric obesity may benefit from prioritizing VPA.
doi:10.3945/ajcn.112.045088
PMCID: PMC3785144  PMID: 23553158
11.  Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial1, 2, 3 
Background
The effect of supplementation with calcium alone on risk fractures in a healthy population is not clear.
Objective
The objective was to determine whether 4 y of calcium supplementation would reduce the fracture risk during treatment and subsequent follow-up in a randomized placebo-controlled trial.
Design
The participants were aged <80 y at study entry (mean age: 61 y), were generally healthy, and had a recent diagnosis of colorectal adenoma. A total of 930 participants (72% men; mean age: 61 y) were randomly assigned to receive 4 y of treatment with 3 g CaCO3 (1200 mg elemental Ca) daily or placebo and were followed for a mean of 10.8 y. The primary outcomes of this analysis were all fractures and minimal trauma fractures (caused by a fall from standing height or lower while sitting, standing, or walking).
Results
There were 46 fractures (15 from minimal trauma) in 464 participants in the calcium group and 54 (29 from minimal trauma) in 466 participants in the placebo group. The overall risk of fracture differed significantly between groups during the treatment phase [hazard ratio (HR): 0.28; 95% CI: 0.09, 0.85], but not during the subsequent posttreatment follow-up (HR: 1.10; 95% CI: 0.71, 1.69). Minimal trauma fractures were also less frequent in the calcium group during treatment (HR: 0; 95% CI: 0, 0.50).
Conclusion
Calcium supplementation reduced the risk of all fractures and of minimal trauma fractures among healthy individuals. The benefit appeared to dissipate after treatment was stopped.
PMCID: PMC3773875  PMID: 18541589
12.  Circulating folic acid in plasma: relation to folic acid fortification 
Background
The implementation of folic acid fortification in the United States has resulted in unprecedented amounts of this synthetic form of folate in the American diet. Folic acid in circulation may be a useful measure of physiologic exposure to synthetic folic acid, and there is a potential for elevated concentrations after fortification and the possibility of adverse effects.
Objective
We assessed the effect of folic acid fortification on circulating concentrations of folic acid and 5-methyltetrahydrofolate in the Framingham Offspring Cohort.
Design
This is a cross-sectional study that used plasma samples from fasting subjects before and after fortification. Samples were measured for folate distribution with the use of an affinity-HPLC method with electrochemical detection.
Results
Among nonsupplement users, the median concentration of folic acid in plasma increased from 0.25 to 0.50 nmol/L (P < 0.001) after fortification, and among supplement users the median increased from 0.54 to 0.68 nmol/L (P = 0.001). Among nonsupplement users, the prevalence of high circulating folic acid (≥85th percentile) increased from 9.4% to 19.1% (P = 0.002) after fortification. Among supplement users, the prevalence of high circulating folic acid increased from 15.9% to 24.3% (P = 0.02). Folic acid intake and total plasma folate were positively and significantly related to high circulating folic acid after adjustment for potential confounding factors (P for trend < 0.001).
Conclusions
Folic acid fortification has resulted in increased exposure to circulating folic acid. The biochemical and physiologic consequences of this are unknown, but these findings highlight the need to understand the effects of chronic exposure to circulating folic acid.
PMCID: PMC3763811  PMID: 18779294
13.  Percentage extremity fat, but not percentage trunk fat, is lower in adolescent boys with anorexia nervosa than in healthy adolescents123 
Background
Anorexia nervosa (AN) is a condition of severe undernutrition associated with altered regional fat distribution in females. Although primarily a disease of females, AN is increasingly being recognized in males and is associated with hypogonadism. Testosterone is a major regulator of body composition in males, and testosterone administration in adults decreases visceral fat. However, the effect of low testosterone and other hormonal alterations on body composition in boys with AN is not known.
Objective
We hypothesized that testosterone deficiency in boys with AN is associated with higher trunk fat, as opposed to extremity fat, compared with control subjects.
Design
We assessed body composition using dual-energy X-ray absorptiometry and measured fasting testosterone, estradiol, insulin-like growth factor-1, leptin, and active ghrelin concentrations in 15 boys with AN and in 15 control subjects of comparable maturity aged 12–19 y.
Results
Fat and lean mass in AN boys was 69% and 86% of that in control subjects. Percentage extremity fat and extremity lean mass were lower in boys with AN (P = 0.003 and 0.0008); however, percentage trunk fat and the trunk to extremity fat ratio were higher after weight was adjusted for (P = 0.005 and 0.003). Testosterone concentrations were lower in boys with AN, and, on regression modeling, positively predicted percentage extremity lean mass and inversely predicted percentage trunk fat and trunk to extremity fat ratio. Other independent predictors of regional body composition were bone age and weight.
Conclusions
In adolescent boys with AN, higher percentage trunk fat, higher trunk to extremity fat ratio, lower percentage extremity fat, and lower extremity lean mass (adjusted for weight) are related to the hypogonadal state.
doi:10.3945/ajcn.2008.26273
PMCID: PMC3722579  PMID: 19064506
14.  Dietary energy density predicts women’s weight change over 6 y1, 2, 3 
Background
Dietary energy density (ED) is positively associated with energy intake, but little is known about long-term effects on weight change.
Objective
We assessed whether dietary ED predicts weight change over 6 y among a sample of non-Hispanic, white women.
Design
Participants were part of a 6-y longitudinal study (n = 186), assessed at baseline and biennially. ED (in kcal/g) was calculated from the energy content of all foods (excluding beverages) with the use of three 24-h recalls. Height and weight were measured in triplicate to calculate body mass index (BMI; in kg/m2). Repeated measures (PROC MIXED) were used to examine the influence of ED on weight change, before and after adjusting for initial weight status. Food choices were examined among subjects consuming low-, medium-, and high-ED diets at study entry.
Results
ED did not change across time for a subject. ED was positively associated with weight gain and higher BMI over time; this association did not vary by BMI classification. Food group data showed that, compared with women consuming higher-ED diets, women consuming lower-ED diets reported significantly lower total energy intakes and consumed fewer servings of baked desserts, refined grains, and fried vegetables and more servings of vegetables, fruit, and cereal. Women consuming lower-ED diets ate more meals at the table and fewer meals in front of the television.
Conclusions
Findings indicate that consumption of a lower-ED diet moderates weight gain, which may promote weight maintenance. Consuming lower ED diets can be achieved by consuming more servings of fruit and vegetables and limiting intake of high-fat foods.
PMCID: PMC3703774  PMID: 18779283
15.  Snack chips fried in corn oil alleviate cardiovascular disease risk factors when substituted for low-fat or high-fat snacks 
Background
The perception that all high-fat snacks are unhealthy may be wrong.
Objective
We aimed to assess whether replacing low-fat and high-fat snacks with snacks rich in polyunsaturated fatty acids (PUFAs) and low in saturated and trans fatty acids would improve cardiovascular health.
Design
Thirty-three adults participated in a randomized crossover trial of 3 controlled feeding phases of 25 d each in which a different type of snack was provided: low-fat (30.8% of energy from fat, 5.2% of energy from PUFAs), high-PUFA (36.3% of energy from fat, 9.7% of energy from PUFAs), or high-fat (37.9% of energy from fat, 5.8% of energy from PUFAs) snack.
Results
Each diet reduced LDL- and total cholesterol concentrations, but reductions were greater with the low-fat and the high-PUFA diets than with the high-fat diet: LDL cholesterol (11.8% and 12.5% compared with 8.8%, respectively; P = 0.03 and 0.01), total cholesterol (10.5% and 10.7% compared with 7.9%, respectively; P = 0.03 and 0.02). The high-PUFA diet tended to reduce triacylglycerol concentrations (9.4%; P = 0.06), and this change was greater than that with the low-fat (P = 0.028) and high-fat (P = 0.0008) diets.
Conclusions
These data show that snack type affects cardiovascular health. Consuming snack chips rich in PUFA and low in saturated or trans fatty acids instead of high-saturated fatty acid and trans fatty acid or low-fat snacks leads to improvements in lipid profiles concordant with reductions in cardiovascular disease risk. Am J Clin Nutr 2007;85:1503–10.
PMCID: PMC3666855  PMID: 17556685
Snacks; polyunsaturated fat; trans fat; saturated fat; cholesterol; cardiovascular disease; corn oil
16.  [No title available] 
PMCID: PMC3645894  PMID: 18258647
17.  Genetic variation at the SLC23A1 locus is associated with circulating levels of L-ascorbic acid (Vitamin C). Evidence from 5 independent studies with over 15000 participants 
Background
L-ascorbic acid is an essential part of the human diet and has been associated with a wide-range of chronic complex diseases including cardiovascular outcomes. To date, there are no confirmed genetic correlates of circulating levels of L-ascorbic acid.
Objectives
We aimed to confirm the existence of association between common variation at the SLC23A1 gene locus and circulating levels of L-ascorbic acid.
Design
We employed a two-stage design which used a discovery cohort (the British Women’s Heart and Health Study) and a series of follow-up cohorts and meta-analysis (totalling 15087 participants) to assess the relationship between variation at SLC23A1 and circulating levels of L-ascorbic acid.
Results
In the discovery cohort, variation at rs33972313 was associated with a reduction in circulating levels of L-ascorbic acid (−4.15μmol/L (95%CI −0.49, −7.81), p=0.03 reduction per minor allele). Pooled analysis of the relationship between rs33972313 and circulating L-ascorbic acid across all studies confirmed this, showing that each additional rare allele was associated with a reduction in circulating levels of L-ascorbic acid of −5.98μmol/L (95%CI −8.23, −3.73), p=2.0×10−7 per minor allele.
Conclusion
Work here has identified a genetic variant (rs33972313) in the SLC23A1 vitamin C active transporter locus that is reliably associated with circulating levels of L-ascorbic acid in the general population. This finding has implications more generally for the epidemiological investigation of relationships between circulating L-ascorbic acid and health outcomes.
doi:10.3945/ajcn.2010.29438
PMCID: PMC3605792  PMID: 20519558
Vitamin C; genotype; L-ascorbic acid
18.  Validation of soy protein estimates from a food-frequency questionnaire with repeated 24-h recalls and isoflavonoid excretion in overnight urine in a Western population with a wide range of soy intakes2 
Background
Evidence of the benefits of soy on cancer risk in Western populations is inconsistent, in part because of the low intake of soy in these groups.
Objective
We assessed the validity of soy protein estimates from food-frequency questionnaires (FFQs) in a sample of Adventist Health Study-2 participants with a wide range of soy intakes.
Design
We obtained dietary intake data from 100 men and women (43 blacks and 57 nonblacks). Soy protein estimates from FFQs were compared against repeated 24-h recalls and urinary excretion of daidzein, genistein, total isoflavonoids (TIFLs), and equol (measured by HPLC/photodiode array/mass spectrometry) as reference criteria. We calculated Pearson and Spearman correlation coefficients (with 95% CIs) for FFQ–24-h recall, 24 h-recall–urinary excretion, and FFQ–urinary excretion pairs.
Results
Among soy users, mean (± SD) soy protein values were 12.12 ± 10.80 g/d from 24-h recalls and 9.43 ± 7.83 g/d from FFQs. The unattenuated correlation (95% CI) between soy protein estimates from 24-h recalls and FFQs was 0.57 (0.32, 0.75). Correlation coefficients between soy protein intake from 24-h recalls and urinary isoflavonoids were 0.72 (0.43, 0.96) for daidzein, 0.67 (0.43, 0.91) for genistein, and 0.72 (0.47, 0.98) for TIFLs. Between FFQs and urinary excretion, these were 0.50 (0.32, 0.65), 0.48 (0.29, 0.61), and 0.50 (0.32, 0.64) for daidzein, genistein, and TIFLs, respectively.
Conclusions
Soy protein estimates from questionnaire were significantly correlated with soy protein from 24-h recalls and urinary excretion of daidzein, genistein, and TIFLs. The Adventist Health Study-2 FFQ is a valid instrument for assessing soy protein in a population with a wide range of soy intakes.
PMCID: PMC3564955  PMID: 18469267
19.  Added sugar, sugar-sweetened foods and beverages and risk of pancreatic cancer in the NIH-AARP Diet and Health Study 
Background
Although hyperglycemia, hyperinsulinemia and insulin resistance have been hypothesized to be involved in the development of pancreatic cancer, results from epidemiologic studies on added sugar intake are inconclusive.
Objective
Our objective was to investigate whether the consumption of total added sugar, sugar-sweetened foods and beverages is associated with pancreatic cancer risk.
Design
We prospectively examined 487922 men and women aged 50–71 years and free of cancer and diabetes in 1995–96. Total added dietary sugar intake in teaspoons per day (based on USDA’s Pyramid Servings Database) was assessed with a food frequency questionnaire. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated with adjustment for total energy and potential confounding factors.
Results
During an average 7.2 years of follow-up, 1258 incident pancreatic cancer cases were ascertained. The median intakes for the lowest and highest quintiles of total added sugar intake were 12.6 g/day and 96.2 g/day. No overall increased risk of pancreatic cancer was observed in men or women with high intake of total added sugar or sugar-sweetened foods and beverages. For men and women combined, the multivariate RRs of the highest versus lowest intake categories were 0.85 (95% CI: 0.68, 1.06; P trend= 0.07) for total added sugar, 1.01 (95% CI: 0.82,1.23; P trend= 0.58) for sweets, 0.98 (95% CI: 0.82,1.18; P trend= 0.49) for dairy desserts, 1.12 (95% CI: 0.91,1.39; P trend= 0.35) for sugar added to coffee and tea, and 1.01 (95% CI: 0.77,1.31; P trend= 0.76) for sugar-sweetened soft drinks.
Conclusion
Our results do not support the hypothesis that consumption of added sugar, or sugar-sweetened foods and beverages is associated with overall risk of pancreatic cancer.
PMCID: PMC3500146  PMID: 18689380
20.  A TRIAL OF B VITAMINS AND COGNITIVE FUNCTION AMONG WOMEN AT HIGH RISK OF CARDIOVASCULAR DISEASE 
Background
High homocysteine levels may be neurotoxic and contribute to cognitive decline in older persons.
Objective
Examine the effect of supplementation with folic acid, vitamin B12 and vitamin B6 on cognitive change among women with cardiovascular disease (CVD) or CVD risk factors.
Design
The Women's Antioxidant and Folic Acid Cardiovascular Study is a randomized, placebo-controlled trial to test a combination of B vitamins (folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg, daily) for secondary prevention of CVD. Randomization took place among 5,442 female health professionals, 40+ years, with CVD or at least three coronary risk factors in 1998 (after folic acid fortification began in the US). Shortly after randomization (mean=1.2 years), a cognitive function substudy was initiated among 2009 participants aged 65+ years. Telephone cognitive function testing was administered up to four times over 5.4 years with 5 tests of general cognition, verbal memory and category fluency. Repeated measures analyses were conducted. The primary outcome was a global composite score averaging all tests.
Results
Mean cognitive change from baseline did not differ between the B vitamin and placebo groups (difference in change in global score= 0.03, 95% CI −0.03, 0.08; p=0.30). However, supplementation appeared to confer benefits in preserving cognition among women with low baseline dietary intake of B vitamins.
Conclusions
Combined B vitamin supplementation did not delay cognitive decline among women with CVD or CVD risk factors. Possible cognitive benefits of supplementation among women with low dietary intake of B vitamins warrant further study.
doi:10.3945/ajcn.2008.26404
PMCID: PMC3470481  PMID: 19064521
21.  Maternal vitamin D status during pregnancy and body composition and cardiovascular risk markers in Indian children: the Mysore Parthenon study 
Background
Metabolic consequences of vitamin D deficiency have become a recent research focus. Maternal vitamin D status is thought to influence musculo-skeletal health in children, but its relationship with offspring metabolic risk is not known.
Objective
We aimed to examine the association between maternal vitamin D status and anthropometry, body composition and cardiovascular risk markers in Indian children.
Design
Serum 25-hydroxy D (25(OH)D ) concentrations were measured at 28-32 weeks gestation in 568 women who delivered at Holdsworth Memorial Hospital, Mysore. Anthropometry, glucose and insulin concentrations, blood pressure (BP) and fasting lipid concentrations were measured in the offspring at 5 and 9.5 years of age. Muscle-grip strength was measured using a hand held dynamometer at 9.5 years. Arm-muscle-area was calculated as a measure of muscle mass. Fasting insulin resistance was calculated using the HOMA equation.
Results
67% of women had vitamin D deficiency (serum 25(OH)D concentration <50 nmol/l). At 5 and 9.5 years, children born to vitamin D deficient mothers had smaller arm-muscle-area compared to children born to mothers without deficiency (P<0.05). There was no difference in grip strength between offspring of women with and without vitamin D deficiency. At 9.5 years, children of vitamin D deficient mothers had higher fasting insulin resistance than children of non-deficient women (P=0.04). There were no associations between maternal vitamin D status and other offspring risk factors at either age.
Conclusions
Intra-uterine exposure to low 25(OH)D concentrations is associated with lower muscle mass and higher insulin resistance in children.
doi:10.3945/ajcn.110.003921
PMCID: PMC3407368  PMID: 21228264
22.  Alcohol and coronary artery calcium prevalence, incidence and progression: results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Alcohol use has been consistently found to have a J-shaped association with coronary heart disease, with moderate drinkers exhibiting a decreased risk compared to both heavy drinkers and non-drinkers. However, studies of the association between alcohol use and subclinical coronary artery disease have conflicted.
Objective
To determine whether alcohol is associated with the presence, amount, or progression of coronary calcium over a 2- to 4-year period.
Design
MESA is a prospective community-based cohort study of subclinical cardiovascular disease in a multi-ethnic cohort. In 2000–2002, 6814 participants free of clinical cardiovascular disease were enrolled at 6 participating centers.
Results
There were 3766 (55.5%) current drinkers, 1635 (24.1%) former drinkers, and 1390 (20.5%) never drinkers included in the analysis. Although light to moderate alcohol consumption was associated with lower coronary heart disease risk, we found no evidence of a protective or J-shaped association of alcohol and coronary artery calcium (CAC). In fact there was evidence that heavy consumption of hard liquor was associated with greater CAC accumulation. Other alcoholic beverages were not associated with CAC prevalence, incidence or progression.
Conclusions
This is the first large study to evaluate the association of alcohol and coronary artery calcium in four racial/ethnic groups, and to evaluate progression of calcification. These results suggest that the cardiovascular benefits that may be derived from light to moderate alcohol consumption are not mediated through reduced CAC accumulation.
doi:10.3945/ajcn.2008.26420
PMCID: PMC3319440  PMID: 19064520
23.  Iron supplementation in early childhood: health benefits and risks123 
The prevalence of iron deficiency among infants and young children living in developing countries is high. Because of its chemical properties—namely, its oxidative potential—iron functions in several biological systems that are crucial to human health. Iron, which is not easily eliminated from the body, can also cause harm through oxidative stress, interference with the absorption or metabolism of other nutrients, and suppression of critical enzymatic activities. We reviewed 26 randomized controlled trials of preventive, oral iron supplementation in young children (aged 0–59 mo) living in developing countries to ascertain the associated health benefits and risks. The outcomes investigated were anemia, development, growth, morbidity, and mortality. Initial hemoglobin concentrations and iron status were considered as effect modifiers, although few studies included such subgroup analyses. Among iron-deficient or anemic children, hemoglobin concentrations were improved with iron supplementation. Reductions in cognitive and motor development deficits were observed in iron-deficient or anemic children, particularly with longer-duration, lower-dose regimens. With iron supplementation, weight gains were adversely affected in iron-replete children; the effects on height were inconclusive. Most studies found no effect on morbidity, although few had sample sizes or study designs that were adequate for drawing conclusions. In a malaria-endemic population of Zanzibar, significant increases in serious adverse events were associated with iron supplementation, whereas, in Nepal, no effects on mortality in young children were found. More research is needed in populations affected by HIV and tuberculosis. Iron supplementation in preventive programs may need to be targeted through identification of iron-deficient children.
PMCID: PMC3311916  PMID: 17158406
Iron; supplementation; children; development; growth; infection
24.  Predicting cardiovascular disease risk factors in mid-adulthood from childhood body mass index: utility of different cut-offs for childhood BMI 
Background
Identifying adults at increased risk of cardiovascular disease (CVD) from childhood BMI could be informative for disease prevention, but depends on the utility of childhood BMI cut-offs.
Objective
We aimed to establish how well the International Obesity Task Force (IOTF) and population-specific cut-offs for childhood BMI predict CVD risk factors in mid-adulthood.
Design
We used the 1958 British birth cohort, whose BMI measures were collected at 7, 11, 16y and CVD risk factors (obesity, hypertension, adverse lipid levels, type 2 diabetes risk) at 45y. Sensitivity and specificity of IOTF and population-specific cut-offs for childhood BMI were calculated for each CVD risk factor.
Results
Prevalence of overweight or obesity was low in childhood (<11%, using IOTF cut-offs) compared to adulthood (75% men; 56% women). IOTF cut-offs had high specificities (91.6-97.9%) but low sensitivities (7.1-31.5%) for predicting adult outcomes. In comparison, population-specific cut-offs identified large groups of children (e.g. >38% for predicting adult obesity) that had improved sensitivities (17.3-67.3%), but lower specificities (52.9-84.6%) than IOTF cut-offs. Accelerated BMI gains in childhood predicted adult obesity and type 2 diabetes risk, but prediction was no greater than for childhood BMI at one age (AUC 0.55-0.65 vs 0.59-0.75). Childhood BMI and BMI gain were weak predictors for adult hypertension and adverse lipid levels.
Conclusions
Neither the IOTF nor our population-specific cut-offs for childhood BMI provided adequate diagnostic tools for adult CVD risk factors in a population experiencing rapid change in obesity prevalence over their lifetime.
doi:10.3945/ajcn.110.001222
PMCID: PMC3308204  PMID: 21430113
Child body mass index cut-offs; Overweight and obesity; IOTF; Cardiovascular risk factors; Great Britain
25.  The association between non-subcutaneous adiposity and calcified coronary plaque: A substudy of the Multi-Ethnic Study of Atherosclerosis 
Background
Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.
Objective
We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden.
Design
Participants in the Multi-Ethnic Study of Atherosclerosis underwent CT assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men and 43% black), ages 47–86 years, from Forsyth County, NC during 2002–2005, using cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index using the standard scores of non-subcutaneous fat depots.
Results
A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors and height, calcified coronary plaque was associated with a one standard deviation increment in the non-subcutaneous fat index (OR = 1.41; 95% CI: 1.08, 1.84), pericardial fat (OR = 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR = 1.35; 95% CI: 1.03, 1.76), but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR = 1.40; 95% CI: 1.00, 1.94). The relation did not differ by gender and ethnicity.
Conclusions
The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.
PMCID: PMC3282464  PMID: 18779279

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