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Background Moderate acute malnutrition (MAM) affects 33 million children annually. Investments in formulations of corn-soy blended flours and lipid-based nutrient supplements have effectively improved MAM recovery rates. Information costs and cost-effectiveness differences are still needed. Objectives We assessed recovery and sustained recovery rates of MAM children receiving a supplementary food: ready-to-use supplementary food (RUSF), corn soy whey blend with fortified vegetable oil (CSWB w/oil), or Super Cereal Plus with amylase (SC + A) compared to Corn Soy Blend Plus with fortified vegetable oil (CSB+ w/oil). We also estimated differences in costs and cost effectiveness of each supplement. Methods In Sierra Leone, we randomly assigned 29 health centers to provide a supplement containing 550 kcal/d for ∼12 wk to 2691 children with MAM aged 6–59 mo. We calculated cost per enrollee, cost per child who recovered, and cost per child who sustained recovery each from 2 perspectives: program perspective and caregiver perspective, combined. Results Of 2653 MAM children (98.6%) with complete data, 1676 children (63%) recovered. There were no significant differences in the odds of recovery compared to CSB+ w/oil [0.83 (95% CI: 0.64–1.08) for CSWB w/oil, 1.01 (95% CI: 0.78–1.3) for SC + A, 1.05 (95% CI: 0.82–1.34) for RUSF]. The odds of sustaining recovery were significantly lower for RUSF (0.7; 95% CI 0.49–0.99) but not CSWB w/oil or SC + A [1.08 (95% CI: 0.73–1.6) and 0.96 (95% CI: 0.67–1.4), respectively] when compared to CSB+ w/oil. Costs per enrollee [US dollars (USD)/child] ranged from $105/child in RUSF to $112/child in SC + A and costs per recovered child (USD/child) ranged from $163/child in RUSF to $179/child in CSWB w/oil, with overlapping uncertainty ranges. Costs were highest per sustained recovery (USD/child), ranging from $214/child with the CSB+ w/oil to $226/child with the SC + A, with overlapping uncertainty ranges. Conclusions The 4 supplements performed similarly across recovery (but not sustained recovery) and costed measures. Analyses of posttreatment outcomes are necessary to estimate the full cost of MAM treatment. This trial was registered at clinicaltrials.gov as NCT03146897.

Examining the role of environmental enteric dysfunction (EED) in child growth requires noninvasive, field-appropriate biomarkers. Alternatives to the traditionally used lactulose:mannitol (L:M) test have been explored, but few studies have compared the L:M test to host fecal mRNA transcripts. The objectives of this study were to examine whether 1) host fecal mRNA transcripts could predict presence and severity of EED, measured using the L:M test, and 2) EED modifies the effect of specialized nutritious foods (SNFs) on recovery from moderate acute malnutrition (MAM). This substudy was nested within a cluster randomized trial comparing four SNFs in the treatment of MAM among children 6 to 59 months in Sierra Leone. EED was assessed at enrollment using the L:M test and 15 host fecal mRNA transcripts on 522 children. Recovery from MAM was defined as achieving mid-upper arm circumference ≥ 12.5 cm within 12 weeks of supplementation. Random forest classification models were used to examine prediction of presence and severity of EED by host fecal mRNA transcripts. Logistic regression was used to test for effect modification by L:M test variables including % lactulose excreted (%L). Eight host fecal mRNA transcripts (AQP9, REG3A, IFI30, DECR1, BIRC3, SELL, PIK3AP1, DEFA6) identified EED (%L ≥ 0.2) and severe EED (%L ≥ 0.45) with high sensitivity and specificity. The L:M test variables did not modify the effect of SNFs on recovery from MAM. In this study, we found host fecal mRNA transcripts that could be biomarkers of EED but did not find EED to modify the effect of SNFs on MAM treatment.

Background Measures that better describe “healthy” and sustainable recovery during nutritional treatment of children with moderate acute malnutrition (MAM) are needed. Objectives We compared changes to body composition among children receiving 1 of 4 specialized nutritious food (SNFs) during treatment of MAM and by recovery and relapse outcomes. Methods The study was nested within a prospective, cluster-randomized, community-based, cost-effectiveness trial assessing 4 SNFs to treat children aged 6–59 mo with MAM [midupper arm circumference (MUAC) ≥11.5 cm and

Background: There is a potential role of choline in cardiovascular and cerebrovascular disease through its involvement in lipid and one-carbon metabolism.Objective: We evaluated the associations of plasma choline and choline-related compounds with cardiometabolic risk factors, history of cardiovascular disease, and cerebrovascular pathology.Design: A cross-sectional subset of the Nutrition, Aging, and Memory in Elders cohort who had undergone MRI of the brain (n = 296; mean ± SD age: 73 ± 8.1 y) was assessed. Plasma concentrations of free choline, betaine, and phosphatidylcholine were measured with the use of liquid-chromatography-stable-isotope dilution-multiple-reaction monitoring-mass spectrometry. A volumetric analysis of MRI was used to determine the cerebrovascular pathology (white-matter hyperintensities and small- and large-vessel infarcts). Multiple linear and logistic regression models were used to examine relations of plasma measures with cardiometabolic risk factors, history of cardiovascular disease, and radiologic evidence of cerebrovascular pathology.Results: Higher concentrations of plasma choline were associated with an unfavorable cardiometabolic risk-factor profile [lower high-density lipoprotein (HDL) cholesterol, higher total homocysteine, and higher body mass index (BMI)] and greater odds of large-vessel cerebral vascular disease or history of cardiovascular disease but lower odds of small-vessel cerebral vascular disease. Conversely, higher concentrations of plasma betaine were associated with a favorable cardiometabolic risk-factor profile [lower low-density lipoprotein (LDL) cholesterol and triglycerides] and lower odds of diabetes. Higher concentrations of plasma phosphatidylcholine were associated with characteristics of both a favorable cardiometabolic risk-factor profile (higher HDL cholesterol, lower BMI, lower C-reactive protein, lower waist circumference, and lower odds of hypertension and diabetes) and an unfavorable profile (higher LDL cholesterol and triglycerides).Conclusion: Choline and its metabolites have differential associations with cardiometabolic risk factors and subtypes of vascular disease, thereby suggesting differing roles in the pathogenesis of cardiovascular and cerebral large-vessel disease compared with that of small-vessel disease.

OBJECTIVES: The objective of the study was to examine whether EED at enrollment modifies the effect of specialized nutritious foods (SNFs) on graduation from a moderate acute malnutrition (MAM) treatment program. METHODS: This sub-study was nested within a cluster randomized trial of MAM children 6–59 months of age supplemented with one of four SNFs: Super Cereal Plus w/amylase (SC + A), Corn Soy Blend Plus w/oil (CSB + w/oil - referent), Corn Soy Whey Blend w/oil (CSWB w/oil), and Ready to Use Supplementary Food (RUSF). Children with mid-upper arm circumference (MUAC) ≥11.5 cm and

OBJECTIVES: The objectives of the study were to 1) develop an EED score using fecal host mRNA transcripts, 2) compare three EED biomarkers, and 3) examine associations between EED biomarkers and growth outcomes and recovery from MAM. METHODS: In a study nested within a supplementary feeding program for children 6–59 months of age with MAM in Sierra Leone, EED was assessed in all children enrolled using: 1) lactulose: mannitol (L: M) test (n = 422), 2) fifteen host fecal mRNA transcripts (n = 441), and 3) host fecal proteins [alpha-1-anti trypsin (AAT), myeloperoxidase (MPO), neopterin (NEO)] (n = 200). Data were also collected on anthropometry and z scores computed for length-for-age (LAZ), and weight-for-length (WLZ). Length and weight gain were assessed over 2 weeks and recovery from MAM was defined as mid-upper arm circumference ≥12.5 cm. Factor analysis was used to identify EED scores using the mRNA transcripts and mixed effects regression was conducted to test for associations. RESULTS: The fifteen host fecal mRNA transcripts clustered into three scores using factor analysis (Eigen value >1). These were termed the Gut Inflammation (GI) score (Eigen value = 5.55), Gut Structure (GS) score (Eigen value = 2.48), and Gut Defense (GD) score (Eigen value = 2.22). We found agreement between the GI score and MPO (P

Background There is a variety of specialized nutritious foods available for use in programs targeting undernutrition, but evidence supporting the choice of product is limited. Objectives We compared the cost-effectiveness of 4 specialized nutritious foods to prevent stunting and wasting in children aged 6–23 mo in Burkina Faso. Methods Four geographic regions were randomly assigned to 1 of 4 intervention arms: Corn-Soy Blend Plus (CSB+) programmed with separate fortified vegetable oil (the reference food), Corn-Soy-Whey Blend (CSWB; a new formulation) with oil, SuperCereal Plus (SC+), and ready-to-use supplementary food (RUSF). We compared the effects of each intervention arm on growth (length-for-age z score (LAZ), weight-for-length z score (WLZ), end-line stunting (LAZ < −2), and total monthly measurements of wasting (WLZ < −2). Rations were ∼500 kcal/d, distributed monthly. Children were enrolled in the blanket supplementary feeding program at age ∼6 mo and measured monthly for ∼18 mo. Average costs per child reached were linked with effectiveness to compare the cost-effectiveness of each arm with CSB+ with oil. Results In our sample of 6112 children (CSB+, n = 1519; CSWB, n = 1503; SC+, n = 1564; RUSF, n = 1526), none of the foods prevented declines in growth. Children in the SC+ and RUSF arms were not significantly different than those in the CSB+ with oil arm. Children in the CSWB with oil arm experienced higher end-line (measurement at age 22.9–23.9 mo) stunting (OR: 2.07; 95% CI: 1.46, 2.94) and more months of wasting (incidence rate ratio: 1.29; 95% CI: 1.09, 1.51). CSB+ with oil was the least-expensive ration in all costing scenarios ($113–131 2018 US dollars/enrolled child) and similar in effectiveness to SC+ and RUSF, and thus the most cost-effective product for the defined purposes. Conclusions CSB+ with oil was the most cost-effective ration in the prevention of wasting and stunting in this trial. This trial was registered at clinicaltrials.gov as NCT02071563.

This report on vitamin B-12 (B12) is part of the Biomarkers of Nutrition for Development (BOND) Project, which provides state-of-the art information and advice on the selection, use, and interpretation of biomarkers of nutrient exposure, status, and function. As with the other 5 reports in this series, which focused on iodine, folate, zinc, iron, and vitamin A, this B12 report was developed with the assistance of an expert panel (BOND B12 EP) and other experts who provided information during a consultation. The experts reviewed the existing literature in depth in order to consolidate existing relevant information on the biology of B12, including known and possible effects of insufficiency, and available and potential biomarkers of status. Unlike the situation for the other 5 nutrients reviewed during the BOND project, there has been relatively little previous attention paid to B12 status and its biomarkers, so this report is a landmark in terms of the consolidation and interpretation of the available information on B12 nutrition. Historically, most focus has been on diagnosis and treatment of clinical symptoms of B12 deficiency, which result primarily from pernicious anemia or strict vegetarianism. More recently, we have become aware of the high prevalence of B12 insufficiency in populations consuming low amounts of animal-source foods, which can be detected with ≥1 serum biomarker but presents the new challenge of identifying functional consequences that may require public health interventions.

Factors associated with relapse among children who are discharged after reaching a threshold denoted ‘recovered’ from moderate acute malnutrition (MAM) are not well understood. The aim of this study was to identify factors associated with sustained recovery, defined as maintaining a mid-upper-arm circumference≥12·5 cm for 1 year after release from treatment. On the basis of an observational study design, we analysed data from an in-depth household (HH) survey on a sub-sample of participants within a larger cluster randomised controlled trial (cRCT) that followed up children for 1 year after recovery from MAM. Out of 1497 children participating in the cRCT, a subset of 315 children participated in this sub-study. Accounting for other factors, HH with fitted lids on water storage containers (P=0·004) was a significant predictor of sustained recovery. In addition, sustained recovery was better among children whose caregivers were observed to have clean hands (P=0·053) and in HH using an improved sanitation facility (P=0·083). By contrast, socio-economic status and infant and young child feeding practices at the time of discharge and HH food security throughout the follow-up period were not significant. Given these results, we hypothesise that improved water, sanitation and hygiene conditions in tandem with management of MAM through supplemental feeding programmes have the possibility to decrease relapse following recovery from MAM. Furthermore, the absence of associations between relapse and nearly all HH-level factors indicates that the causal factors of relapse may be related mostly to the child’s individual, underlying health and nutrition status.

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer’s disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

Background: Folate status has been positively associated with cognitive function in many studies; however, some studies have observed associations of poor cognitive outcomes with high folate. In search of an explanation, we hypothesized that the association of folate with cognition would be modified by the interaction of high-folate status with a common 19-bp deletion polymorphism in the dihydrofolate reductase (DHFR) gene. To our knowledge, the cognitive effects of this gene have not been studied previously. Objective: We examined the association between cognitive outcomes with the 19-bp deletion DHFR polymorphism, folate status, and their interaction with high or normal plasma folate. Design: This was a pooled cross-sectional study of the following 2 Boston-based cohorts of community living adults: the Boston Puerto Rican Health Study and the Nutrition, Aging, and Memory in Elders study. Individuals were genotyped for the DHFR 19-bp deletion genotype, and plasma folate status was determined. Cognitive outcomes included the Mini-Mental State Examination, Center for Epidemiologic Studies Depression Scale, and factor scores for the domains of memory, executive function, and attention from a set of cognitive tests. Results: The prevalence of the homozygous deletion (del/del) genotype was 23%. In a multivariable analysis, high folate status (>17.8 ng/mL) was associated with better memory scores than was normal-folate status (fourth–fifth quintiles compared with first–third quintiles: β ± SE = −0.22 ± 0.06, P < 0.01). Carriers of the DHFR del/del genotype had worse memory scores (β ± SE = −0.24 ± 0.10, P < 0.05) and worse executive scores (β = −0.19, P < 0.05) than did those with the del/ins and ins/ins genotypes. Finally, we observed an interaction such that carriers of the del/del genotype with high folate had significantly worse memory scores than those of both noncarriers with high-folate and del/del carriers with normal-folate (β-interaction = 0.26 ± 0.13, P < 0.05). Conclusions: This study identifies a putative gene-nutrient interaction that, if confirmed, would predict that a sizable minority carrying the del/del genotype might not benefit from high-folate status and could see a worsening of memory. An understanding of how genetic variation affects responses to high-folate exposure will help weigh risks and benefits of folate supplementation for individuals and public health.

Background Nutrition programs frequently approach wasting and stunting as 2 separate conditions with distinct causes and effects. Although several cross-sectional studies have identified an association between the 2 conditions, longitudinal studies are useful to quantify the risk of acute malnutrition based on the trajectory of linear growth. Objective We analyzed data from a longitudinal study to explore associations between linear growth and relapse to acute malnutrition in high-risk children during the year after recovery from moderate acute malnutrition (MAM). Methods This was a secondary data analysis from a cluster randomized trial involving 1487 Malawian children 6-62 mo old treated for MAM and enrolled upon recovery. Children were followed for 1 y, during which data were collected on anthropometric progress, symptoms of illness, and household food security. Multivariate fixed-effects logistic regression was used to identify associations between linear growth and relapse to acute malnutrition. Results Children who have recovered from MAM proved to be a high-risk population, with nearly half experiencing a decrease in height-for-age z score (HAZ) for 12 mo. Children whose HAZ was declining were more likely to relapse to MAM or SAM than were those whose linear growth rate maintained or increased their HAZ (P

Background: Objectives: Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, stroke and dementia. Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent. The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function. We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients. Design: The study was a longitudinal ancillary of the FAVORIT trial, a randomized, placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinically stable kidney transplant recipients with elevated tHcy. Participants: 584 participants from 18 sites across North America. Intervention: The intervention consisted of a daily multivitamin containing high-doses of folate (5.0 mg), vitamin B12 (1.0 mg) and vitamin B6 (50 mg). The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 (0 mg folate; 2.0 µg vitamin B12; 1.4 mg vitamin B6). Measurements: Annual neuropsychological assessment for up to 5 years (mean 3.3 years) using a standardized test battery. Efficacy was analyzed on an intention-to-treat basis using end-of-trial data. Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations. Results: At baseline, cognitive impairment was common with 61% of participants falling more than one standard deviation below published norms for at least one cognitive test. Fewer than 1% of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However, 44.6% had plasma B6 concentrations < 30 nmol/L. At follow-up, processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls (p≤0.05). There was no interaction between baseline tHcy, B-vitamin status and treatment on the cognitive outcomes. Conclusions: High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy. Since nearly all participants were folate and vitamin B12 sufficient at baseline, the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined.

OBJECTIVES: To determine differential changes in children's body composition—fat-free mass (FFM) and fat mass (FM)—after 4 weeks of treatment for moderate acute malnutrition (MAM) with one of 4 four specialized nutritious foods (SNFs). METHODS: This sub-study was nested within a larger cluster-randomized trial comparing the cost-effectiveness of 4 isocaloric SNFs in treating MAM among children 6–59 months in Pujehun District, Sierra Leone: Corn-Soy Blend Plus w/oil (CSB + w/oil), Super Cereal Plus w/amylase (SC + A), Corn-Soy-Whey Blend w/oil (CSWB w/oil) and Ready-to-use-Supplementary Food (RUSF). Children with mid-upper arm circumference (MUAC) ≥11.5 cm and

OBJECTIVES: This study compared the effectiveness of 4 specialized nutritious foods (SNFs) used for the treatment of moderate acute malnutrition (MAM) in children

Changes in small bowel function early in infancy in developing countries are increasingly being demonstrated, probably accompanied by altered mucosal architecture in most individuals, including reduced enterocyte mass and evidence of immune activation and inflammation in the mucosa. These alterations appear to be the result of factors of uncertain nature in the environment, and may be a cause of growth faltering and stunting in young children. For these reasons, this constellation of findings is being referred to as environmental enteropathy, or as we propose herein, environmental enteric dysfunction. If the causes were known and effective interventions were available, strategies and policies to intervene at—or possibly before—birth could be developed and promoted in order to prevent subsequent malnutrition and recurrent infection, which are known to interact in a cyclical and synergistic manner in a downward clinical course often ending in death. Resources would be mobilized and applied differently, and the emphasis would change from treatment to prevention. In order to move in this highly desired direction, investments in research will be required to establish the criteria to assess environmental enteric dysfunction, determine its predictive value for growth faltering and stunting, identify the causes, and propose and test potential interventions. The concepts and tools are available. What is required is the decision to move forward along this pathway to better health for infants and children in low-income countries.

We are worried by the following statement in a recent editorial on the safety of folic acid fortification: “No important adverse effects have been identified to date, probably because a modest level of fortification has proved very effective in preventing these devastating birth defects.”1 It is unusual in medicine to claim that a treatment is safe just because it is effective in treating or preventing one condition—objective evidence is needed on overall safety and the side effect profile in all people exposed to the “treatment,” not only those who benefit. It seems that WHO also has not fully assessed the possible harmful effects of folic acid because its guideline on folate and neural tube defects (NTDs) states: “high folic acid intake has not reliably been shown to be associated with negative health effects.”2 The editorial’s claim that half of all NTDs could be prevented by mandatory fortification in Europe is misleading, because the effectiveness of fortification depends on the baseline prevalence of NTDs, …

The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene differs in frequency in various ethnic groups that have differing prevalence of age-related cognitive impairments. We used a series of neuro-psychological tests to examine the association of the MTHFR C677T polymorphism with cognition and depression and also to assess whether genotype modifies the association of folate and homocysteine with these outcomes. This study analyzed pooled cross-sectional data from 2 ethnically diverse cohorts of community-living adults: the Boston Puerto Rican Health Study (n = 939) and the Nutrition, Aging, and Memory in Elders study (n = 1017). Individuals in both cohorts underwent anthropometric and laboratory measurements and dietary and health assessments using validated questionnaires between the years 2003 and 2007. Cognitive outcomes included measures of global cognition [Mini-Mental Status Exam (MMSE)], depression (Center for Epidemiological Studies Depression Scale), and 3 factor scores for the domains of attention, executive function, and memory that were derived from a detailed set of neuropsychological tests. Low plasma vitamin B-12 concentrations were associated with poorer MMSE scores and higher depression scores, and low vitamin B-6 concentrations were associated with lower MMSE and worse attention and executive function in the multivariate analysis. In contrast, MTHFR genotype, folate, and homocysteine were not associated with cognition or depression in either ethnicity-pooled or stratified analysis. The current study did not find evidence of an association between the MTHFR C677T TT genotype and impaired cognition or depression in a population with adequate folate status and a high prevalence of cognitive impairment and depression.

This review examines the current knowledge of water intake as it pertains to human health, including overall patterns of intake and some factors linked with intake, the complex mechanisms behind water homeostasis, and the effects of variation in water intake on health and energy intake, weight, and human performance and functioning. Water represents a critical nutrient, the absence of which will be lethal within days. Water's importance for the prevention of nutrition-related noncommunicable diseases has received more attention recently because of the shift toward consumption of large proportions of fluids as caloric beverages. Despite this focus, there are major gaps in knowledge related to the measurement of total fluid intake and hydration status at the population level; there are also few longer-term systematic interventions and no published randomized, controlled longer-term trials. This review provides suggestions for ways to examine water requirements and encourages more dialogue on this important topic.

Background Folate deficiency has serious consequences for the fetus. Folic acid fortification of food addresses this problem. However, clinical consequences of vitamin B-12 deficiency may be worsened by high folic acid intakes, perhaps as a direct result of unmetabolized folic acid, which does not occur naturally in body tissues. Objective We attempted to attribute associations that we previously found between higher folate status and anemia and cognitive test performance to circulating unmetabolized folic acid or 5-methyltetrahydrofolate (5MeTHF). Design The subjects (n = 1858) were senior participants in the US National Health and Nutrition Examination Survey (1999-2002) who had normal renal function and reported no history of stroke, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries. Subjects had undergone a phlebotomy, a complete blood count, and cognitive and dietary assessments. Results Circulating unmetabolized folic acid was detected in approximately 33% of the subjects and was related to an increased odds of anemia in alcohol users. In seniors with a serum vitamin B-12 concentration or =210 nmol/L, the presence compared with the absence of detectable circulating unmetabolized folic acid was related to lower cognitive test scores and lower mean cell volume. In the same subgroup, higher serum 5MeTHF was related to an increased odds of anemia and a marginally significantly decreased odds of macrocytosis. In seniors with a normal vitamin B-12 status, a higher serum 5MeTHF concentration was related to higher cognitive test scores. Conclusion Results of this epidemiologic study were somewhat consistent with reports on the folic acid treatment of patients with pernicious anemia, but some findings were unexpected.

Anemia and micronutrient deficiencies are common among Indian schoolchildren. We assessed the effectiveness of micronutrient fortification of meals cooked and fortified at school on anemia and micronutrient status of schoolchildren in Himalayan villages of India. In this placebo-controlled, cluster-randomized study, 499 schoolchildren (6-10 y) received either multiple micronutrients (treatment group) or placebo (control group) as part of school meals (6 d/wk) for 8 mo. Both groups were dewormed at the beginning of the study. The micronutrient premix provided 10 mg iron, 375 microg vitamin A, 4.2 mg zinc, 225 microg folic acid, and 1.35 microg vitamin B-12 for each child per day (approximately 75% recommended dietary allowance). Blood samples drawn before and after the intervention were analyzed for hemoglobin, ferritin, retinol, zinc, folate, and vitamin B-12. Baseline prevalence of anemia (37%), iron deficiency anemia (10%), low serum ferritin (24%), retinol (56%), zinc (74%), folate (68%), and vitamin B-12 (17%) did not differ between groups. Postintervention, fewer in the treatment group had lower serum retinol [odds ratio (OR) (95% CI): 0.57 (0.33-0.97)] and folate [OR (95% CI): 0.47 (0.26-0.84)] than the control group. The serum vitamin B-12 concentration decreased in both groups, but the magnitude of change was less in the treatment than in the control group (P < 0.05). Total body iron (TBI) increased in both groups; however, the change was greater in the treatment than in the control group (P < 0.05). Micronutrient fortification of school meals by trained school personnel was effective in improving vitamin A, folate, and TBI status while also reducing the magnitude of a decrease in vitamin B-12 status.

Background: The S-adenosylmethionine synthetase type 1 (MAT1A) gene encodes a key enzyme in one-carbon nutrient metabolism. Objective: This study aimed to determine the association of MAT1A variants with homocysteine, DNA damage, and cardiovascular disease (CVD). Design: Eight variants of MAT1A were examined for associations with hypertension, stroke, CVD, homocysteine, and DNA damage in 1006 participants of the Boston Puerto Rican Health Study. Two variants were replicated in 1147 participants of the Nutrition, Aging, and Memory in Elders Study. Results: Two variants and haplotypes were strongly associated with hypertension and stroke, independent of methylenetetrahydrofolate reductase (MTHFR) variants. Homozygotes of the MAT1A d18777A (rs3851059) allele had a significantly greater likelihood of stroke (odds ratio: 4.30; 95% CI: 1.34, 12.19; P = 0.006), whereas 3U1510A (rs7087728) homozygotes had a lower likelihood of hypertension (odds ratio: 0.67; 95% CI: 0.48, 0.95; P = 0.022) and stroke (odds ratio: 0.35; 95% CI: 0.15, 0.82; P = 0.015). A similar trend of association was observed in a second elderly population. Furthermore, strong interactions between MAT1A genotypes and vitamin B-6 status were found. Carriers of the nonrisk allele 3U1510A had a lower 8-hydroxydeoxyguanosine concentration—a biomarker of oxidative DNA damage—when plasma vitamin B-6 was high, whereas homozygotes for the risk-allele 3U1510G had higher 8-hydroxydeoxyguanosine concentrations, regardless of vitamin B-6 status. Conclusions: MAT1A variants were strongly associated with hypertension and stroke. Improving folate and vitamin B-6 status might decrease the CVD risk of only a subset of the population, depending on genotype. These findings suggest that impairments in methylation activity, independent of homocysteine, have an effect on CVD risk.

Background and Purpose— Gait impairment is common in the elderly, especially those with stroke and white matter hyperintensities on conventional brain MRI. Diffusion tensor imaging (DTI) is more sensitive to white matter damage than conventional MRI. The relationship between DTI measures and gait has not been previously evaluated. Our purpose was to investigate the relationship between the integrity of white matter in the corpus callosum as determined by DTI and quantitative measures of gait in the elderly. Methods— One hundred seventy-three participants of a community-dwelling elderly cohort had neurological and neuropsychological examinations and brain MRI. Gait function was measured by Tinetti gait (0 to 12), balance (0 to 16) and total (0 to 28) scores. DTI assessed fractional anisotropy in the genu and splenium of the corpus callosum. Conventional MRI was used to evaluate for brain infarcts and white matter hyperintensity volume. Results— Participants with abnormal gait had low fractional anisotropy in the genu of the corpus callosum but not the splenium. Multiple regressions analyses showed an independent association between these genu abnormalities and all 3 Tinetti scores ( P Conclusions— The independent association between quantitative measures of gait function and DTI findings shows that white matter integrity in the genu of corpus callosum is an important marker of gait in the elderly. DTI analyses of white matter tracts in the brain and spinal cord may improve knowledge about the pathophysiology of gait impairment and help target clinical interventions.

Epidemiologic research is increasingly being focused on elderly persons, many of whom exhibit mild-to-moderate cognitive impairment. This presents a challenge for collection and interpretation of self-reported dietary data. There are few reports on the impact of cognitive function and dementia on the validity of self-reported dietary intakes. Using plasma phospholipid fatty acid profiles as a biomarker of intake, the authors assessed the validity of an interviewer-administered food frequency questionnaire (FFQ) to estimate intakes of 2 marine-based omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), among 273 community-dwelling adults aged > or =60 years participating in the Nutrition, Aging, and Memory in Elders Study (Boston, Massachusetts, 2002-2008). Age- and energy-adjusted Pearson correlation coefficients for correlations between dietary intakes and plasma phospholipids were consistent across categories of high and low cognitive function (r = 0.48), based on Mini-Mental State Examination score, and were similar across clinically diagnosed categories of normal functioning (r = 0.49), mild cognitive impairment (r = 0.45), and dementia (r = 0.52). The FFQ ranked 78% of subjects to within 1 quartile of their plasma phospholipid EPA + DHA quartile. This frequency was consistently high across all cognitive categories. With interviewer administration, this FFQ seems to be a valid method of assessing dietary EPA + DHA intake in older adults with mild-to-moderate cognitive impairment.

Background Albuminuria, a kidney marker of microvascular disease, may herald microvascular disease elsewhere, including in the brain. Study Design Cross sectional. Setting & Participants Boston, MA, elders receiving home health services to maintain independent living who consented to brain magnetic resonance imaging. Predictor Urine albumin-creatinine ratio (ACR). Outcome Performance on a cognitive battery assessing executive function and memory by using principal components analysis and white matter hyperintensity volume on brain imaging, evaluated in logistic and linear regression models. Results In 335 participants, mean age was 73.4 ± 8.1 years and 123 participants had microalbuminuria or macroalbuminuria. Each doubling of ACR was associated with worse executive function (β = −0.05; P = 0.005 in univariate and β = −0.07; P = 0.004 in multivariable analyses controlling for age, sex, race, education, diabetes, cardiovascular disease, hypertension, medications, and estimated glomerular filtration rate [eGFR]), but not with worse memory or working memory. Individuals with microalbuminuria or macroalbuminuria were more likely to be in the lower versus the highest tertile of executive functioning (odds ratio, 1.18; 95% confidence interval, 1.06 to 1.32; odds ratio, 1.19; 95% confidence interval, 1.05 to 1.35 per doubling of ACR in univariate and multivariable analyses, respectively). Albuminuria was associated with qualitative white matter hyperintensity grade (odds ratio, 1.13; 95% confidence interval, 1.02 to 1.25; odds ratio, 1.15; 95% confidence interval, 1.02 to 1.29 per doubling of ACR) in univariate and multivariable analyses and with quantitative white matter hyperintensity volume (β = 0.11; P = 0.007; β = 0.10; P = 0.01) in univariate and multivariable analyses of log-transformed data. Results were similar when excluding individuals with macroalbuminuria. Limitations Single measurement of ACR, indirect creatinine calibration, and reliance on participant recall for elements of medical history. Conclusions Albuminuria is associated with worse cognitive performance, particularly in executive functioning, as well as increased white matter hyperintensity volume. Albuminuria likely identifies greater brain microvascular disease burden.

Some countries have introduced mandatory folic acid fortification, whereas others support periconceptional supplementation of women in childbearing age. Several European countries are considering whether to adopt a fortification policy. Projections of the possible beneficial effects of increased folic acid intake assume that the measure will result in a considerable reduction in neural-tube defects (NTD) in the target population. Therefore, the objective of the present study is to evaluate the beneficial effects of different levels of folic acid administration on the prevalence of NTD. Countries with mandatory fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTD. This was also true for supplementation trials. However, the prevalence of NTD at birth declined to approximately five cases at birth per 10 000 births and seven to eight cases at birth or abortion per 10 000 births. This decline was independent of the amount of folic acid administered and apparently reveals a ‘floor effect’ for folic acid-preventable NTD. This clearly shows that not all cases of NTD are preventable by increasing the folate intake. The relative decline depends on the initial NTD rate. Countries with NTD prevalence close to the observed floor may have much smaller reductions in NTD rates with folic acid fortification. Additionally, potential adverse effects of fortification on other vulnerable population groups have to be seriously considered. Policy decisions concerning national mandatory fortification programmes must take into account realistically projected benefits as well as the evidence of risks to all vulnerable groups.

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

The sustained effort to witness and participate in the targeted translation of nutritional science and policy forms the structure of this narrative. The memoir starts with an early career-directing experience with nutrition and cholera and proceeds with a long thread of interest in folic acid malabsorption as one of the determinants of nutritional anemia in Asia and the tropics. The thread continues with the relationship of folate and associated vitamins to brain function and aging as a prototype of the study of the interface of aging biology and nutritional biology. My current interest in world hunger and famine and their impact on human security may circle back to studies of the great Bengal famine and the first Bangladesh survey of malnutrition.

Our previous studies demonstrated a significant decline in brain function and behavior in Fischer 344 (F344) rats with age. The present study was designed to test the hypothesis that dysregulation in calcium homeostasis (as assessed through (45)Ca flux) may contribute to the increase in age-related vulnerability to oxidative stress in brain regions, and result in a deficit in behavior-mediated signaling. Crude membrane (P-2) and more purified synaptosomal fractions were isolated from the striatum, hippocampus, and frontal cortex of young (6 months) and old (22 months) F344 rats and were assessed for calcium flux and extracellular-regulated kinase activity 1 (ERK) under control and oxidative stress conditions induced by low dose hydrogen peroxide (final concentration 5 microM). The level of oxidative stress responses was monitored by measuring reactive oxygen species (ROS) and glutathione (GSH). The results showed a significant difference in oxidative stress responses between young and old rats in evaluated brain regions. Old rats showed higher sensitivity to oxidative stress than young rats. The present findings show the differential effects of oxidative stress on calcium flux in brain regions with age that are dependent upon the brain areas examined and the fraction assessed. The accumulation of ROS and the decrease in GSH in the frontal cortex were sufficient to decrease ERK activity in old rats. This is the first study, to our knowledge, that demonstrates age-related differential sensitivity to oxidative stress expressed as a function of behavior-mediated signaling and stress levels among different fractions isolated from brain regions controlling behavior.

We conducted a systematic review to evaluate the association between folate, vitamin B-6, vitamin B-12, and cognitive function in the elderly. Our search was conducted in Medline for English-language publications of human subjects from 1966 through November 2006; we supplemented these results with information from article reviews and domain experts. We included longitudinal cohort and case-control studies of B vitamins and analyses of cognitive tests or Alzheimer's disease. We evaluated the quality and heterogeneity of study outcomes and assessed 30 different cognitive function tests. Of 24 studies that met eligibility criteria, 16 were determined to be of fair quality. A majority of the studies reviewed 2 or more B vitamins. Considerable heterogeneity was found among B-vitamin-level thresholds, comparisons, and data analyses. Six of 10 folate studies reported a significant association between low baseline blood folate concentrations and subsequent poor test performance in the global cognitive domain, and 4 of 9 folate studies found associations between low blood folate concentrations and increased prevalence of Alzheimer's disease. Studies did not reveal an association of vitamin B-6 and vitamin B-12 blood concentrations with cognitive-test performance or Alzheimer's disease, nor was B-vitamin dietary intake associated with cognitive function. Higher plasma homocysteine concentrations were associated with poorer cognitive function. Although the majority of studies indicated that low blood folate concentrations predicted poorer cognitive function, data supporting this association were limited because of the heterogeneity in cognition-assessment methodology, and scarcity of good quality studies and standardized threshold levels for categorizing low B-vitamin status.

Background : Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical. Objective : We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score 210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine. Results : After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR) : 2.7; 95% CI : 1.7, 4.2], macrocytosis (OR : 1.8; 95% CI : 1.01, 3.3), and cognitive impairment (OR : 2.5; 95% CI : 1.6,3.8). In the group with a low vitamin B-12 status, serum folate >59 nmol/L (80th percentile), as opposed to ≤59 nmol/L, was associated with anemia (OR : 3.1; 95% CI : 1.5, 6.6) and cognitive impairment (OR : 2.6; 95% CI : 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were < 1.0 (f interaction < 0.05), but significantly < 1.0 only for cognitive impairment (0.4; 95% CI : 0.2, 0.9). Conclusion : In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.

I suppose I should establish my bonafides for participation in this symposium. I did participate in 3 Interdepartmental Committee on Nutrition for National Defense (ICNND) surveys as far separated as one on the Blackfeet Indian Reservation (1) in Montana and 2 in Asia-Burma (2) and East Pakistan (3). In fact, the Blackfeet Reservation and Burma surveys were my training grounds for becoming the clinical chief for the East Pakistan survey and later the codirector. More importantly, in 1962, I followed Alan Forbes, who is much missed at this symposium, as the deputy to Arnie Schaefer at ICNND and NIH, and did have experience of an office in the Stone House on the NIH campus. There I participated in the transmutation of the ICNND to the Interdepartmental Committee on National Development and its alignment with the Office of International Research at the NIH and a repositioning within the Department of Health and Human Services. It was from this position that ICNND went on to organize some civilian surveys in the mid-1960s, including those in Central America and Panama (4), and it was from this position that the groundwork was laid for the application of ICNND techniques to the first U.S. domestic survey outside of an Indian reservation, culminating in the Ten State Nutrition Survey (5), which documented that there was hunger in America, as well as abroad.

The purpose of this study was to determine skeletal muscle cutpoints for identifying elevated physical disability risk in older adults. Subjects included 4,449 older (> or = 60 years) participants from the Third National Health and Nutrition Examination Survey during 1988-1994. Physical disability was assessed by questionnaire, and bioimpedance was used to estimate skeletal muscle, which was normalized for height. Receiver operating characteristics were used to develop the skeletal muscle cutpoints associated with a high likelihood of physical disability. Odds for physical disability were compared in subjects whose measures fell above and below these cutpoints. Skeletal muscle cutpoints of 5.76-6.75 and < or =5.75 kg/m2 were selected to denote moderate and high physical disability risk in women. The corresponding values in men were 8.51-10.75 and < or =8.50 kg/m2. Compared with women with low-risk skeletal muscle values, women with moderate- and high-risk skeletal muscle values had odds for physical disability of 1.41 (95% confidence interval (CI): 0.97, 2.04) and 3.31 (95% CI: 1.91, 5.73), respectively. The corresponding odds in men were 3.65 (95% CI: 1.92, 6.94) and 4.71 (95% CI: 2.28, 9.74). This study presents skeletal muscle cutpoints for physical disability risk in older adults. Future applications of these cutpoints include the comparison of morbidity risk in older persons with normal muscle mass and those with sarcopenia, the determination and comparison of sarcopenia prevalences, and the estimation of health-care costs attributable to sarcopenia.

We commend Semba et al. (2016) for examining child stunting in the context of protein and amino acids, which, beyond supplying essential nitrogen for protein synthesis, are involved in regulation of linear growth, an issue that has not been addressed sufficiently. The authors reported significant associations between low levels of serum amino acids and stunting in a cross-sectional study of young children in rural Malawi. As the authors note, studies of micronutrient and lipid supplements have failed to demonstrate improved linear growth in malnourished children. Furthermore, the ten most effective interventions recommended for scale up at the global level are likely to reduce stunting by only ~ 20% even at a coverage level of 90% (Bhutta et al., 2013). Thus, we are writing to comment on the findings of Semba et al., highlight relevant past and current research and advocate for further collaborative effort forward in the area of protein quality and childhood stunting. The results of Semba et al. raise a number of questions, including the interpretation of circulating amino acids. Plasma concentrations are static, representing the net effect of changes in production and utilization of an amino acid, unlike the dynamic flux. For example, plasma citrulline flux, which indicates enterocyte mass and function, is not reflected in its plasma concentration (Kao et al., 2016). Thus, among stunted children, are low circulating amino acids a biomarker of recent protein intake, the body's amino acid pool, acute protein deficiency, or simply a reflection of short-term physiological processes such as digestion and absorption (Cetin et al., 2015)? Or do the levels of circulating amino acids represent a response to entirely different biological processes such as presence of infection (Laurichesse et al., 1998) or a metabolic adjustment to preserve nutrients critical for maintaining lean body mass during periods of low intake of quality protein? What is clear from the novel approach used by Semba et al. is that physiological outcomes such as stunting and nutritional factors such as protein and amino acids and their metabolism and turnover are complex phenomena, and additional research will be required to answer these questions. While the emphasis from protein shifted to energy and micronutrients in the late 1970's, as noted by Semba et al., it was by no means an end to the work on protein quality; we would be remiss not to mention the decades of seminal work conducted since then through the leadership of the late Drs. Nevin Scrimshaw and Vernon Young. This included elucidating the relationship of protein and energy interactions, redefining protein and amino acid requirements within the context of high and low energy availabilities, and investigating the health impacts from improving protein quality via increased intake of essential amino acids (EAAs)—especially lysine, the most limiting EAA in cereal based diets. Dr. Scrimshaw's seminal protein work has continued through the Nevin Scrimshaw International Nutrition Foundation, which co-organized a workshop on the topic of protein quality and growth in 2012 (Suri et al., 2013). One reason that protein and amino acids are often overlooked in relation to stunting may be that while children in low-resource, developing country contexts appear to have adequate protein intake; however, there are two issues that may, in fact, put them at risk of inadequacy. First, failure to adjust for protein quality—a composite of the EAA profile as compared to the requirement pattern, and the “digestibility”, or absorption and utilization of the amino acids in foods, both of which can decrease the effective protein available to the body—results in overestimates of dietary protein adequacy. Second, the needs of children in these contexts are systematically underestimated; current protein and amino acid requirements do not account for conditions of energy deficit, and persistent or subclinical infections, which could be compounded by sub-optimal digestive and absorptive intestinal function; emerging research also suggests a connection with the microbiome (Kao et al., 2016). The link to dietary protein quality is of particular interest from a public health lens; as the authors note, “dietary intake of essential amino acids may be insufficient in children with stunting”. Previous research supports this hypothesis: An analysis of dietary and anthropometric data collected on Ghanaian children aged 2–13 years, found an association between dietary protein inadequacy (adjusting for quality) and risk of being stunted (Ghosh et al., 2010). A meta-analysis of consumption of conventional versus quality protein maize (higher in lysine and tryptophan) showed significantly higher rates of weight and height gain among young children with mild to moderate undernutrition from populations in which maize is the major staple food (Gunaratna et al., 2010). Additionally, an analysis of national food balance sheet data from developing countries found an inverse association between rates of stunting and the per capita availability of “utilizable” protein (adjusted for quality) but not total protein (Ghosh et al., 2012). Finally, the authors conclude, “randomized controlled trials would ultimately be required to determine whether essential amino acids…play a causal role in the pathogenesis of child stunting”. We whole-heartedly agree with this statement and point to some interesting findings emerging from an RCT recently completed in Ghana (Ghosh et al., 2014). This trial examined the effect of adding a protein quality and micronutrient-improved complementary food supplement to the diets of Ghanaian infants from age 6 to 18 months. Results show a dose response effect of receiving the supplement on HAZ scores at 18 months of age (unpublished). Biomarkers of inflammation, micronutrient status, and plasma amino acids were collected as well. We look forward to presenting the findings of this longitudinal analyses in comparison with the cross sectional association of stunting and amino acids as observed by Semba et al. Overall, the findings reported by Semba et al. add to evidence for the link between inadequate protein and amino acid intake and stunting in children. We expect that this important discussion on protein quality continue, in conjunction with newer research on the potential effects of the microbiome, enteric infections and chronic inflammation, in collaborative efforts to combat child stunting.

Plasma homocysteine is cross-sectionally associated with blood pressure in large, community-based studies. It is unknown whether elevated plasma homocysteine predicts hypertension incidence. We investigated the relations of baseline plasma total homocysteine levels to hypertension incidence and blood pressure tracking in 2104 Framingham Heart Study participants (mean age, 57 years; 58% women), who were free of hypertension, myocardial infarction, heart failure, atrial fibrillation, or renal failure at baseline. Baseline mean±SD plasma homocysteine was 10.1±3.7 μmol/L. On follow-up 4 years from baseline, 360 persons (17.1%) had developed hypertension, and 878 persons (41.7%) had progressed to a higher blood pressure stage. In unadjusted analyses, a 1-SD higher log homocysteine value was associated with increased odds of developing hypertension (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.05 to 1.32) and increased odds of blood pressure progression (OR, 1.17; 95% CI, 1.07 to 1.27). The relations of plasma homocysteine to the incidence of hypertension or blood pressure progression were statistically nonsignificant in age- and sex-adjusted logistic regression models (OR, 0.98; 95% CI, 0.87 to 1.11 and OR, 1.05; 95% CI, 0.96 to 1.16, respectively) and in multivariable models adjusted for age, sex, body mass index, diabetes, interim weight change, smoking, serum creatinine, baseline blood pressure, and blood pressure category (OR, 0.92; 95% CI, 0.81 to 1.06 and OR, 1.07; 95% CI, 0.97 to 1.18, respectively). In conclusion, we found no major relation of baseline plasma homocysteine levels to hypertension incidence or longitudinal blood pressure progression in a large, community-based cohort of nonhypertensive individuals after adjustment for age, sex, and other important covariates.

The C677T variant of methylenetetrahydrofolate reductase (MTHFR), a key enzyme in the remethylation of homocysteine to methionine, is a frequent genetic cause of mild hyperhomocysteinemia among individuals with low folate status. However, little is known about the influence of subject characteristics, such as age and sex, on the relation between the C677T MTHFR polymorphism and fasting plasma total homocysteine (tHcy) concentrations. The aim of the present study was to explore the influence of age and gender, together with folate status, on the association between the C677T polymorphism and tHcy concentrations. The C677T genotype was determined for 1820 participants from the fifth examination of the Framingham Offspring Study. Mean age of the participants was 56 y (range 28-82 y). The allelic distribution was not different from the Hardy-Weinberg equilibrium, with a TT frequency comparable in men and women (14%). Geometric mean tHcy was 15% higher in men than in women (P < 0.001), and women had significantly higher plasma folate levels (P < 0.001). Geometric mean tHcy was significantly higher in TT participants (P = 0.001) than in participants with the CC and CT genotypes among those with plasma folate

Although the elevation of circulating total serum homocysteine (tHcy) concentration in a fasting state is associated with an increased risk of occlusive vascular disease in adults, the implications of elevated levels in children are not known. The goals of this study were to describe the distribution of tHcy among a representative sample of children and adolescents in the United States, and to test for differences in tHcy among sex, age and race-ethnicity categories. Using surplus sera from Phase 2 of the third National Health and Nutrition Examination Survey, we measured tHcy for a nationally representative sample of 942 boys and 1085 girls aged 4-19 y. The age-adjusted geometric mean tHcy concentrations were 6.2 and 5.8 micro mol/L in non-Hispanic Caucasian boys and girls, 6.4 and 6.1 micro mol/L in non-Hispanic African-American boys and girls, and 6.4 and 5.5 micro mol/L in Mexican American boys and girls, respectively. A significant interaction between age and sex (P < 0.01) reflected the divergence of tHcy concentrations at about age 10 y, with higher concentrations in boys than in girls throughout adolescence. These first data on homocysteine concentrations in a nationally representative sample of American youth suggest that sexual dimorphism of tHcy concentrations occurs earlier, at approximately 10 y of age, than previously reported on the basis of smaller nonrepresentative samples. Improved understanding of the determinants of levels during growth and development may provide important clues to the etiology of adult disease.

In 1996, the U.S. Food and Drug Administration issued a regulation requiring that all enriched cereal-grain products be fortified with folic acid by January 1998. An average increase in folic acid intake of 100 micro g/d was projected as a result of this fortification. The objective of the present study was to estimate the effect of this fortification on the intake of folic acid and total folate, and on the prevalence of individuals with inadequate folate intake and with high folic acid intake. We used data on food and nutrient intake from 1480 individuals who participated in the 5th and 6th examinations of the Framingham Offspring Cohort Study. Fortification was instituted during the 6th examination so that 931 participants were examined before its implementation (nonexposed) and 549 after implementation (exposed). Published data on total folate in enriched cereal-grain products were used to correct folate content in these foods to reflect fortification. Among nonsupplement users, folic acid intake increased by a mean of 190 [95% confidence interval (CI): 176, 204] micro g/d (P < 0.001) and total folate intake increased by a mean of 323 (95% CI: 296-350) micro g dietary folate equivalents (DFE)/d (P < 0.001) in the exposed participants. Similar increases were seen among supplement users exposed to fortification. The prevalence of exposed individuals with total folate intake below the estimated average requirement (320 micro g DFE/d) decreased from 48.6% (95% CI: 44.2-53.1%) before fortification to 7.0% (95% CI: 3.1-10.9%) after fortification in individuals who did not use folic acid supplements. This prevalence was approximately 1% or less for users of supplements both before and after fortification. Prevalence of individuals with folic acid intake above the upper tolerable intake level (1000 micro g folic acid/d) increased only among supplement users exposed to fortification (from 1.3 to 11.3%, P < 0.001). No changes in folic acid intake were observed over time in the nonexposed participants. By these estimations, folic acid fortification resulted in a mean increase in folic acid intake that was approximately twice as large as previously projected.

Background — A causal role for mildly elevated plasma homocysteine (tHcy) in cardiovascular disease remains undetermined. To address the unresolved issue of the antecedent-consequent directionality of the relationship, we assessed the familial association of tHcy with parental myocardial infarction (MI) in young Israeli men and women. We also compared tHcy concentrations in Jerusalem, where rates of coronary heart disease (CHD) are high, with the United States Third National Health and Examination Survey (NHANES III). Methods and Results — A total of 8646 17-year-olds and 6952 parents were examined from 1976 to 1979 in Jerusalem. At ages 28 to 32 years, offspring of parents who experienced a documented MI during a 10-year follow-up (n=133 men, 62 women; 72% response) and offspring of CHD-free parents (n=389 men, 208 women; 71% response) were reexamined. tHcy levels were determined by the same laboratory for the NHANES non-Hispanic white population aged 25 to 34 years (n=379) and the Jerusalem population sample (n=858). Men from Jerusalem, but not women, had clearly higher tHcy levels than the sample from the United States (90th percentile, 23 versus 14 μmol/L). This difference was largely attributable to lower plasma vitamin B 12 levels in the Israeli population. Male case offspring had higher adjusted tHcy than did controls (1.9 μmol/L, P =0.002). Logistic modeling revealed a graded increase in risk of parental MI across quintiles of offspring tHcy, with an adjusted odds ratio of 2.7 in the 5th quintile ( P =0.0026 for trend). Conclusions — The higher tHcy in young male offspring of parents with CHD suggests that elevated tHcy precedes manifestation of CHD. The elevated population tHcy in men may contribute to the high incidence of CHD in Israel.