Folic acid supplementation in a mouse model of diabetes in pregnancy alters insulin sensitivity in female mice and beta cell mass in offspring.

Epidemiological studies have reported discrepant findings on the relationship between folic acid intake during pregnancy and risk for gestational diabetes mellitus (GDM). To begin to understand how folic acid impacts metabolic health during pregnancy, we determined the effects of excess folic acid supplementation (5× recommendation) on maternal and fetal offspring metabolic health. Using a mouse (female C57BL/6J) model of diet-induced diabetes in pregnancy (western diet) and control mice, we show that folic acid supplementation improved insulin sensitivity in the female mice fed the western diet and worsened insulin sensitivity in control mice. We found no unmetabolized folic acid in liver from supplemented mice suggesting the metabolic effects of folic acid supplementation are not due to unmetabolized folic acid. Male fetal (gestational day 18.5) offspring from folic acid supplemented dams (western and control) had greater beta cell mass and density than those from unsupplemented dams; this was not observed in female offspring. Differential sex-specific hepatic gene expression profiles were observed in the fetal offspring from supplemented dams but this differed between western and controls. Our findings suggest that folic acid supplementation affects insulin sensitivity in female mice, but is dependent on their metabolic phenotype and has sex-specific effects on offspring pancreas and liver.

Supplementation with (6S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada.

Folic acid supplementation is recommended during pregnancy to support healthy fetal development; (6S)-5-methyltetrahydrofolic acid ((6S)-5-MTHF) is available in some commercial prenatal vitamins as an alternative to folic acid, but its effect on blood folate status during pregnancy is unknown. To address this, we randomised sixty pregnant individuals at 8-21 weeks' gestation to 0·6 mg/d folic acid or (6S)-5-MTHF × 16 weeks. Fasting blood specimens were collected at baseline and after 16 weeks (endline). Erythrocyte and serum folate were quantified via microbiological assay (as globally recommended) and plasma unmetabolised folic acid (UMFA) via LC-MS/MS. Differences in biochemical folate markers between groups were explored using multivariable linear/quantile regression, adjusting for baseline concentrations, dietary folate intake and gestational weeks. At endline (n 54), the mean values and standard deviations (or median, inter-quartile range) of erythrocyte folate, serum folate and plasma UMFA (nmol/l) in those supplemented with (6S)-5-MTHF v. folic acid, respectively, were 1826 (sd 471) and 1998 (sd 421); 70 (sd 13) and 78 (sd 17); 0·5 (0·4, 0·8) and 1·3 (0·9, 2·1). In regression analyses, erythrocyte and serum folate did not differ by treatment group; however, concentrations of plasma UMFA in pregnancy were 0·6 nmol/l higher (95 % CI 0·2, 1·1) in those supplementing with folic acid as compared with (6S)-5-MTHF. In conclusion, supplementation with (6S)-5-MTHF may reduce plasma UMFA by ∼50 % as compared with supplementation with folic acid, the biological relevance of which is unclear. As folate is currently available for purchase in both forms, the impact of circulating maternal UMFA on perinatal outcomes needs to be determined.

Maternal nutrition and effects on offspring vascular function.

Maternal nutrition during pregnancy may have profound effects on the developing fetus and impact risk for cardiovascular disease later in life. Here, we provide a narrative review on the impact of maternal diet during pregnancy on offspring vascular function. We review studies reporting effects of maternal micronutrient (folic acid, iron) intakes, high-fat diets, dietary energy restriction, and low protein intake on offspring endothelial function. We discuss the differences in study design and outcomes and potential underlying mechanisms contributing to the vascular phenotypes observed in the offspring. We further highlight key gaps in the literature and identify targets for future investigations.

In Situ Observation of Solvent Exchange Kinetics in a MOF with Coordinatively Unsaturated Sites.

Solvent exchange of synthesis solvent within metal-organic frameworks (MOFs) is an essential process for the activation of coordinatively unsaturated sites (CUS) to achieve an optimal surface area; activation of the CUS is required to exploit the versatile applications of MOFs. However, it is challenging to replace CUS-bound synthesis solvent prior to MOF activation, which can lead to a structural collapse and reduced surface area post-evacuation. Herein, we quantify the exchange behavior of a copper paddlewheel-based CUS-MOF (HKUST-1) in the presence of three different solvents: ethanol (EtOH), dichloromethane (DCM), and N,N-dimethylformamide (DMF). The DMF release profiles are monitored via in situ observation of the exchange solvent composition via 1H NMR and Raman spectroscopy at the macroscopic scale. Furthermore, the change in solvent within a single crystal is measured to directly elucidate the exchange behavior. We demonstrate the DMF release profile from HKUST-1 exhibits different rate laws depending on whether the solvent exchange occurs at the CUS or is purely diffusive through the pores. This contribution represents the first characterization of release from a CUS-MOF as a function exchange solvent and reveals that solvent exchange in a CUS-MOF is not diffusion-limited, but rather is limited by the solvent exchange kinetics at the metal center. Insights from this study can be generalized to the variety of copper-paddlewheel-based MOFs, informing best practices for solvent exchange.

Children Aged 5-6 Years in Vancouver, Canada Meet Dietary Recommendations for Folate and Vitamin B12 but not Choline.

BACKGROUND: Choline, folate, and vitamin B12 are required for growth and development, but there is limited information on the intakes and relationships to biomarkers of status in children. OBJECTIVES: The objective of this study was to determine the choline and B-vitamin intakes and relationship to biomarkers of status in children. METHODS: A cross-sectional study was conducted in children (n = 285, aged 5-6 y) recruited from Metro Vancouver, Canada. Dietary information was collected by using 3 24-h recalls. Nutrient intakes were estimated by using the Canadian Nutrient File and United States Department of Agriculture database for choline. Supplement information was collected by using questionnaires. Plasma biomarkers were quantified by using mass spectrometry and commercial immunoassays, and relationships to dietary and supplement intake were determined by using linear models. RESULTS: Daily dietary intakes of choline, folate, and vitamin B12 were [mean (SD)] 249 (94.3) mg, 330 (120) DFE µg, and 3.60 (1.54) µg, respectively. Top food sources of choline and vitamin B12 were dairy, meats, and eggs (63%-84%) and for folate, were grains, fruits, and vegetables (67%). More than half of the children (60%) were consuming a supplement containing B-vitamins, but not choline. Only 40% of children met the choline adequate intake (AI) recommendation for North America (≥250 mg/d); 82% met the European AI (≥170 mg/d). Less than 3% of children had inadequate folate and vitamin B12 total intakes. Some children (5%) had total folic acid intakes above the North American tolerable upper intake level (UL; >400 µg/d); 10% had intakes above the European UL (>300 µg/d). Dietary choline intake was positively associated with plasma dimethylglycine, and total vitamin B12 intake was positively associated with plasma B12 (adjusted models; P < 0.001). CONCLUSIONS: These findings suggest that many children are not meeting the dietary choline recommendations, and some children may have excessive folic acid intakes. The impact of imbalanced one-carbon nutrient intakes during this active period of growth and development requires further investigation.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Thermoneutral Housing and a Western Diet Combination Exacerbates Dysferlin-Deficient Muscular Dystrophy.

INTRODUCTION/AIMS: Most mouse models of muscular dystrophy (MD) show mild phenotypes, which limits the translatability of experimental therapies to patients. A growing body of evidence suggests that MD is accompanied by metabolic abnormalities that could potentially exacerbate the primary muscle wasting process. Since thermoneutral (TN) housing of mice (~30°C) has been shown to affect many metabolic parameters, particularly when combined with a Western diet (WD), our aim was to determine whether the combination of TN and WD exacerbates muscle wasting in dysferlin-deficient BLAJ mice, a common model of limb-girdle MD type 2b (LGMD2b). METHODS: The 2-mo-old wild-type (WT) and BLAJ mice were housed at TN or room temperature (RT) and fed a WD or regular chow for 9 mo. Ambulatory function, muscle histology, and protein immunoblots of skeletal muscle were assessed. RESULTS: BLAJ mice at RT and fed a chow diet showed normal ambulation function similar to WT mice, whereas 90% of BLAJ mice under WD and TN combination showed ambulatory dysfunction (p < 0.001), and an up to 4.1-fold increase in quadriceps and gastrocnemius fat infiltration. Western blotting revealed decreased autophagy marker microtubules-associated protein 1 light chain 3-B (LC3BII/LC3BI) ratio and up-regulation of protein kinase B/AKT and ribosomal protein S6 phosphorylation, suggesting inefficient cellular debris and protein clearance in TN BLAJ mice fed a WD. Male and female BLAJ mice under TN and WD combination showed heterogenous fibro-fatty infiltrate composition. DISCUSSION: TN and WD combination exacerbates rodent LGMD2b without affecting WT mice. This improves rodent modeling of human MD and helps elucidate how metabolic abnormalities may play a causal role in muscle wasting.

Sex-specific effects of neonatal oral sucrose treatment on growth and liver choline and glucocorticoid metabolism in adulthood.

Hospitalized preterm infants experience painful medical procedures. Oral sucrose is the nonpharmacological standard of care for minor procedural pain relief. Infants are treated with numerous doses of sucrose, raising concerns about potential long-term effects. The objective of this study was to determine the long-term effects of neonatal oral sucrose treatment on growth and liver metabolism in a mouse model. Neonatal female and male mice were randomly assigned to one of two oral treatments (n = 7-10 mice/group/sex): sterile water or sucrose. Pups were treated 10 times/day for the first 6 days of life with 0.2 mg/g body wt of respective treatments (24% solution; 1-4 µL/dose) to mimic what is given to preterm infants. Mice were weaned at age 3 wk onto a control diet and fed until age 16 wk. Sucrose-treated female and male mice gained less weight during the treatment period and were smaller at weaning than water-treated mice (P ≤ 0.05); no effect of sucrose treatment on body weight was observed at adulthood. However, adult sucrose-treated female mice had smaller tibias and lower serum insulin-like growth factor-1 than adult water-treated female mice (P ≤ 0.05); these effects were not observed in males. Lower liver S-adenosylmethionine, phosphocholine, and glycerophosphocholine were observed in adult sucrose-treated compared with water-treated female and male mice (P ≤ 0.05). Sucrose-treated female, but not male, mice had lower liver free choline and higher liver betaine compared with water-treated female mice (P < 0.01). Our findings suggest that repeated neonatal sucrose treatment has long-term sex-specific effects on growth and liver methionine and choline metabolism.

Greater Arterial Stiffness in Children with or without Second-generation Antipsychotic Treatment for Mental Health Disorders: Rigidité Artérielle Plus Importante Chez Les Enfants Avec ou Sans Traitement Par Antipsychotiques de la Deuxième Génération Pour des Troubles de Santé Mentale.

OBJECTIVE: Second-generation antipsychotics (SGAs) are used for a variety of mental disorders and are associated with cardiometabolic side effects in children. The objective of this study was to assess the cardiovascular health of children with mental disorders that are SGA-treated or SGA-naive. METHODS: SGA-treated (n = 47) or SGA-naive (n = 37) children (aged 6 to 18 years) with mental disorders and control children (n = 83, no mental disorder) underwent assessment for cardiac function and morphology by echocardiography, aortic pulse wave velocity (PWV), and carotid intima-media thickness (cIMT). Body mass index (BMI) z-scores, waist circumference z-scores, systolic and diastolic blood pressure (BP) percentiles for height and sex, and fasting plasma glucose, insulin, triglycerides, and cholesterol were also assessed. Differences between SGA-treated, SGA-naive, and control children were assessed by linear and log-linear regression models. RESULTS: SGA-treated children had greater BMI z-scores and overweight/obesity (BMI ≥ 85th percentile for age and sex) and hypertension than SGA-naive and control children. The PWV geometric mean was 11.1% higher in SGA-treated (95%CI, 3.95 to 18.77) and 12.9% higher in SGA-naive children (95% CI, 5.60 to 20.59) compared to controls in models adjusted for age, sex, BMI, and systolic BP percentile. Left ventricular (LV) end-diastolic dimension/body surface area (BSA), LV end-systolic dimension/BSA, and LV ejection fraction were lower in SGA-treated and SGA-naive children compared to controls in models adjusted for sex and age. CONCLUSIONS: Children with mental disorders have greater arterial stiffness and altered cardiac structure/function than children with no mental health diagnosis. SGA treatment in children is not associated with alterations in cardiovascular structure/function.

Biomarkers of Docosahexaenoic Acid but Not Arachidonic Acid Reflect Dietary Intakes in Toddlers at Ages 1 and 2 Years Who Are Not Meeting Dietary Recommendations.

BACKGROUND: Long-chain n-6 and n-3 PUFAs are important for growth and development. However, little is known about requirements and current dietary intakes of these fatty acids in toddlers. OBJECTIVES: This study assessed dietary intakes of n-6 and n-3 PUFAs and determined the relation to circulating PUFAs in toddlers at ages 1 and 2 y. METHODS: This is a secondary analysis of data from toddlers enrolled in a double-blind randomized controlled trial of arachidonic acid (ARA) and DHA supplementation between ages 1 and 2 y. Dietary intakes of fatty acids were estimated by 3-d food records, and fatty acid composition in plasma total phospholipids, red blood cell phosphatidylethanolamine (PE), and phosphatidylcholine (PC) were assessed by GC at baseline in all subjects (n = 110; mean age 1.12 y; 64% male) and in the control subjects at 2 y (n = 43). RESULTS: The dietary intakes of ARA, EPA, and DHA at age 1 y (baseline) were [mean (median)] 36.8 (30.0), 16.0 (0.00), and 31.1 (10.0) mg/d, respectively. Dietary intakes increased to 52.7 (45.0), 35.8 (0.00), and 64.8 (20.0) mg/d, respectively, at age 2 y (P < 0.05). The predominant dietary source of EPA and DHA was fish/seafood; eggs were an important source of ARA and DHA. Dietary DHA intakes were positively associated with plasma PE and PC DHA (P < 0.05). No relations between dietary ARA intakes and plasma PE and PC ARA (P > 0.05) were observed. CONCLUSIONS: These findings suggest that most toddlers are not meeting the recommendation for dietary PUFA intakes and that higher dietary DHA intakes are reflected in plasma PE and PC DHA composition. Further work is required to investigate a biomarker for dietary ARA intake. This trial is registered at clinicaltrials.gov as NCT01263912.

Ambulatory blood pressure and carotid intima media thickness in children with type 1 diabetes.

BACKGROUND/OBJECTIVE: Blood pressure abnormalities may play an important role in macrovascular damage in type 1 diabetes. Little is known about blood pressure abnormalities and macrovascular damage in children with type 1 diabetes. METHODS: Children with type 1 diabetes (n = 57) for a short (3 months-2 years; n = 24) or long duration (≥5 years; n = 33) and a group of control children without diabetes (n = 29) completed 24-h ambulatory blood pressure monitoring (ABPM). Carotid intima media thickness (cIMT), a subclinical indicator of atherosclerosis, was assessed by carotid ultrasound. RESULTS: ABPM abnormalities were more prevalent (57% vs 24%, respectively), and daytime, nighttime and 24-h systolic, diastolic, and mean arterial blood pressure indices were higher in children with type 1 diabetes compared to control children. The odds estimate of an ABPM abnormality was 6.68 (95% confidence interval: 1.95, 22.9; P = .003) in children with type 1 diabetes compared to controls after adjusting for age, sex, and BMI standardized for age and sex (zBMI). An interaction between ABPM and zBMI on cIMT was observed. In children with type 1 diabetes and ABPM abnormalities, every 1 SD increase in zBMI was associated with a 0.030 mm increase in cIMT (95% confidence interval: 0.002, 0.041; P = .031). This was not observed in control children with ABPM abnormalities or in children with normal ABPM, regardless of type 1 diabetes status. CONCLUSIONS: Children with type 1 diabetes have a high prevalence of ABPM abnormalities independent of disease duration and this is related to early indicators of cardiovascular damage.

Suboptimal Biochemical Riboflavin Status Is Associated with Lower Hemoglobin and Higher Rates of Anemia in a Sample of Canadian and Malaysian Women of Reproductive Age.

BACKGROUND: Riboflavin is required for several redox reactions. Clinical riboflavin deficiency occurs mainly in low-income countries, where it is associated with anemia. The functional significance of suboptimal riboflavin status in different populations and its role in anemia is not well understood. OBJECTIVES: We assessed the biomarker status of riboflavin and its association with hemoglobin concentration and anemia in women living in Vancouver, Canada, and Kuala Lumpur, Malaysia. METHODS: Healthy nonpregnant, nonbreastfeeding women (19-45 y) were recruited from Canada ( n = 206) and Malaysia (n = 210) via convenience sampling. Fasting blood was collected to assess riboflavin status [erythrocyte glutathione reductase activity coefficient (EGRac)], hematological indicators, soluble transferrin receptor (sTfR), ferritin, vitamin A, folate, and vitamin B-12 concentrations. Linear and logistic regression models were used to assess the association of riboflavin status with hemoglobin concentration and anemia. RESULTS: EGRac (mean ± SD) values were higher, indicating poorer riboflavin status, in Malaysian compared with Canadian women (1.49 ± 0.17 compared with 1.38 ± 0.11). Likewise, riboflavin biomarker deficiency (EGRac ≥1.40) was significantly more prevalent among Malaysians than Canadians (71% compared with 40%). More Malaysian than Canadian women were anemic (hemoglobin <120 g/L; 18% compared with 7%). With use of linear regression (pooled sample; n = 416), EGRac values were negatively associated with hemoglobin concentration (r = -0.18; P < 0.001). This relation remained significant (P = 0.029) after adjusting for age, parity, ethnicity, vitamin B-12, folate, sTfR, ferritin, and vitamin A. Women with riboflavin deficiency (EGRac ≥1.40) were twice as likely to present with anemia (adjusted OR: 2.38; 95% CI: 1.08, 5.27) compared with women with EGRac <1.40. CONCLUSIONS: Biochemical riboflavin deficiency was observed in Canadian and Malaysian women, with higher rates of deficiency among Malaysian women. Deficient biomarker status of riboflavin was a weak but significant predictor of hemoglobin and anemia, suggesting that the correction of riboflavin deficiency may potentially play a small protective role in anemia, but this requires further investigation.

Maternal folic acid supplementation with vitamin B12 deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet.

Epidemiologic studies have reported relationships between maternal high folate and/or low B12 status during pregnancy and greater adiposity and insulin resistance in children. The goal of this study was to determine the effects of maternal folic acid supplementation (10 mg/kg diet), with (50 µg/kg diet) and without B12, on adult female offspring adiposity and glucose homeostasis. Female C57BL/6J mice were fed 1 of 3 diets from weaning and throughout breeding, pregnancy, and lactation: control (2 mg/kg diet folic acid, 50 µg/kg diet B12), supplemental folic acid with no B12 (SFA-B12), or supplemental folic acid with adequate B12 (SFA+B12). Female offspring were weaned onto the control diet or a Western diet (45% energy fat, 2 mg/kg diet folic acid, 50 µg/kg diet B12) for 35 wk. After weaning, control diet-fed offspring with SFA-B12 dams had fasting hyperglycemia, glucose intolerance, lower ß cell mass, and greater islet hepatocyte nuclear factor 1 homeobox α and nuclear receptor subfamily 1 group H member 3 mRNA than did offspring from control dams. In Western diet-fed offspring, those with SFA-B12 dams had lower fasting blood glucose and plasma insulin concentrations, and were smaller than control offspring. Our findings suggest that maternal folic acid supplementation with B12 deficiency during pregnancy/lactation programs the metabolic health of adult female offspring but is dependent on offspring diet.-Henderson, A. M., Tai, D. C., Aleliunas, R. E., Aljaadi, A. M., Glier, M. B., Xu, E. E., Miller, J. W., Verchere, C. B., Green, T. J., Devlin, A. M. Maternal folic acid supplementation with vitamin B12 deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet.

Plasma Betaine Is Positively Associated with Developmental Outcomes in Healthy Toddlers at Age 2 Years Who Are Not Meeting the Recommended Adequate Intake for Dietary Choline.

Background: Choline is an important nutrient during development. However, there are limited data on dietary choline intake and status in toddlers and the relation to neurodevelopmental outcomes. Objective: This study assessed dietary choline intake and status in healthy toddlers at ages 1 and 2 y and determined the relation to neurodevelopmental outcomes. Methods: This is a secondary analysis of data from healthy toddlers enrolled in a double-blind, randomized controlled trial of long-chain polyunsaturated fatty acid supplementation between ages 1 and 2 y. Dietary intakes of betaine and choline were estimated by 3-d food records; plasma free choline, betaine, and dimethylglycine were quantified by liquid chromatography-tandem mass spectrometry. Developmental outcomes were assessed at age 2 y with the use of the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), Cognitive and Language composites, and the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI). Results: The mean ± SD daily intake for total choline at age 1 y was 174 ± 56.2 mg/d and increased (P < 0.001) to 205 ± 67.5 mg/d at age 2 y. At ages 1 and 2 y, 71.8% and 55.8%, respectively, of toddlers did not meet the recommended 200-mg/d Adequate Intake (AI) for dietary choline. At age 1 y, mean ± SD plasma free choline, betaine, and dimethylglycine concentrations were 10.4 ± 3.3, 41.1 ± 15.4, and 4.1 ± 1.9 µmol/L, respectively. Plasma free choline (8.5 ± 2.3 µmol/L) and dimethylglycine (3.2 ± 1.3 µmol/L) concentrations were lower (P < 0.001) at age 2 y. Plasma betaine concentrations were positively associated with the Beery-VMI (ß = 0.270; 95% CI: 0.026, 0.513; P = 0.03) at age 2 y. Conclusions: These findings suggest that most toddlers are not meeting the recommended AI for dietary choline and that higher plasma betaine concentrations are associated with better visual-motor development at age 2 y. Further work is required to investigate choline metabolism and its role in neurodevelopment in toddlers. The trial is registered at clinicaltrials.gov as NCT01263912.

l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women.

Background: Folic acid fortification of grains is mandated in many countries to prevent neural tube defects. Concerns regarding excessive intakes of folic acid have been raised. A synthetic analog of the circulating form of folate, l-5-methyltetrahydrofolate (l-5-MTHF), may be a potential alternative. Objective: The objective of this study was to determine the effects of folic acid or l-5-MTHF supplementation on blood folate concentrations, methyl nutrient metabolites, and DNA methylation in women living in Malaysia, where there is no mandatory fortification policy. Methods: In a 12-wk, randomized, placebo-controlled intervention trial, healthy Malaysian women (n = 142, aged 20-45 y) were randomly assigned to receive 1 of the following supplements daily: 1 mg (2.27 µmol) folic acid, 1.13 mg (2.27 µmol) l-5-MTHF, or a placebo. The primary outcomes were plasma and RBC folate and vitamin B-12 concentrations. Secondary outcomes included plasma total homocysteine, total cysteine, methionine, betaine, and choline concentrations and monocyte long interspersed nuclear element-1 (LINE-1) methylation. Results: The folic acid and l-5-MTHF groups had higher (P < 0.001) RBC folate (mean ± SD: 1498 ± 580 and 1951 ± 496 nmol/L, respectively) and plasma folate [median (25th, 75th percentiles): 40.1 nmol/L (24.9, 52.7 nmol/L) and 52.0 nmol/L (42.7, 73.1 nmol/L), respectively] concentrations compared with RBC folate (958 ± 345 nmol/L) and plasma folate [12.6 nmol/L (8.80, 17.0 nmol/L)] concentrations in the placebo group at 12 wk. The l-5-MTHF group had higher RBC folate (1951 ± 496 nmol/L; P = 0.003) and plasma folate [52.0 nmol/L (42.7, 73.1 nmol/L); P = 0.023] at 12 wk than did the folic acid group [RBC folate, 1498 ± 580 nmol/L; plasma folate, 40.1 nmol/L (24.9, 52.7 nmol/L)]. The folic acid and l-5-MTHF groups had 17% and 15%, respectively, lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk; there were no differences between the folic acid and l-5-MTHF groups. No differences in plasma vitamin B-12, total cysteine, methionine, betaine, and choline and monocyte LINE-1 methylation were observed. Conclusion: These findings suggest differential effects of l-5-MTHF compared with folic acid supplementation on blood folate concentrations but no differences on plasma total homocysteine lowering in Malaysian women. This trial was registered at clinicaltrials.gov as NCT01584050.

Risperidone But Not Quetiapine Treatment Is Associated With Increased Appetite But Not Satiety Hormones in Children During An Oral Glucose Tolerance Test: A Pilot Study.

BACKGROUND: Second-generation antipsychotics (SGAs) are commonly used to treat children with mental health conditions (MHCs) but are associated with adverse effects including obesity, hypertension, dyslipidemia, and type 2 diabetes. The mechanisms underlying these complications are unknown, but it has been suggested that SGAs increase appetite leading to weight gain. The present objective was to perform a pilot study to investigate appetite and satiety hormones in SGA-treated (risperidone or quetiapine) and SGA-naive children with similar mental health conditions. METHODS: Oral glucose tolerance tests (OGTTs) were conducted in SGA-naive (n = 18), risperidone-treated (n = 20), and quetiapine-treated (n = 16) children recruited from the British Columbia Children's Hospital Psychiatry Department. Over 5 time-points during the OGTT, appetite questionnaires using a visual analogue scale were administered, and blood was collected to measure ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, glucagon-like protein 1, leptin, and adiponectin. Mixed model analyses were conducted to examine between-group differences. RESULTS: The children were similar in age, psychiatric diagnosis, and global assessment of functioning scores. Body mass index z-scores were also similar between groups. Appetite was increased during the OGTT in the risperidone-treated compared with the SGA-naive group for 2 questions ("How strong is your desire to eat"; P = 0.003 and "How much food do you think you can eat"; P = 0.028). No differences in satiety hormones were observed between the 3 groups. CONCLUSIONS: Risperidone treatment in youth is associated with elevated appetite during an OGTT, with no differences in gut peptides or adipocytokines to explain risperidone's effect on appetite. Further research is needed to explore other mediators of weight gain and metabolic dysfunction in SGA-treated youth.

Children's stress regulation mediates the association between prenatal maternal mood and child executive functions for boys, but not girls.

Prenatal exposure to maternal mood disturbances shapes children's cognitive development reflected in the critical construct of executive functions (EFs). Little is known, however, about underlying mechanisms. By examining cortisol responses in both everyday and lab challenge settings, we tested whether the child/offspring hypothalamic-pituitary-adrenal axis mediates effects of prenatal maternal mood on child EFs at age 6. In 107 Canadian children born to women with a wide range of anxious and depressive symptoms during pregnancy, we found that in boys but not girls, depressed and/or anxious prenatal maternal mood is associated with heightened diurnal cortisol levels in everyday settings, as well as heightened cortisol reactivity to a lab challenge and that this heightened reactivity was associated with poorer EFs. Among boys we also observed that cortisol reactivity but not diurnal cortisol mediated the association between depressed and/or anxious prenatal maternal mood and EFs. Depressed and/or anxious prenatal maternal mood was related to child EFs for both girls and boys. To our knowledge, this is the first study to demonstrate a mediating role for child stress regulation in the association between prenatal maternal stress-related mood disturbances and child EFs, providing evidence of a mechanism contributing to fetal programming of cognition.

Serum Soluble Transferrin Receptor Concentrations Are Elevated in Congolese Children with Glucose-6-Phosphate Dehydrogenase Variants, but Not Sickle Cell Variants or α-Thalassemia.

Background: Anemia is common in Congolese children, and inherited blood disorders may be a contributing cause. The presence of sickle cell variants, X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency and α-thalassemia, has been previously reported. G6PD A- deficiency is characterized by the co-inheritance of G6PD 376 and 202 variants and is common in sub-Saharan Africa.Objective: We aimed to measure the associations between inherited blood disorders and hemoglobin, ferritin, and soluble transferrin receptor (sTfR) concentrations in Congolese children.Methods: Venous blood was collected from 744 children aged 6-59 mo from 2 provinces. We measured biomarkers of nutritional and inflammation status and malaria. Pyrosequencing was used to detect sickle cell variants. Polymerase chain reaction was used to detect G6PD variants and α-thalassemia deletions.Results: Overall, 11% of children had a sickle cell variant, 19% of boys were G6PD A- hemizygotes, 12% and 10% of girls were G6PD A- hetero- or homozygotes, respectively, and 12% of children had α-thalassemia. Multivariable linear regression models (adjusted for age, province, altitude, malaria, and biomarkers of nutritional and inflammation status) showed that G6PD A- hemizygous boys and G6PD 376 homozygous girls had higher sTfR concentrations [geometric mean ratios (95% CIs): 1.20 (1.03, 1.39) and 1.25 (1.02, 1.53), respectively] than children with no G6PD variants. Hemoglobin and ferritin concentrations were not independently associated with any of the inherited blood disorder genotypes.Conclusions: We found that 2 G6PD variant genotypes were associated with elevated sTfR concentrations, which limits the accuracy of sTfR as a biomarker of iron status in this population.

Obesity and arterial stiffness in children: systematic review and meta-analysis.

OBJECTIVE: Childhood obesity is associated with risk factors for cardiovascular disease. Arterial stiffness is considered one of the earliest detectable measures of vascular damage. There is controversy in the literature regarding the effects of childhood obesity on arterial stiffness. The objective of this study is to systematically review the literature and to conduct a meta-analysis comparing measures of central arterial stiffness in children and adolescents with obesity to healthy body mass index controls. APPROACH AND RESULTS: Literature searches were conducted using databases (eg, MEDLINE, EMBASE) and citations cross-referenced. Studies assessing central pulse wave velocity or ß-stiffness index were included. A random effects meta-analysis of the standardized mean difference and 95% confidence intervals in arterial stiffness between children with obesity and control children was performed for each arterial stiffness measure. A total of 523 studies were identified. Fifteen case-control studies were included, with 2237 children/adolescents (1281 with obesity, 956 healthy body mass index controls) between 5 and 24 years of age. All studies measuring carotid and aortic ß-stiffness index and 10/12 studies measuring central pulse wave velocity reported greater arterial stiffness in children/adolescents with obesity compared with controls. A random effects meta-analysis was performed revealing a significant effect of obesity on pulse wave velocity (standardized mean difference=0.718; 95% confidence interval=0.291-1.415), carotid ß-stiffness index (0.862; 0.323-1.402), and aortic ß stiffness index (1.017; 0.419-1.615). CONCLUSION: These findings indicate that child/adolescent obesity is associated with greater arterial stiffness. However, further research is needed to address confounders, such as pubertal status, that may affect this relationship in children. In the future, these techniques may be useful in risk stratification and guiding clinical management of obese children to optimize cardiovascular outcomes.

Sculpting infant soothability: the role of prenatal SSRI antidepressant exposure and neonatal SLC6A4 methylation status.

The role of prenatal Selective Serotonin Reuptake Inhibitor (SSRI) exposure and SLC6A4 promoter methylation status in shaping soothability at 3 and 6 months of age, for infants exposed to antidepressant medication prenatally (n = 46) and those not exposed (n = 69) was investigated. SSRI exposure status and duration of exposure (number of days) were examined along with neonatal methylation status at mean CpG 9,10 and via factor analysis across 10 CpG sites yielding PC1 (CpGs sites: 3,4,5,7) and PC2 (CpG 1,8). Analyses revealed interactions for methylation markers and SSRI exposure variables. A significant interaction between SSRI exposure and mean SLC6A4 methylation at CpG 9,10 and separately for PC1 emerged, controlling for multiple birth/medical and background covariates (e.g., Apgar scores, maternal education). Increased neonatal methylation status was associated with increased soothability changes from 3 to 6 months among infants prenatally exposed to SSRIs.