Red Blood Cell Folate Levels Research Articles

Folate, homocysteine, interleukin-6, and tumor necrosis factor alfa levels, but not the methylenetetrahydrofolate reductase C677T polymorphism, are risk factors for schizophrenia

The methylenetetrahydrofolate reductase ( MTHFR) C677T mutation has been associated to high homocysteine levels and schizophrenia. Since cytokines are altered in schizophrenia and increments of homocysteine could promote an inflammatory response, it was investigated whether interleukin-6 (IL-6) and tumor necrosis factor alfa (TNFα) levels are modulated by the MTHFR genotype. Serum levels of TNFα, IL-6, B 12, homocysteine, folate and red blood cell (RBC) folate as well as the MTHFR genotype were determined in a group of schizophrenic patients and compared to those of a control group. RBC folate levels were reduced and homocysteine and the two cytokines’ concentrations were elevated in all patients as compared to controls. RBC folate in both heterozygous (CT) and homozygous (TT) patients was significantly different to that of their respective control groups. Homocysteine levels found in patients were significantly higher than those found in controls, only in individuals carrying the TT genotype. Cytokine levels were augmented in the group of patients irrespective of the genotype, and significant differences were found in all cases, except for TNFα levels in those subjects carrying the CC genotype. After adjusting for sex, low levels of RBC folate, high levels of homocysteine, both medium and high levels of TNFα and high IL-6 levels were associated with schizophrenia. MTHFR genotype was not a risk factor for developing the disease, although a larger sample is required to confirm this finding.

N-acetyltransferase 2 activity and folate levels

Aims To determine whether increased N-acetyltransferase (NAT) activity might have a toxic effect during development and an influence on folate levels since previous work has shown that only low levels of exogenous NAT can be achieved in constitutionally transgenic mice ( Cao et al. 2005). Main methods A human NAT1 tet-inducible construct was used that would not be expressed until the inducer was delivered. Human NAT1 cDNA was cloned into pTRE2 and injected into mouse oocytes. Two transgenic lines were crossed to mouse line TgN(rtTahCMV)4Uh containing the CMV promoted “tet on”. Measurements of red blood cell folate levels in inbred strains of mice were performed. Key findings Only low levels of human NAT1 could be achieved in kidney (highly responsive in other studies) whether the inducer, doxycycline, was given by gavage or in drinking water. An inverse correlation of folate levels with Nat2 enzyme activity was found. Significance Since increasing NAT1 activity decreases folate in at least one tissue, the detrimental effect of expression of human NAT1 in combination with endogenous mouse Nat2 may be a consequence of increased catabolism of folate.

The Reduced Folate Carrier (SLC19A1) c.80G>A Polymorphism is Associated with Red Cell Folate Concentrations Among Women

Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor or marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within SLC19A1, the gene that encodes RFC1, may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland. The SLC19A1 c.80G>A polymorphism was not strongly associated with either serum folate or homocysteine concentrations in either men or women. However, in women, but not in men, this polymorphism explained 5% of the variation in red blood cell (RBC) folate levels (P= 0.02). Relative to women with the SLC19A1 c.80GG genotype, women with the GA and AA genotypes had higher RBC folate concentrations. Consequently, compared to women with the SLC19A1 c.80GA and AA genotypes, women who are homozygous for the 80G allele may be at increased risk of having a child affected with a neural tube defect and of developing pathologies that have been associated with folate insufficiency, such as cardiovascular disease.

Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long‐term methotrexate treatment

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) in the management of rheumatoid arthritis (RA). MTX is transported into cells, where additional glutamate moieties are added and it is retained as MTX polyglutamates (MTXGlu [referred to as a group as MTXGlun]). There is large interpatient variability in MTXGlun concentrations. This study was undertaken to determine nongenetic factors that influence red blood cell (RBC) MTXGlun concentrations in patients receiving long-term stable low-dose oral MTX. One hundred ninety-two patients receiving long-term oral MTX for the treatment of RA were recruited. Trough MTXGlun concentrations were measured by high-performance liquid chromatography. Univariate analysis was performed to determine variables influencing MTXGlun concentrations. Backward stepwise multivariate regression analysis was done to determine variables that affect individual MTXGlun concentrations; variables with P values of <0.1 in the univariate analysis for any MTXGlun were included. Univariate analysis revealed that increased age, lower estimated glomerular filtration rate (GFR), higher MTX dosage, longer duration of MTX treatment, and use of prednisone were associated with significantly higher MTXGlun concentrations. Smokers had significantly lower concentrations of MTXGlu3, MTXGlu3-5, and MTXGlu1-5. Sex, rheumatoid factor and anti-cyclic citrullinated peptide status, RBC folate level, and body mass index had no significant effect on MTXGlun levels. Concomitant use of other DMARDs was associated with lower MTXGlu2 levels, and treatment with nonsteroidal antiinflammatory drugs was associated with lower MTXGlu3 and MTXGlu1-5 concentrations. Multivariate regression analysis revealed that age, MTX dosage, and estimated GFR were the major determinants of MTXGlun concentrations. Large interpatient variability in MTXGlun concentrations can be explained, at least in part, by a combination of factors, particularly age, MTX dosage, and renal function. There are complex interactions between smoking, RBC folate levels, and concentrations of MTXGlun.

Nutrition and depression: the role of folate.

A relationship between folate and neuropsychiatric disorders has been inferred from clinical observation and from the enhanced understanding of the role of folate in critical brain metabolic pathways. Depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency. Conversely, borderline low or deficient serum or red blood cell folate levels have been detected in 15-38% of adults diagnosed with depressive disorders. Recently, low folate levels have been linked to poorer antidepressant response to selective serotonin reuptake inhibitors. Factors contributing to low serum folate levels among depressed patients as well as the circumstances under which folate and its derivatives may have a role in antidepressant pharmacotherapy must be further clarified.

Maternal serum homocysteine and risk for neural tube defects in a Texas‐Mexico border population

To better understand the neural tube defect (NTD) causal pathway, the authors measured homocysteine, an indicator of tissue micronutrient deficiencies. The authors examined independent and joint associations of serum homocysteine, B12, and folate and red blood cell (RBC) folate with NTD-affected pregnancies. Case women in this population-based study had NTD-affected pregnancies and resided and delivered in one of the 14 Texas-Mexico border counties from 1995 through 2000. Control women were study area residents delivering normal live births during the same period. The authors measured homocysteine levels using tandem mass spectroscopy; competitive binding was used for other biomarkers. Homocysteine testing was done on 103 cases and 139 controls. Odds ratios (ORs) were increased in all upper homocysteine quintiles compared to the lowest quintile (1.7, 1.3, 2.8, 2.4). Women with high homocysteine values had increased ORs regardless of high versus low levels for B12 (OR = 3.5, 4.8, respectively) or RBC folate (OR = 2.9, 3.5, respectively). High serum homocysteine levels are associated with NTD-affected pregnancies. Moreover, high homocysteine levels have a detrimental effect on NTD-risk even when serum B12 or RBC folate levels are high. Excess homocysteine might play an independent role in the development of NTDs.

The maternal Mediterranean dietary pattern is associated with a reduced risk of spina bifida in the offspring

The objective of this study was to test the hypothesis whether a maternal dietary pattern is associated with the risk of spina bifida (SB) in the offspring. Case-control study. Eight clinic sites in the Netherlands, 1999-2001. A total of 50 mothers of children with SB and 81 control mothers. Maternal food intakes were obtained by food frequency questionnaires at the standardised study moment of 14 months after the birth of the index child. Principal component factor analysis (PCA) and reduced rank regression (RRR) were used to identify dietary patterns. Maternal biomarkers were used as response measures in the RRR analysis and composed of serum and red blood cell (RBC) folate, serum vitamin B12 and total plasma homocysteine. The strength of the use of the dietary pattern in association with SB risk was estimated by odds ratios and 95% CI with the highest quartiles of the dietary pattern as reference. A predominantly Mediterranean dietary pattern was identified by both PCA and RRR. Those dietary patterns were highly correlated (r = 0.51, P < 0.001) and characterised by joint intakes of fruit, vegetables, vegetable oil, alcohol, fish, legumes and cereals and low intakes of potatoes and sweets. We observed a significantly increased risk of SB offspring in mothers with a weak use of the Mediterranean dietary pattern, OR 2.7 (95% CI 1.2-6.1) and OR 3.5 (95% CI 1.5-7.9). The Mediterranean dietary pattern was correlated with higher levels of serum and RBC folate, serum vitamin B12 and lower plasma homocysteine. The Mediterranean dietary pattern seems to be associated with reduction in the risk of offspring being affected by SB.

Zinc supplementation does not alter plasma homocysteine, vitamin B12 and red blood cell folate concentrations in French elderly subjects

Background/aims In ageing, low folates and vitamin B12 status are frequent and can explain the increase of plasma homocysteine level. Zinc is involved in the folates and vitamin B12 metabolism with opposite actions. The aim of this study was to investigate the effects of zinc supplementation on homocysteine and vitamin B12 plasma levels as well as red blood cell folate level in French ageing subjects participating in the ZENITH study. Methods Apparently healthy middle-aged (55–70 years) and free-living older (70–85 years) subjects were enrolled. They were randomly allocated to three groups: 0, 15 or 30 mg Zn per day for 6 months as zinc gluconate in addition to their usual dietary intake. Results At baseline, plasma homocysteine levels (15.2±3.5 μmol/L) in older people were higher than in the middle-aged subjects (12.7±2.7 μmol/L) and was negatively correlated with vitamin B12 values ( p=0.0036, r=−0.215) and with RBC folate levels ( p<0.0001, r=−0.30). These results are in agreement with previous data. However, we found no correlation between the biomarkers of zinc status and homocysteine, vitamin B12 or folate levels at baseline. Moreover, 6-month zinc supplementation did not modify homocysteine, vitamin B12 and RBC folate values in either of the groups. Conclusions Zinc supplementation at moderate doses do not lead to deleterious effect on folate or vitamin B12 status in ageing healthy free-living people, but does not have any beneficial effects on homocysteine metabolism either.

Impact of High and Low Folate Diets on Tissue Folate Receptor Levels and Antitumor Responses Toward Folate-Drug Conjugates

Herein, we present a detailed analysis on the effects of feeding laboratory mice both high and low folic acid (folate)-containing diets as related to associated changes in serum and red blood cell (RBC) folate levels, tissue-derived folate receptor levels, and the ability of folate-drug conjugates to bind and effectuate activity against folate receptor (FR)-positive tumor xenografts. Our data show that serum and RBC folate concentrations sharply drop immediately after mice are switched to low folate diets; however, both parameters reach steady-state, "human-like" levels after 6 weeks. Interestingly, tissue-related folate binding capacities were also lowered during the dietary modulation period, whereas the net uptake of a radiolabeled folate conjugate was simultaneously increased 2.6- and 5-fold in FR-positive kidney and tumor tissue, respectively. Finally, the performances of several clinically and preclinically relevant folate-drug conjugates were evaluated against tumors in mice that were fed high or low folate diets. Except when administered at a dose level 6-fold less than that required to saturate endogenous FRs, no significant loss of antitumor activity was observed. From these findings, we conclude that lowering the dietary intake of folates in mice has little impact on the biological activity of repetitively dosed folate-targeted agents but that low folate diet regimens will reduce serum and RBC folate levels down to levels that more closely approximate the normal human ranges.

Effect of different dosage and administration schedules of folic acid on blood folate levels in a population of Honduran women of reproductive age

Observational studies and clinical trials have shown conclusive evidence that periconceptional folic acid supplementation prevents up to 70 % of neural tube defects (NTD). The Honduran government wanted to implement a supplementation programme of folic acid but needed to assess the relative effects of two dosages of folic acid. To determine the effect of two dosages of folic acid on blood folate levels in Honduran female factory workers aged 18 to 49 years. This was a randomized, double-blind control supplementation trial conducted in Choloma, Honduras. A total of 140 eligible women were randomly assigned to two dosage groups and followed up for 12 weeks. One group received a daily dosage of 1 mg folic acid and the other a once weekly dosage of 5 mg. Serum folate and red blood cell folate levels were determined by radioassay at baseline, 6 weeks and 12 weeks. Serum folate levels increased from 6.3 (se 0.2) to 14.9 (se 0.6) ng/ml (P < 0.0001) in women assigned to the 1 mg/d group and from 6.9 (se 0.3) to 10.1 (se 0.4) ng/ml (P < 0.0001) in those assigned to the 5 mg/week group. Red blood cell folate concentrations also increased significantly in both groups, albeit more slowly. Educational level, age and BMI were not associated with the changes in serum and red blood cell folate levels during the supplementation period. However, a differential effect on serum folate levels by dosage group and time was observed. Although both folate supplementation regimens increased serum and red blood cell folate levels significantly among the women studied, blood folate levels that are considered to be protective of NTD were reached faster with the daily dosage of 1 mg folic acid.

Quantification of key red blood cell folates from subjects with defined MTHFR 677C>T genotypes using stable isotope dilution liquid chromatography/mass spectrometry.

Red blood cell (RBC) folate levels are established at the time of erythropoiesis and therefore provide a surrogate biomarker for the average folate status of an individual over the preceding four months. Folates are present as folylpolyglutamates, highly polar molecules that cannot be secreted from the RBCs, and must be converted into their monoglutamate forms prior to analysis. This was accomplished using an individual's plasma pteroylpolyglutamate hydrolase by lysing the RBCs in whole blood at pH 5 in the presence of ascorbic acid. Quantitative conversion of formylated tetrahydrofolate derivatives into the stable 5,10-methenyltetrahydrofolate (5,10-MTHF) form was conducted at pH 1.5 in the presence of [(13)C(5)]-5-formyltetrahydrofolate. The resulting [(13)C(5)]-5,10-MTHF was then used as an internal standard for the formylated forms of tetrahydrofolate that had been converted into 5,10-MTHF as well any 5,10-MTHF that had been present in the original sample. A stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry method was validated and then used for the accurate and precise quantification of RBC folic acid, 5-methyltetrahydrofolate (5-MTHF), tetrahydrofolate (THF), and 5,10-MTHF. The method was sensitive and robust and was used to assess the relationship between different methylenetetrahydrofolate reductase (MTHFR) 677C>T genotypes and RBC folate phenotypes. Four distinct RBC folate phenotypes could be identified. These were classified according to the relative amounts of individual RBC folates as type I (5-MTHF >95%; THF <5%; 5,10-MTHF <5%), type II (5-MTHF <95%; THF 5% to 20%; 5,10-MTHF <5%), type III (5-MTHF >55%; THF >20%; 5,10-MTHF >5%), and type IV (5-MTHF <55%; THF >20%; 5,10-MTHF >5%).

Folate and Clefts of the Lip and Palate—A U.K.-Based Case-Control Study: Part II: Biochemical and Genetic Analysis

To investigate associations between nonsyndromic oral clefts and biochemical measures of folate status and the MTHFR C677T variant in the United Kingdom, where there has been no folic acid fortification program. Dietary details were obtained from the mothers of 112 cases of cleft lip with or without cleft palate (CL+/-P), 78 cleft palate only (CP) cases, and 248 unaffected infants. Infant and parental MTHFR C677T genotype was determined. Red blood cell (RBC) and serum folate and homocysteine levels were assessed in 12-month postpartum blood samples from a subset of mothers. The data were analyzed by logistic and log-linear regression methods. There was an inverse association between CL+/-P and maternal MTHFR CT (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.31-0.95) and TT (OR = 0.6, 95% CI = 0.21-1.50) genotypes, with similar risk estimates for CP. There was no clear association with infant MTHFR genotype. Higher levels of maternal postpartum RBC and serum folate were associated with a lower risk for CL+/-P and an increased risk for CP. Higher levels of serum homocysteine were associated with a slightly increased risk for both CL+/-P and CP. While the inverse relation between the mother's having the MTHFR C677T variant and both CL+/-P and CP suggests perturbation of maternal folate metabolism is of etiological importance, contrasting relations between maternal postpartum levels of RBC and serum folate by type of cleft are difficult to explain.

Commentary: Health policies in the US: can they increase or decrease the gap between subgroups of the population? The case of folic acid

Effective on January 1, 1998, the Food and Drug Administration (FDA) amended the standards to identify several enriched grain products, bromated flour, vegetable macaroni and vegetable noodle products by requiring folic acid fortication. Specifically, the FDA required that these products be fortified with folic acid levels ranging from 0.43 to 1.4 mg/pound or 95 to 309 mg/100 g of product. Although this requirement affects the entire population, the purpose of this amendment was to ensure that women of childbearing age consume the US Public Health Service recommended daily allowance of at least 0.4 mg (400 mg) of folic acid daily to reduce their risk of having a child with spina bifida or other neural tube defects (NTDs). Spina bifida and anencephaly affect approximately 4000 children in the US prior to the folic acid fortification amendment. However, approximately 1000 of these cases have been prevented with folic acid fortification. As with most conditions in the US, estimates for NTDs vary by race and ethnicity, with Hispanics exhibiting the highest estimates and blacks and Asians the lowest. Moreover, NTDs varies by socioeconomic status defined using income and education with the least educated and those with low income exhibiting the highest estimates. Low folate levels not only affect children in utero, but also evidence suggests that low folate levels are associated with increased prevalence of cancer, cardiovascular disease, physical and mental functioning. Thus, despite the fact that the fortification was targeted to women of childbearing age, the FDA amendment could be a preventive paradox for population health by benefiting everyone. The latter could have implications for health disparities across subgroups of the population if differences exist across the outcomes benefiting from the fortification. Findings from existing studies on folic acid preand post-fortification suggest that there are disparities between groups. For instance, Ford and Bowman showed differences in red blood cell (RBC) folate concentrations between non-Hispanic blacks and nonHispanic whites with the highest differences among those with greater than a high school diploma regardless of gender. Conversely, differences between Mexican Americans and non-Hispanic whites were significant for men with at least 9 years of education and for women at the educational attainment extreme (<9 years of education and more than a high school diploma). Ganji and Kafai showed a decrease in prevalence of low RBC folate between 1988–94 and 1999–2002 across all racial/ ethnic and poverty-income ratio groups. However, nonHispanic blacks continue to exhibit a higher prevalence of low RBC folate through this period. Unlike previous studies examining trends between the preand post-fortification period, Dowd and Aiello focused on investigating the magnitude of the racial/ethnic and socioeconomic status (defined using poverty to income ratio) disparities assessed as absolute and relative differences. Using data from the National Health and Nutrition Examination Surveys (NHANES), Dowd and Aiello examined racial/ethnic and income disparities in folate status in US adults aged 25 years or older before (1991–1994) and after (1999–2002) enactment of the folic acid fortification. They found an increase in relative, but a decrease, in absolute difference before and after the fortification. Non-Hispanic blacks had 1.6 (95% CI: 1.4–1.9) greater odds of having low RBC folate (<362.6 nmol) levels compared with non-Hispanic whites in the pre-fortification period. This estimate was 3.7 (95% CI: 2.8–5.0) in the postfortification period. In the pre-fortification period, individuals in the bottom income quartile had a 1.3 (95% CI: 1.1–1.4) greater odds of having low RBC compared with those in the highest income quartile. Finally, in the post-fortification period, this estimate was 2.1 (95% CI: 1.6–2.7). The corresponding absolute differences were 233 (pre-) and 121 (post-fortification) Department of Health Sciences, Graduate Program in Public Health, Lehman College, CUNY, 250 Bedford Park Boulevard West, Gillet 336, Bronx, NY 10468, USA. E-mail: Luisa.Borrell@lehman.cuny.edu Published by Oxford University Press on behalf of the International Epidemiological Association

National Neural Tube Defects Prevention Program in China

Neural tube defects (NTD) are among the most common and devastating birth defects. Annually, in China, between 80,000 and 100,000 pregnancies result in children born with NTD. Northern China has the highest known rate of NTD in the world. Birth defects are becoming the leading cause of infant mortality in the urban and developed areas in China. The results of studies conducted in the early 1990s and early 2000s showed significant geographic and seasonal variations of folate status among Chinese women of childbearing age, with lower serum and red blood cell folate levels in northern China. In the north, 32% to 35% of women had low plasma folate and low red blood cell folate, and folate levels were significantly lower in spring than in fall. Since 1993, Peking University Health Science Center (formerly Beijing Medical University), collaborating with the US Centers for Disease Control and Prevention (CDC), has conducted a large-scale study to evaluate a public health campaign in China among women preparing for marriage in order to determine the effectiveness of daily supplementation of 400 microg of folic acid alone in preventing NTD in both the north and the south of China. The results showed that among the fetuses or infants of the women who took periconceptional folic acid, the reduction in risk of NTD was 85% in the northern region and 40% in the southern region. Daily intake of 400 microg of folic acid may also reduce the risk of nonsyndromic orofacial clefts. We found no evidence that daily consumption of folic acid before and during early pregnancy influenced the risk of miscarriage or twinning. In 2001, the Chinese Ministry of Health and the Chinese Disabled Person Federation released a National Action Plan for Reducing Birth Defects and Disabilities in China for 2002-2010. The Action Plan aims to improve birth outcomes, to reduce infant mortality by reducing the risk of birth defects and disabilities, and to ensure that every baby is born healthy.

Infrequency of low red blood cell (RBC) folate levels despite no folate fortification program: a study based on results from routine requests for RBC folate

We investigated the prevalence of a low level of red blood cell (RBC) folate in individuals suspected to be deficient and further evaluated the clinical consequence of identifying an individual with a low folate level in a population where no fortification with folate has been introduced. We conducted a retrospective review of all RBC folate analyses requested in one of the university hospitals in Denmark and identified patients with abnormally low (<350 nmol/L) and high (>1700nmol/L) folate levels. For requests from the hospital, we evaluated the clinicians' response to a decreased level of folate. A total of 12,932 RBC folates requested from the hospital (26%) or from general practitioners (GPs) (74%) were investigated. RBC folate levels were low in a comparable fraction of those requested from the hospital (1.7%) and from the GPs (1.3%). A high level of RBC folate was observed more often than a low RBC folate and occurred considerably more frequently (p<0.0001) in patients referred from the hospital (4.9%) than amongst those referred from GPs (1.2%). The clinicians' response rate to a low folate was around 60% and occurred more often for patients with a low level of cobalamins than in other patients. Low RBC folate values are rare in Danish patients despite no folate fortification program. Further, the clinical reaction to a low folate value is unexpectedly low.

RETIRED: Pre-conceptional Vitamin/Folic Acid Supplementation 2007: The Use of Folic Acid in Combination With a Multivitamin Supplement for the Prevention of Neural Tube Defects and Other Congenital Anomalies

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Down‐regulation of reduced folate carrier may result in folate malabsorption across intestinal brush border membrane during experimental alcoholism

Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The intestinal folate uptake is tightly and diversely regulated, and disturbances in folate homeostasis are observed in alcoholism, attributable, in part, to intestinal malabsorption of folate. The aim of this study was to delineate the regulatory mechanisms of folate transport in intestinal absorptive epithelia in order to obtain insights into folate malabsorption in a rat model of alcoholism. The rats were fed 1 g.kg(-1) body weight of ethanol daily for 3 months. A reduced uptake of [(3)H]folic acid in intestinal brush border membrane was observed over the course of ethanol administration for 3 months. Folate transport exhibited saturable kinetics and the decreased intestinal brush border membrane folate transport in chronic alcoholism was associated with an increased K(m) value and a low V(max) value. Importantly, the lower intestinal [(3)H]folic acid uptake in ethanol-fed rats was observed in all cell fractions corresponding to villus tip, mid-villus and crypt base. RT-PCR analysis for reduced folate carrier, the major folate transporter, revealed that reduced folate carrier mRNA levels were decreased in jejunal tissue derived from ethanol-fed rats. Parallel changes were observed in reduced folate carrier protein levels in brush border membrane along the entire crypt-villus axis. In addition, immunohistochemical staining for reduced folate carrier protein showed that, in alcoholic conditions, deranged reduced folate carrier localization was observed along the entire crypt-villus axis, with a more prominent effect in differentiating crypt base stem cells. These changes in functional activity of the membrane transport system were not caused by a general loss of intestinal architecture, and hence can be attributed to the specific effect of ethanol ingestion on the folate transport system. The low folate uptake activity observed in ethanol-fed rats was found to be associated with decreased serum and red blood cell folate levels, which might explain the observed jejunal genomic hypomethylation. These findings offer possible mechanistic insights into folate malabsorption during alcoholism.

Serum Levels of Folate and Cobalamin Are Lower in Depressed Than in Nondepressed Hemodialysis Subjects

The purpose of this study was to evaluate if there was a significant difference in serum and RBC folate or serum cobalamin levels in depressed and nondepressed subjects on hemodialysis (HD). A cross-sectional design was used in this study. Each subject's serum folate and cobalamin, and red blood cell (RBC) folate were measured. The Beck Depression Index II (BDI-II) was used to assess for depression. Subjects with scores of 10 or greater were considered depressed. Other laboratory, anthropometric, and demographic data were obtained from the subjects' medical records. To assess for significant differences (P < 0.05) in the laboratory values of the outcome variables between depressed and nondepressed subjects, t tests were performed on the groups' mean values. The study was conducted with patients in two dialysis centers in Texas. Seventy-three individuals undergoing HD for at least six months who met study inclusion criteria were solicited to participate in the study after the study was approved by the respective institutional review board. Depression and mental status of each subject were assessed using the BDI-II and the Folstein Mini-Mental State Exam, respectively. Serum folate, cobalamin, total homocysteine, and RBC folate were measured and mean values were evaluated for significant differences in the depressed and nondepressed groups. Of the subjects in this study, 43.8% had BDI-II scores > 10 indicating depression. The nondepressed subjects had significantly higher mean serum folate (281 +/- 649 vs. 52 +/- 137 ng/mL), serum cobalamin (1162 +/- 1014 vs. 757 +/- 463 pg/mL), and RBC folate (1433 +/- 1757 vs. 810 +/- 654 ng/mL) levels than did depressed subjects. In the nondepressed group, 39% of subjects were taking a supplement containing 35-42 mg folacin and 7 mg cobalamin per week while only 9.1% of depressed subjects were taking a vitamin containing these levels of B vitamins. The group means were not significantly different for age, months on HD, body mass index, erythropoietin/kg body weight, total homocysteine, hemoglobin, albumin, or ferritin. As with the general population, lower serum folate, RBC folate, and serum cobalamin levels were found in depressed as compared to nondepressed subjects on HD. Plasma levels of these vitamins may be one of many factors related to depression, but larger studies with stronger designs are needed to confirm the results of this study.

Evaluation of folate status by serum and erythrocyte folate levels and dietary folate intake in Taiwanese schoolchildren.

The folate status and dietary folate intake of Taiwanese schoolchildren was investigated by analysis of both serum and red blood cell (RBC) folate levels and dietary folate intake in 1105 boys and 958 girls aged 6-13 years sampled from the Nutrition and Health Survey in Taiwan Elementary School Children 2001-2002 (NAHSIT Children 2001-2002). Mean serum folate levels were 18.3+/-8.8 nmol/L (8.1+/-3.9 ng/mL) in boys and 20.3+/-9.7 nmol/L (9.0+/-4.3 ng/mL) in girls. Mean RBC folate levels were 700+/-320 nmol/L (308+/-141 ng/mL) in boys and 751+/-347 nmol/L (331+/-153 ng/mL) in girls. The prevalence of serum folate deficiency was 1.4% in boys and girls, and the prevalence of marginal serum folate deficiency (7-14 nmol/L) was 31.1% in boys and 25.8% in girls. In addition, 8.5% of boys and 7.4% girls had RBC folate deficiency (RBC folate < 318 nmol/L), and 17% of children had marginal RBC folate deficiency (RBC folate of 318-454 nmol/L). Our results suggesting that Taiwanese schoolchildren have poor folate status especially during periods of rapid growth and development such as the transition from childhood to early adolescence (boys at age 12-12.9, girls at age 11-12.9). The average estimated folate intakes were 269+/-9 microg/d in boys and 259+/-9 microg/d in girls, and 42% of Taiwanese schoolchildren had a dietary folate intake below 2/3 of the RDA, indicating a poor dietary folate intake in this population. This study shows that the folate status of Taiwanese schoolchildren is currently inadequate and strategies are needed for improvement.

Endothelial Function in Newborn Infants Is Related to Folate Levels and Birth Weight

Low maternal folate levels during pregnancy correlate with low birth weight, a perinatal risk factor for later cardiovascular disease. We studied relationships between red blood cell folate levels, birth weight, and vascular endothelial function (a key factor in the early pathophysiologic processes of heart disease) in newborn infants. We included 82 infants (30 low birth weight) and their mothers. A laser Doppler technique was used to measure skin perfusion during transdermal iontophoresis of acetylcholine (an endothelium-dependent vasodilator). Red blood cell folate, vitamin B12, and homocysteine levels were determined. The perfusion response to acetylcholine was lower in low birth weight infants than in normal birth weight control subjects (mean: 35 vs 76 perfusion units). The neonatal acetylcholine response correlated with red blood cell folate levels in both infants and their mothers. The folate levels of low birth weight and control infants did not differ significantly (mean: 1603 vs 1795 nmol/L), but mothers of low birth weight infants had lower folate levels than did mothers of control infants (mean: 805 vs 1109 nmol/L). In multivariate analysis, low birth weight and red blood cell folate levels contributed independently to endothelial function in newborn infants. The levels of vitamin B12 and homocysteine were similar in the 2 groups and did not correlate with endothelial function. The data presented here provide the first evidence for a relationship between folate levels and vascular endothelial function in newborn infants.