Red Cell Folate Research Articles

Perfluoroalkyl Substances (PFAS) and Red Blood Cell Folate Levels in the U.S. Adult Population, NHANES

BACKGROUND AND AIM: Adequate folate is essential for many physiological processes, and low folate levels have been associated with cardiovascular disease, anemia, and various health outcomes, including developmental outcomes in relation to low folate status during pregnancy. On the other hand, perfluoroalkyl substance (PFAS) have been associated with multiple health outcomes, with scarce data on the mechanistic pathways by which these substances exert their effects. Our objective is to investigate the individual and joint associations of a mixture of PFAS with red blood cell (RBC) folate concentrations in the adult U.S. population. METHODS: We assessed associations of five chemical biomarkers of 8961 participants ages 18-80 from the U.S. National Health and Nutrition Examination Survey (2007-2016). RBC folate were quantified using a micro bioassay and mass spectrometry. We estimated covariate-adjusted independent and joint associations between PFAS and RBC folate concentrations and triangulated evidence from three approaches developed to examine chemical mixtures: Exposome Wide Association (ExWAS), Bayesian Kernel Regression (BKMR), and Quantile G-Computation (QgComp). We additionally evaluated potential effect modification by sex. RESULTS:The geometric mean RBC folate was 468 µg/L (geometric standard deviation: 1.5 µg/L). In ExWAS analyses, all PFAS were associated with lower RBC folate concentrations. For instance, a twofold increase in Perfluorononanoic acid was associated with a 10% (95% CI: 9%, 11%) decrease in RBC folate concentrations. BKMR and QgComp showed convergent results with a one quartile increase in the PFAS mixture associated with comparable decreases in RBC folate concentrations. Associations did not differ between males and females. CONCLUSIONS:This study is the first to examine the associations between PFAS and RBC folate concentrations in a nationally representative sample. These results may deepen our understanding of the mechanistic pathways by which PFAS impact health outcomes. KEYWORDS: PFAS,Folate,Methods,BKMR,ExWAS,G-Computation

Effects of Folate and Vitamin B12 Nutritional Status on Cognitive Function in Bangladeshi Adolescents

BACKGROUND AND AIM: Deficiencies in folate and vitamin B12 are widespread in Bangladesh. These micronutrients are essential for the synthesis of neurotransmitters and myelin, and for one-carbon metabolism, which supports synthesis of proteins and nucleotides during periods of rapid growth. Micronutrient deficiency has been associated with poorer cognitive function in adults and children, but this association has not been fully characterized in adolescents. This study aims to examine associations between the predictors of red blood cell (RBC) folate, plasma folate, and plasma B12, and the outcome of cognitive function in Bangladeshi adolescents. METHODS: The Metals, Arsenic, & Nutrition in Adolescents Study (MANAS) is a cross-sectional study of 572 Bangladeshi adolescents aged 14-16 years. Venous blood was collected for measurement of RBC folate, plasma folate, and plasma B12. Participants completed the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and an abbreviated Cambridge Neuropsychological Test Automated Battery (CANTAB), with subtests assessing cognitive function. Linear models were employed to assess associations. RESULTS:For CANTAB outcome measures, positive associations were observed between plasma folate and Spatial Recognition Memory (SRM) (β=1.32, p0.05), and between B12 and Spatial Working Memory (SWM) (β=2.10, p0.05). No significant associations were observed between folate and B12 nutritional predictors and the WISC-IV outcome measures. CONCLUSIONS:The positive associations between folate and SRM and between B12 and SWM are consistent with previous findings linking folate and B12 deficiencies to memory deficits. Mild SRM impairments may include difficulty noticing that an object has been moved, whereas mild SWM impairments might include difficulty recalling where an object was placed. This research suggests that further investigation into the associations between folate and B12 nutritional status and measures of cognitive function in adolescents is needed. Additionally, these findings suggest that nutritional interventions involving B12 and folate supplementation may have a positive impact on overall adolescent health and cognition. KEYWORDS: Micronutrient deficiencies, Cognitive function, Neurotoxicology, Adolescent cognitive neurotoxicology, Folate and B12 deficiency, Nutritional status

Biophysical evidence to support and extend the vitamin D-folate hypothesis as a paradigm for the evolution of human skin pigmentation.

To test the "vitamin D-folate hypothesis for the evolution of human skin pigmentation." Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n= 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n= 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). UV-wavelength exhibits a dose-response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. Three dietary antioxidants (vitamins C, E, and β-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3 . New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.

P-MD011. Persistent cerebellar dysfunction post toluene sniffing

Introduction . Toluene toxicity from glue, paint thinners and petrol (gasoline) sniffing is being recognized globally for its neurotoxic effect. We describe 2 patients (siblings) with toluene induced encephalopathy at our centre. Both of them presented with cerebellar signs and had glue sniffing activities. Methods . A 24 years old gentleman presented with progressive hand tremor, unsteadiness with abnormal eye movement for 3 years duration. Patient was an active substance abuser and glue sniffer. On examination, he had an ataxic gait. He was dysarthric and had rotatory nystagmus in both eyes. He demonstrated past pointing, intention tremor with dysdiadochokinesia. The Romberg test was normal. He had normal tone, power, reflexes and sensory over all limbs. He had normal full blood count, renal function, liver function test, serum B12, red cell folate, T4, TSH, urine microscopy, HIV- 1 and 2, ANA, C-reactive protein, ESR, creatinine kinase and serum magnesium. MRI of the brain revealed symmetrical T2W/FLAIR hyperintense signals in substantia nigra of midbrain and surrounding the third ventricles. No enhancing brain parenchymal lesion. There was presence of cerebral and cerebellar atrophy. His sibling is a 22 years old gentleman with underlying bronchial asthma, active heroin chaser and glue sniffer presented with complex partial seizure with post-ictal drowsiness. He had ataxic gait, staccato speech, right upper limb past pointing, dysdiadochokinesia and bilateral eyes nystagmus. Romberg test is normal. Neurological examination revealed normal tone and reflexes, and full power of all extremities. His CT brain, cerebrospinal fluid analysis and other blood investigations were normal. He remained ataxic upon discharge but subsequently defaulted follow up. Conclusion . Chronic toluene exposures can affect central nervous system by causing demyelination and gliosis in cerebral and cerebellar white matter. This case series highlight the presence of persistent cerebellar signs post toluene abuse.

Frequency of Vitamin B12 and Red Cell Folate Deficiency in Macrocytic Anaemia

Background: Macrocytosis refers to a condition in which red blood cells are larger than normal, with or without anemia. Macrocytic anemia occur due to variety of illnesses and requires further clinical and laboratory assessment. Both folate and vitamin B12 have been known to cause macrocytic anemia since the deficiencies of these two vitamins are very common in Pakistan, it would be imperative to investigate their role in causing megaloblastic anemia.Objective: To determine the frequency of vitamin B12 and folate deficiencies in cases of macrocytic anemia.Material and Methods: This is a descriptive cross-sectional study conducted in the | department of medicine of Abbasi Shaheed hospital from January 2012 to June 2012. A total of 95 patients (65 males and 30 females) with an age of above 13 years, who admitted with macrocytic anemia (MCV>96) with hemoglobin < 12 mg/dl in females and < 13 mg/dl in males were enrolled and data pertaining to complete blood count, serum level of vitamin B12 and RBC folate were analyzed. Result: A total of 95 patients (65 males and 30 females) with hemoglobin < 12 mg/dl in females and < 13 mg/dl in males were taken. Mostly were non vegetarian and majority of the patients belongs to age group of 34-54 years. It was found that 69 patients (48 males and 21 females) from total of 95 had vitamin B12 deficiency which is 72.6% and 43 patients (20 males and 23 females) from total of 95 had folate deficiency which is 45.26%.Conclusion: Our study concludes that vitamin B12 is a major contributing factor of macrocytic anemia in our population. Dietary insufficiency, poor absorption and increase demand might be contributing to high prevalence of vitamin B12 deficiency in our population. Therefore our medical community should seriously consider the merit of early screening for vitamin B12 deficiency and take precautions against the clinical consequences of vitamin B12 deficiency.

Stopping Folic Acid Supplementation in Hydroxyurea Treated Children with Sickle Cell Disease

Daily folic acid supplementation for all children with sickle cell disorders is a widely used preventative measure in UK practice. However, a Cochrane review in 2016 concluded there is little evidence for this practice (CD011130). The only randomised clinical trial of folate supplementation in children, conducted in 1983, showed no evidence of benefit. (Rabb et al. ,1983).More convincing evidence as to the benefits of hydroxyurea and penicillin exists. However, adherence to these effective therapies can be a problem. We hypothesised that stopping folic acid could be clinically useful as this would reduce treatment burden on patients and allow them to focus on adherence to more effective medicines.We reviewed the medical records of children receiving hydroxyurea for sickle cell disorders managed in our treatment centre. Children were selected for withdrawal from folic acid supplementation based on an absence of uncontrolled haemolysis; reticulocytes <200 x109/L and bilirubin <80µmol/L, and an absence of low serum folate or low red cell folate. Clinical and laboratory monitoring was performed every 4 weeks to establish whether any benefit or adverse effect could be identified. This included monitoring Hb, HbF, MCV, neutrophils, platelets, reticulocytes, serum folate and red cell folate levels.We withdrew folic acid supplementation from 30 children with sickle cell disorders (mean age 9.5 years (range 2-18)) and monitored clinical and laboratory parameters. At the time of this review, mean follow up time was 11.5 months (range 7-14).Baseline investigations showed that serum folate levels in 14 children were so high in comparison to normal reference ranges that they were unquantifiable by standard laboratory analysis at our centre. The mean serum folate level in the other 16 children was 39.5 nmol/L (reference range 3.4-38.5 nmol/L). Similarly, red cell folate levels in 5 children were above maximum quantifiable levels. The mean red cell folate level in the other 25 children was 1445 nmol/L (reference range 272-1948 nmol/L).On withdrawal of folic acid supplementation, all patients' serum folate and red cell folate levels returned to within the normal range. At the end of this observation period, mean serum folate level was 20.9 nmol/L and mean red cell folate level was 617.2 nmol/L, with no patients developing low serum folate or low red cell folate levels. No patients developed megaloblastic changes or any other clinical need to restart supplementation. Folic acid levels began to reduce immediately on withdrawal of supplementation and in most cases reached a plateau by 6 months. However, plateauing levels were not recorded in all patients and this is likely attributable to the shorter follow up time for some patients.All patients were managed as per our standard protocol of escalating hydroxyurea therapy to maximum tolerated dose. An increase in mean dose from 27.0 mg/kg/day to 30.3 mg/kg/day (p=0.0003) was recorded during the observation period. Other statistically significant changes in haematological parameters were: increased HbF (25.8% to 29.7%, p=0.0002 and increased MCV (91.2 to 94.7, p=0.026). No significant differences were recorded in haemoglobin, neutrophils, platelets or reticulocytes (statistical analysis was performed by paired T-test).Stopping folic acid supplementation has caused no observable adverse effects either clinically or in laboratory haematological parameters. The significant increases in HbF and MCV observed here can be explained by the significant increase in hydroxyurea dose during the observation period and are not likely to be an effect of stopping folic acid.Stopping folic acid is a minor change in patient management however, patients generally don't like taking medicines and stopping a medicine that is not required was seen as an improvement in quality of life. At the end of our observation period, laboratory parameters had improved and there was no evidence of any adverse effect of stopping folic acid supplementation in children with sickle cell disease.Dixit et al., 2016. Cochrane Review, CD011130Rabb et al., 1983. British Journal of Haematology 54(4):589-94 DisclosuresNo relevant conflicts of interest to declare.

Folate Transporters Are Found Throughout the Colon of Humans and Their mRNA Expression Appears to Be Unaffected by Low Dose Folic Acid Supplementation

ObjectivesA large depot of folate resides in the colon and can exceed dietary intake. Little is known about the capacity of the colon to absorb folate. We aimed to determine the expression of key folate transporters, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT), throughout the colon of healthy adults and the impact of low dose folic acid (FA) supplementation. MethodsIn this 16 wk open-labelled randomized control trial, healthy adults (n = 25) from a colonoscopy waiting list were randomized to receive daily a multivitamin plus a 400 μg FA (400FA, n = 12) or no FA supplement (0FA, n = 13). Subjects were provided with low FA bread and pasta and instructions how to follow a low FA containing diet. Six 24-hr diet recalls were administered throughout the study and blood samples were collected at baseline, 8 and 16 wk. At colonoscopy (16 wk), 4 tissue biopsies were collected from the terminal ileum, cecum, ascending and descending colon. Blood folates were determined by microbial assay; mRNA levels of folate transporters were assessed using qPCR. ResultsOne subject was removed from analysis due to missing data (0FA). No group differences in age, sex, BMI, dietary intake, vitamin B12, red blood cell (RBC) and plasma folate levels at baseline were observed. Mean ± SD FA supplement adherence was 92 ± 12% and 96 ± 9% at 8 and 16 wk, respectively. Subjects in the 400FA group had higher total folate intake (P < 0.05) and higher RBC and plasma folate levels (P < 0.01) at 8 and 16 wk compared to 0FA subjects. RBC values at 16 wk were 1764 ± 636 and 865 ± 190 nmol/L in the 400FA and 0FA group, respectively. RFC and PCFT were detected in terminal ileum and colon biopsies (n = 96) and their mRNA levels in each section did not differ between groups. However, expression of RFC was markedly higher than PCFT across all biopsy sections (P < 0.05) and highest in the terminal ileum, compared to the cecum, ascending and descending colon in both groups (P < 0.05). ConclusionsWe demonstrated expression of folate transporters, RFC and PCFT, throughout the human colon suggesting their potential contribution to overall folate absorption. mRNA expressions were not affected by a low dose FA supplement. A deeper understanding of how FA and folate status affect colonic transporter regulation may inform future revisions of folate intake recommendations. Funding SourcesNatural Sciences and Engineering Research Council.

Estimating the Serum Folate Concentration Associated With the Red Blood Cell Folate Threshold for Optimal Neural Tube Defects Prevention: A Population Based Biomarker Survey

ObjectivesTo estimate the serum folate insufficiency threshold (sf-IT) corresponding to the red blood cell (RBC) folate insufficiency threshold for optimal neural tube defect (NTD) prevention. MethodsParticipants were 977 women of reproductive age (WRA; 15–40y; not pregnant or lactating) from a population-based biomarker survey in Southern India. Venous blood samples were collected at enrollment. Plasma, serum, and red blood cells were centrifuged, processed, and stored < -80°C until batch analysis. Total vitamin B12 concentrations were measured via chemiluminescence; RBC and serum folate concentrations were measured using the World Health Organization-recommended microbiological assay. Vitamin B12 deficiency was defined as total vitamin B12 < 148 pmol/L. Folate insufficiency was defined as RBC folate < 748 nmol/L, the recommended calibrator-adjusted equivalent of the threshold for population optimal NTD prevention. A previously developed Bayesian model and the RBC and serum folate distributions in this population were used to estimate the sf-IT corresponding to the RBC folate insufficiency threshold for optimal NTD prevention, overall and by age, body mass index (BMI) category, HbA1c, anemia, and vitamin B12 status. ResultsThe overall estimated median sf-IT was 37.8 nmol/L (95% credible interval [33.8–43.3]). This threshold was lower in overweight WRA (BMI: ≥25.0 kg/m2: 32.0 nmol/L [27.3–40.2] vs. BMI < 25.0 kg/m2: 36.2 nmol/L [32.2–43.3]), and varied by age (< 25y: 61.3 nmol/L [44.3–111.8]; 25 to 35y: 35.7 nmol/L [30.8–43.5]; ≥35y: 30.8 nmol/L [26.9–37.2]). The sf-IT was lower in anemic WRA (32.9 nmol/L [28.5–40.1]) compared to non-anemic WRA (42.0 nmol/L [36.1–51.3]), and lower in WRA with elevated HbA1c (≥5.7% to < 6.5: 32.4 nmol/L [27.3–41.6]; ≥6.5%: 20.9 nmol/L [17.8–25.6]) vs. WRA with HbA1c < 5.7% (43.8 nmol/L, [37.5–53.7]). The median sf-IT was higher in WRA with vitamin B12 deficiency (72.1 nmol/L [52.0–126.0]), compared to women who were not vitamin B12 deficient (28.1 nmol/L [25.6–31.5]). ConclusionsThe estimated sf-IT is dependent on anemia, elevated HbA1c, BMI, age, and vitamin B12 status. Funding SourcesCenters for Disease Control and Prevention; AF was supported by the National Institutes of Health #5 T32 HD087137.

Ancestry-Specific Interactions Between Circulatory Folate and One-Carbon Metabolism Genes’ Haplotypes for Higher-Grade Cervical Intraepithelial Neoplasia

Abstract Objectives Determine ancestry-specific interactions between circulatory folate concentrations, haplotypes of the one-carbon (1C) pathway genes and risk of higher-grade cervical intraepithelial neoplasia (CIN2+) in the US post-folic acid fortification era. Methods Study included self-reported African American and Caucasian American women positive for high-risk human papillomavirus (HPV) genotypes and diagnosed with ≤ CIN1 (non-cases, n = 340) or CIN2+ (cases, n = 337). Plasma and red blood cell (RBC) folate, vitamins B12 (B12) and C, and total carotene levels were measured. 660 single nucleotide polymorphisms of the 1C pathway genes and 104 ancestry informative markers (AIMs) were analyzed using buffy coat DNA and customizable Illumina GoldenGate arrays. Global African ancestry (GA) was estimated using the AIMs. Ancestry-based African American (AFR) had GA ≥ 0.8 and European Americans (EA) otherwise. Common haplotype blocks (n = 50) were tested for interactions with circulatory folate using logistic regression adjusting for age, education, body mass index (BMI), body fat %, smoking, parity, hormonal contraception use, plasma total carotene, B12 and C. False discovery rate &amp;lt; 0.1 was considered significant. Results Some of the main findings were, increasing plasma folate (1 SD) decreases the risk of CIN2 + when homozygous for haplotype CG at (rs575425, rs586199) of BHMT gene in EA (odds ratio/OR = 0.13, CI = 0.04,0.44), and for haplotype TA at (rs559062, rs515064) of CTH in AFR (OR = 0.23, CI = 0.1,0.52); increasing RBC folate (1 SD) decreases risk of CIN2 + when homozygous for haplotypes TA at (rs559062, rs515064) of CTH (OR = 0.27, CI = 0.12,0.61), AC at (rs7706298, rs10512934) of MTRR (OR = 0.21, CI = 0.08,0.57), and AGA at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 0.4, CI = 0.18,0.90) in AFR; and increasing RBC folate (1 SD) increases the risk of CIN2 + when homozygous for haplotypes GG at (rs3856027, rs4650051) of CTH gene (OR = 3.52, CI = 1.27,9.71), and CGG at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 5.70, CI = 1.86,17.49) in AFR. Conclusions Circulatory folate differentially modulates the risk for CIN2 + by interacting with haplotypes of the 1C pathway genes according to ancestry in reproductive-aged women exposed to US folic acid fortification program. Funding Sources National Cancer Institute

Intrauterine Exposure to Vitamin B12 and Folate Imbalance and Brain Structure in Young Adults of the Pune Maternal Nutrition Study (PMNS) Birth Cohort

ObjectivesIntrauterine nutritional exposures to vitamin B12 and folate are known to influence neurodevelopment. We tested the hypothesis that intrauterine exposure to high folate in presence of low vitamin B12 is associated with poor neurodevelopmental outcomes in young adult offspring. MethodsPMNS is a preconceptional birth cohort in its 24th year of follow up. We examined Intelligence Quotient (IQ) and obtained brain structural MPRAGE T1 sequence on a 3T MRI Scanner [participants selected based on exposure to maternal B12 at 18 wk pregnancy <103 PM(Low maternal B12 group n = 97) and >175 pM (high maternal B12 group, n = 93)]. Brain morphometric measurements (cortical volumes, thickness and subcortical volumes) were performed on Freesurfer software. ResultsThe mean age of participants was 22.3 ± 0.5 years (n = 190, 96 boys). High maternal B12 group showed greater cortical thickness in temporal regions (P < 0.001) and cortical thinning in frontal regions (P < 0.01). Higher maternal folate (median Red Cell Folate at 28 wk pregnancy 420 ng/ml) was associated with greater frontal cortical volumes in the high maternal B12 group but cortical thinning in multiple temporal and parietal cortical areas in the low B12 group(P < 0.05). There was a significant interaction between maternal B12 and folate status in relation to subcortical volumes. Exposure to higher maternal folate was associated with greater subcortical volume in high B12 group but lower volumes in low B12 group (P = 0.02, adjusted for age, education, gender and total intracranial volume). Higher IQ score was associated with larger subcortical brain volume (r = 0.34, P < 0.001) in the offspring. ConclusionsIntrauterine exposure to higher maternal folate in the presence of low vitamin B12 was associated with poorer cortical development in young adult offspring. Higher maternal folate with adequate B12 benefits subcortical brain development which reflects in higher IQ score. Optimizing maternal vitamin B12 and folate concentrations during pregnancy would benefit neurocognitive development in the offspring. Funding SourcesDBT Wellcome India Alliance Clinical and Public Health Intermediate Fellowship.

Red blood cell folate, high-risk human papillomavirus risk and cervical intraepithelial neoplasia development: A large Chinese community-based cohort study of cervical screening.

10547 Background: Although low folate status has been implicated in cervical carcinogenesis, large-scale population-based prospective cohort studies controlling for high-risk types of human papillomavirus (hrHPV) infection are lacking. The aim of this study is to evaluate the associations of red blood cell (RBC) folate, hrHPV infection risk and cervical intraepithelial neoplasia (CIN) development. Methods: In this prospective, population-based cohort study, we analyzed the cross-sectional data of 2304 women from a large cervical cancer screening program of 40,000 women aged 19-65 years in the Chinese rural area from 2014-2015. We conducted a nested case-control study including 35 CIN1 progression cases and 105 CIN1 regression controls. A logistic regression model was used to evaluate the associations of RBC folate and hrHPV infection risk and CIN1 development. Results: The median RBC folate concentration decreased gradually with cervical lesion severity. The risks of CIN 1 and CIN2 or worse (CIN 2+) in the 1st quartile of RBC folate concentration were significantly higher than those in the 4th quartile (Odds Ratio [OR], 2.27; 95% confidence interval [CI], 1.71-3.01 and OR, 2.33; 95% CI,1.52-3.56; respectively). We did not observe a significant relationship between hrHPV infection and CIN1 risk in the unadjusted and adjusted models, however, a statistically significant association was observed for CIN2+. Interestingly, RBC folate concentration was not associated with hrHPV infection among women with CIN1 or CIN2+. After full adjustment for potential confounders, a highly significant inverse linear relation between RBC folate concentration and CIN2+ was observed ( P-overall＜0.001, P-nonlinearity = 0.969). We further observed a positive additive interaction between RBC folate concentration and hrHPV infection on the risk of CIN2+ ( P-interaction＜0.01). Moreover, during the 21-month follow-up, CIN1 progression risk was significantly higher in the lowest RBC folate quartile (1st quartile compared with 4th quartile: OR, 3.86; 95% CI,1.01-14.76). Conclusions: Our findings indicates that RBC folate is inversely associated with the risk of higher-grade CIN and CIN1 progression in the Chinese rural population, either with or without hrHPV infection. Therefore, improving folate status has the potential to prevent higher-grade CIN and cervical cancer among women in the areas without mandatory folic acid food fortification. Clinical trial information: ChiCTR-ROC-15006479 .

Impact of the increasing concentrations of selected perfluoroalkyl acids on the observed concentrations of red blood cell folate among US adults aged ≥20 years.

For the first time (N = 6291), a study was undertaken to estimate associations between the concentratio ns of red blood cell folate (RBCF) and concentration of six perfluoroalkyl acids (PFAAs), namely, perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUnDA) for US adults aged ≥20 years by fitting regression models for the data from National Health and Nutrition Examination Survey for 2007-2014. In almost consistent fashion, increasing concentrations of PFAAs were associated with decreasing concentrations of RBCF. For the total population, for a 10% increase in the concentrations of PFOA, PFOS, PFDA, PFHxS, PFNA, and PFUnDA, percent decreases in RBCF concentrations were found to be 0.33%, 0.66%, 0.83%, 0.16%, 0.89%, and 0.43%, respectively. RBCF concentrations of PFAAs were found to be 1104, 1042, 100, and 936 nmol/L across the four quartiles of PFOS; 112, 1068, 1009, and 948 nmol/L across the four quartiles of PFDA; 1125, 1054, 1005, and 967 nmol/L across the four quartiles of PFNA; and 1099, 1094, 989, and 952 nmol/L across the four quartiles of PFUnDA. Perfluorinated carboxylic acids with carbon chain length > 8 decreased concentrations of RBCF to a greater degree than those carbon chain length ≤ 8. Perfluorinated chemicals with a sulfonic group with carbon chain length > 6 decreased concentrations of RBCF to a greater degree than those carbon chain length ≤ 6. The degree to which concentrations of RBCF decrease varied by age, gender, and race/ethnicity. Non-Hispanic blacks as compared to non-Hispanic whites and Hispanics had the lowest decreases in RBCF concentrations. Mechanisms responsible for negative associations between RBCF and PFAA concentrations are not known and will need to be researched further.

A child with Imerslund-Gr\xe4sbeck syndrome concealed by co\u2010existing \u03b1-thalassaemia presenting with subacute combined degeneration of the spinal cord: a case report

BackgroundImerslund-Gräsbeck syndrome is a rare genetic disease characterised by vitamin B12 deficiency and proteinuria.Case presentationA 4-year old Sri Lankan boy presented with gradually worsening difficulty in walking for two weeks duration. He was previously diagnosed and managed as having non-transfusion-dependent α-thalassaemia based on the presence of hypochromic microcytic anaemia, haemoglobin H inclusion bodies in the blood film and compound heterozygous α-thalassaemia genotype with a gene deletion. However, his transfusion requirement increased over the past three months and he gradually lost his motor developmental milestones during two weeks before admission. The neurological examination revealed generalised hypotonia, exaggerated knee jerks and extensor plantar response. His complete blood count showed pancytopenia, and bone marrow biopsy revealed megaloblastic changes. Serum vitamin B12 and red blood cell folate levels were low. MRI revealed sub-acute combined degeneration of the spinal cord with characteristic ‘inverted V sign’. Urine analysis showed non-nephrotic range proteinuria. The diagnosis of Imerslund-Gräsbeck syndrome was made due to the presence of non-nutritional vitamin B12 deficiency and asymptomatic proteinuria. He showed a rapid haematological and neurological improvement to intramuscular hydroxocobalamin.ConclusionsThis case report presents a rare occurrence of severe vitamin B12 deficiency due to Imerslund-Gräsbeck syndrome masked by co-existent α-thalassaemia, resulting in serious consequences. It highlights the need for a high index of suspicion in evaluating children with severe anaemia, especially in the presence of mixed pathologies.

Nutrition, one-carbon metabolism and arsenic methylation in Bangladeshi adolescents

BackgroundOver 57 million people in Bangladesh are chronically exposed to arsenic-contaminated drinking water. Ingested inorganic arsenic (InAs) undergoes hepatic methylation generating monomethyl- (MMAs) and dimethyl- (DMAs) arsenic species in a process that facilitates urinary As (uAs) elimination. One-carbon metabolism (OCM), a biochemical pathway that is influenced by folate and vitamin B12, facilitates the methylation of As. OCM also supports nucleotide and amino acid synthesis, particularly during periods of rapid growth such as adolescence. While folate supplementation increases As methylation and lowers blood As (bAs) in adults, little data is available for adolescents. ObjectivesTo examine the associations between OCM-related micronutrients and As methylation in Bangladeshi adolescents chronically exposed to As-contaminated drinking water. MethodsWe conducted a cross-sectional study of 679 Bangladeshi adolescents, including 320 boys and 359 girls aged 14–16 years. Nutritional status was assessed by red blood cell (RBC) folate, plasma folate, plasma B12 and homocysteine (Hcys). Arsenic-related outcomes included blood arsenic (bAs), urinary arsenic (uAs), and urinary arsenic metabolites expressed as a percentage of total urinary As: %InAs, %MMAs, %DMAs. ResultsBoys had significantly lower B12, higher Hcys, higher bAs, higher uAs, higher %MMAs, and a trend toward lower RBC folate compared to girls. Therefore, regression analyses controlling for water As and BMI were sex stratified. Among girls, RBC folate was inversely associated with bAs, plasma B12 was inversely associated with uAs, and plasma Hcys was inversely associated with %MMA. Among boys, plasma folate was inversely associated with %InAs and positively associated with %DMA, RBC folate was inversely associated with %InAs and positively associated with %MMA, while Hcys was positively associated with %InAs. ConclusionsThese findings suggest that associations between OCM nutritional status, bAs, and distribution of As metabolites in adolescents are similar to previously reported observations in adults and in children. The As methylation findings are statistically significant among boys but not among girls; this may be related to estrogen which more strongly influences OCM in females. The inverse association between Hcys and %MMA in girls is somewhat unexpected given that Hcys is known to be an indicator of impaired OCM and low folate/B12 in adults. Overall, these results indicate that the associations between OCM-related micronutrients and arsenic methylation in adolescents are generally similar to prior findings in adults, though these associations may differ by sex. Additionally, these findings suggest that more investigation into the role of Hcys in adolescent physiology is needed, perhaps particularly for girls. Additional studies are needed to evaluate the impact of OCM and As methylation on As-related adverse health outcomes (such as cancer and cardiovascular disease) in people exposed to As during adolescence.

Micronutrient Deficiencies and Anemia in Children with Inflammatory Bowel Disease

Children with inflammatory bowel disease (IBD) are at risk of developing nutrition deficiencies, particularly because of reduced intake, restrictive diets, malabsorption, and excessive nutrient loss. The aim of this study was to determine the prevalence and predictors of anemia and micronutrient deficiencies at diagnosis and one year follow up in children and adolescents with inflammatory bowel disease (IBD). Children and young adults diagnosed with IBD before the age of 17 years between 2012 and 2018 were included. Laboratory measurements including serum levels of iron, ferritin, zinc, vitamin D, vitamin A, vitamin E, selenium, copper, vitamin B12, and red blood cell (RBC) folate at diagnosis and one-year follow-up were documented as part of the Manitoba Longitudinal Pediatric Inflammatory Bowel Disease (MALPID) Cohort. A total of 165 patients with IBD were included, 87 (53%) with Crohn’s disease (CD) and 78 (47%) with ulcerative colitis (UC). The prevalence of deficiencies in our cohort at diagnosis and one year follow-up, respectively, were iron (56% and 27%), ferritin (39% and 27%), zinc (10% and 6%), vitamin D (22% and 13%), vitamin A (25% and 25%), vitamin E (5% and 4%), selenium (10 and 7%), copper (17% and 27%), vitamin B12 (2% and 5%), and Red blood cell (RBC) folate (1% and 17%). Anemia was present in 57% and 25% at diagnosis and follow up respectively. In CD patients, age of diagnosis (15y–younger than 18y) was a predictor of moderate to severe anemia and albumin levels (<33 g/L) were protective against anemia. Many children with IBD suffer from anemia and micronutrient deficiencies at diagnosis and some fail to recover after one year despite being in clinical remission.

Weekly iron–folic acid supplements containing 2.8 mg folic acid are associated with a lower risk of neural tube defects than the current practice of 0.4 mg: a randomised controlled trial in Malaysia

IntroductionWeekly iron–folic acid (IFA) supplements are recommended for all menstruating women in countries where anaemia prevalence is >20%. Anaemia caused by folate deficiency is low worldwide, and the need to...

Association of Maternal Folate and Vitamin B12 in Early Pregnancy With Gestational Diabetes Mellitus: A Prospective Cohort Study.

OBJECTIVETo investigate the association of folate and vitamin B12 in early pregnancy with gestational diabetes mellitus (GDM) risk.RESEARCH DESIGN AND METHODSThe data of this study were from a subcohort within the Shanghai Preconception Cohort Study. We included pregnancies with red blood cell (RBC) folate and vitamin B12 measurements at recruitment (between 9 and 13 gestational weeks) and those with three samples available for glucose measurements under an oral glucose tolerance test. GDM was diagnosed between 24 and 28 weeks’ gestation. Odds ratio (OR) and 95% CI of having GDM was used to quantify the association.RESULTSA total of 1,058 pregnant women were included, and GDM occurred in 180 (17.01%). RBC folate and vitamin B12 were significantly higher in pregnancies with GDM than those without GDM (P values were 0.045 and 0.002, respectively) and positively correlated with 1-h and 2-h serum glucose. Daily folic acid supplementation in early pregnancy increases the risk of GDM; OR (95% CI) was 1.73 (1.19–2.53) (P = 0.004). Compared with RBC folate <400 ng/mL, pregnancies with RBC folate ≥600 ng/mL were associated with ∼1.60-fold higher odds of GDM; the adjusted OR (95% CI) was 1.58 (1.03–2.41) (P = 0.033). A significant trend of risk effect on GDM risk across categories of RBC folate was observed (Ptrend = 0.021). Vitamin B12 was significantly associated with GDM risk (OR 1.14 per 100 pg/mL; P = 0.002). No significant association of serum folate and percentile ratio of RBC folate/vitamin B12 with GDM was observed.CONCLUSIONSHigher maternal RBC folate and vitamin B12 levels in early pregnancy are significantly associated with GDM risk, while the balance of folate/vitamin B12 is not significantly associated with GDM.

Study protocol for a randomised controlled trial evaluating the effect of folic acid supplementation beyond the first trimester on maternal plasma unmetabolised folic acid in late gestation

IntroductionTaking folic acid containing supplements prior to and during early pregnancy reduces the risk of neural tube defects. Neural tube defects occur prior to 28 days postconception, after which, there...

Environmental Chemicals and Red Blood Cell Folate levels in the U.S. Population, NHANES

Background/Aim: Inadequate folate during pregnancy has been associated with congenital birth deficits and adverse neurodevelopmental outcomes, including autism spectrum disorders. Recent studies show that folic acid supplementation may protect against the potential adverse effects of gestational chemical exposures on neurodevelopment. However, it is unclear whether these chemicals impact folate metabolism. Therefore, we investigated the relationship between environmental chemicals and red blood cell (RBC) folate concentrations.Methods: We assessed associations of 41 chemical biomarkers including metals, phthalate metabolites, per- and polyfluroalkyl substances (PFAS), parabens, and polycyclic aromatic hydrocarbons with RBC folate concentrations in 41,433 participants ages 1-80 from the U.S. National Health and Nutrition Examination Survey (2007-2016). We triangulated evidence from three statistical methods developed to examine chemical mixtures: Exposome Wide Association (ExWAS), Bayesian Kernel Regression (BKMR), and SuperLearner with G-computation. We examined the individual and joint associations of these chemicals with RBC folate concentrations, while adjusting for confounders. Results: The geometric mean RBC folate was 463 ng/mL (Interquartile range: 361 - 587.2 ng/mL). Some metals, PFAS, phthalates, and cotinine were consistently associated with lower RBC folate concentrations. Using BKMR, an interquartile range increase in perfluorononanoic acid (PFNA), cotinine, mono-ethyl phthalate, and lead was associated with a -0.15 standard deviation (SD) (95% confidence interval (CI): -0.23, -0.07), -0.11 SD (95% CI: -0.17, -0.03), -0.03 SD (95% CI: -0.07, 0.02), and -0.18 SD (95% CI: -0.25, -0.10) decrease in RBC folate concentrations, respectively. Estimates differed slightly between methods, but these findings remained robust. Conclusion: This study, which is the first to examine an association between a mixture of environmental chemicals and RBC folate concentrations in a nationally representative sample, may help enhance our understanding of the interplay between environmental chemicals, folate, and adverse health outcomes.

Dietary Patterns and Nutritional Status in Relation to Consumption of Chickpeas and Hummus in the U.S. Population

Chickpeas, a commonly consumed legume, are the main ingredient in traditional hummus. U.S. dietary guidelines recommend consuming 1–1.5 cups of legumes per week. This study aimed to evaluate temporal changes in hummus and chickpea consumption and describe diet and biomarkers of health in U.S. consumers versus non-consumers. National Health and Nutrition Examination Survey (2005–2016) data were used. Dietary intake was collected using two 24-h recalls; age, gender, and poverty-to-income ratio were adjusted in statistical analyses. The proportion of the population who consumed chickpeas or hummus increased significantly over time. Hummus and chickpea consumers were more likely to obtain recommended legume intake. Consumers had significantly increased intakes of fruits, vegetables, and whole grains and decreased added sugars intakes versus non-consumers. Consumers also had lower concentrations of urinary iodine and higher concentrations of serum 4-pyridoxic acid, total vitamin B6, and red blood cell folate. Adults who consumed chickpeas and hummus were 48% and 62% less likely to have metabolic syndrome, respectively. Consuming chickpeas or hummus may be a practical means of improving diet quality and nutritional status. Future work should evaluate whether chronic disease incidence is reduced by chickpea and hummus consumption through better nutrition or lower metabolic syndrome incidence.