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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 evidence that Alzheimer's disease (AD) has significant cerebrovascular etiopathogenesis. Understanding potentially modifiable risk factors for vascular disease can help design long-term intervention strategies for controlling or preventing cognitive dysfunction attributable to cerebrovascular disease. Objective To evaluate the presence and severity of markers of cerebrovascular pathology, its relationship to diagnostic categories of dementia, including AD, and association with the metabolic biomarker homocysteine. Methods In a cross-sectional observational study, 340 community-dwelling elders received a clinical evaluation including brain MRI and neuropsychological tests. Dementia and mild cognitive impairment (MCI) were diagnosed by consensus committee. Fasting total plasma homocysteine was measured. Statistical analyses were adjusted for demographics and cerebrovascular risk factors. Results Nearly 25% of those diagnosed with AD had small vessel infarcts (SVI). Periventricular white matter hyperintensity (pvWMHI) was prevalent in participants with AD (61%) or MCI (amnesic 61% and non-amnesic 54%, respectively). Participants with SVI and/or pvWMHI also had greater brain atrophy. Homocysteine concentrations were higher in individuals with cerebrovascular findings than in those without. In individuals with cerebrovascular disease, homocysteine was inversely related to executive function (p = 0.022) and directly related to degree of brain atrophy (p = 0.009). Conclusions We demonstrated a significant prevalence of small vessel markers of cerebrovascular pathology in individuals diagnosed with AD, with a significant concurrence between cerebrovascular disease and brain and ventricular atrophy. While current research on AD has focused on amyloid-βpeptide deposition, tau-pathology, and microglial activation and inflammation, greater attention to the cerebrovascular contribution to this neurodegenerative disease presents an additional target for therapeutic prevention and intervention.

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.

Flour fortification with folic acid, mandated for the prevention of neural tube defects (NTD), can be regarded as a positive public health intervention especially for women of childbearing age. However, the denial of the possibility of adverse effects related to interaction between high folic acid intake and vitamin B12 deficiency or the possibility that folic acid fortification and/or supplementation may be associated with adverse effects in some elderly racial/genetic subgroups is a major concern that is being overlooked. Denying the existence of these adverse effects will prevent further and more methodological studies to understand the mechanism and risk of adverse effects of adding folic acid in substantial amounts to any nation’s food supply by fortification and/or supplementation.

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.

Background: Senescent changes in brain microvascular circulation may cause or contribute to age-related cognitive decline. Such changes are promoted partly by aging, but also by chronic hypertension, a leading treatable cause of cognitive decline. 13 14 Objectives: We aimed to non-invasively detect in vivo the senescent changes in brain microvascular circulation associated with age and hypertension, and inquired whether decrements driven by aging would be exacerbated by chronic hypertension. 15 16 Methods: In this longitudinal study, absolute near infrared spectroscopy (NIRS) was used to quantify in vivo cerebral blood volume (CBV) and assess the hemodynamic response to a hypercapnic respiratory challenge in normotensive Wistar-Kyoto (WKY) and spontaneous-hypertensive (SHR) rats. The impact of age and hypertension were evaluated by repeating these measurements on the same animals at 4- and 16-months of age. 17 18 19 20 Results: CBV decreased markedly with age in both strains, from 4.5 ± 0.2 to 2.6 ± 0.1 ml/100g tissue, on average. Chronic hypertension, however, did not significantly exacerbate this age-related decrease in CBV (−48.1 ± 3.7% in WKYs versus −53.3 ± 5.4% in SHRs). In contrast, vasoreactivity was already impaired in the young hypertensive rats (� VMR 0.017 ± 0.014 in young SHRs versus 0.042 ± 0.005 in young WKYs) and further worsened by middle-age (� VMR 0.011 ± 0.017 middle-aged SHRs). 21 22 23 24 25 Conclusion: Whereas a decrease in brain blood volume correlated with age but not hypertension, vasodilatory capacity was diminished due to hypertension but did not appear affected by age alone. The ability of absolute NIRS to distinguish between such senescent changes in brain (micro)vascular circulation in life may allow early detection and intervention to preserve cerebrovascular health with age. 26 27 28 29

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.

In the 1930s, Lucy Wills identified a ‘new hemopoietic factor’ in yeast and liver which cured tropical macrocytic anemia in humans and experimental anemia in monkeys. Janet Watson and William B. Castle named the unknown substance, which would ultimately become a form of folate, ‘Wills’ factor’. Further studies with this unknown substance showed that it was active against nutritional pancytopenia in monkeys and experimental anemia in chicks, leading to various designations such as vitamin M (monkey) and vitamin Bc (chick). Other factors with growth-promoting activity for microorganisms such as Lactobacillus casei were given the interim names including folic acid – in recognition of extracts from leafy greens. Competing pharmaceutical research groups headed by Robert Stokstad at Lederle Laboratories and Joseph John Pfiffner at Parke-Davis Research Laboratory independently isolated factors bearing the biological properties of Wills’ factor and other unknown related factors including folic acid, Lederle Laboratories from a bacterial culture and Parke-Davis Laboratory from yeast and liver as a conjugate of folate. The new vitamin then was crystallized, chemically identified, and synthesized as pteroylglutamic acid and named folic acid between 1943 and 1945. Further studies of the monoglutamic folic acid and the yeast isolate polyglutamyl folate followed through the 1950s and to the present.

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.

"The existence of chemical individuality follows of necessity from that of chemical specificity, but we should expect the differences between individuals to be still more subtle and difficult of detection. Indications of their existence are seen, even in man,... in the quantitative differences in those portions of the end products of metabolism which are endogenous and are not affected by diet.... Even those idiosyncracies with regard to... articles of food which are summed up in the proverbial saying that what is one's man meat is another man's poison, presumably have a chemical basis."

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.

This article reviews the role of nutrition in Crohn's disease, one of the inflammatory bowel diseases. In addition to presenting a comprehensive review of the state-of-the-evidence on nutritional risks and nutritional therapies in Crohn's disease, and making specific nutrient recommendations, this article includes a list of Web-based resources, including websites, blogs, newsletters, and multimedia podcasts that can be utilized by patients and healthcare providers alike to learn more about the etiology, pathophysiology, and nutritional management of Crohn's disease.

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.