Folate deficiency modifies the risk of CIN3+ associated with DNA methylation levels: a nested case-control study from the ASCUS-COL trial.

PURPOSE: To our knowledge, there are very few studies evaluating if the levels of folate modify the risk of cervical intraepithelial neoplasia grade 2 and higher (CIN2+ and CIN3+) associated with the levels of HPV genome methylation, two cofactors related to single carbon metabolism and independently associated with cervical cancer in previous studies. We conducted a case-control study nested in a three-arm randomized clinical pragmatic trial (ASCUS-COL trial) to evaluate the risk of CIN3+ associated with methylation levels according to serum folate concentrations. METHODS: Cases (n = 155) were women with histologically confirmed CIN2+ (113 CIN2, 38 CIN3, and 4 SCC) and controls were age and follow-up time at diagnosis-matched women with histologically confirmed ≤ CIN1 (n = 155), selected from the 1122 hrHPV + women of this trial. The concentrations of serum folate were determined by the radioimmunoassay SimulTRAC-SNB-VitaminB12/Folate-RIAKit and the methylation levels by the S5 classifier. Stepwise logistic regression models were used to estimate the association between folate or methylation levels and CIN2+ or CIN3+. The joint effect of folate levels and methylation on the risk of CIN3+ was estimated using combinations of categorical stratifications. RESULTS: Folate levels were significantly lower in women with CIN3+ than in other diagnostic groups (p = 0.019). The risk of CIN3+ was eight times higher (OR 8.9, 95% CI 3.4-24.9) in women with folate deficiency and high methylation levels than in women with normal folate and high methylation levels (OR 1.4, 95% CI 0.4-4.6). CONCLUSION: High methylation and deficient folate independently increased the risk of CIN3+ while deficient folate combined with high methylation was associated with a substantially elevated risk of CIN3+.

High Serum Folate Concentration, Vitamin B12 Deficiency, and Anthropometric Nutritional Status in Brazilian Children Aged 6-59 Months: Data from the Brazilian National Survey of Child Nutrition.

BACKGROUND: Vitamin B12 and folate are key nutrients that help children reach their full potential in growth and development; however, little is known about the status of these vitamins in Brazilian children. OBJECTIVES: To describe the serum concentrations of vitamin B12 and folate, to investigate the association between high folate concentration (HFC) and vitamin B12 deficiency, and to evaluate the association between vitamin B12 and stunting/underweight in Brazilian children aged 6-59 mo. METHODS: Data from 7417 children aged 6-59 mo collected during the Brazilian National Survey on Child Nutrition were used. Serum concentrations of vitamin B12 of <150 pmol/L and folate of <10 nmol/L were classified as deficient, and folate concentrations of >45.3 nmol/L were classified as HFC. Children with length/height-for-age z-score of less than -2 were considered stunted, and those with weight-for-age z-score of less than -2 were underweight. Logistic regression models were performed. RESULTS: In Brazil, 14.2% (95% CI: 12.2, 16.1) of children aged 6-59 mo had vitamin B12 deficiency, 1.1% (95% CI: 0.5, 1.6) had folate deficiency, and 36.9% (95% CI: 33.4, 40.3) had HFC. Vitamin B12 deficiency was higher in children from the northern region of Brazil (28.5%), between 6 and 24 mo (25.3%), whose mothers had lower formal education (0-7 y; 18.7%). Children with HFC had 62% lower odds (OR: 0.38; 95% CI: 0.27, 0.54) of vitamin B12 deficiency than those with normal/deficient folate. Children with vitamin B12 deficiency and normal/deficient folate had higher odds of stunting (OR: 1.58; 95% CI: 1.02, 2.43) than children without vitamin B12 deficiency and normal/deficient folate. CONCLUSIONS: Vitamin B12 deficiency is a public health problem among Brazilian children aged <2 y with vulnerable socioeconomic status. HFC was inversely associated with vitamin B12 deficiency, and lower odds of stunting were observed in children with HFC and vitamin B12 deficiency than in those with vitamin B12 deficiency and normal/deficient folate.

Folic acid supplementation during pregnancy alters behavior in male rat offspring: nitrative stress and neuroinflammatory implications.

Pregnancy diet can impact offspring's neurodevelopment, metabolism, redox homeostasis, and inflammatory status. In pregnancy, folate demand is increased due to the requirement for one-carbon transfer reactions. The present study was proposed to investigate the effect of folic acid supplementation throughout pregnancy on a battery of behavior tests (olfactory preference, motor activity, exploratory capacity, habituation, memory, anxiety- and depression-like behavior). Redox homeostasis and neuroinflammatory status in cerebral cortex were also investigated. After pregnancy confirmation, the pregnant rats were randomly divided into two groups, according to the diet: group 1, (control) standard diet (2 mg/kg diet of folic acid) and group 2, supplemented diet with 4 mg/kg diet of folic acid. Throughout the gestational period, the pregnant rats received experimental diets. Results show that the supplemented diet with 4 mg/kg diet of folic acid throughout pregnancy impaired memory and motricity of the offspring when compared with control (standard diet). It was also observed an increase in anxiety- and depression-like behavior in this group. Nitrite levels increased in cerebral cortex of the offspring, when compared to control group. In contrast, iNOS expression and immunocontent were not altered. Moreover, we identify an increase in TNF-α, IL-1ß, IL-6, IL-10, and MCP-1 gene expression in the cerebral cortex. In conclusion, our study showed that the supplemented diet with 4 mg/kg diet of folic acid throughout pregnancy may cause behavioral and biochemical changes in the male offspringGraphical abstract After pregnancy confirmation, the pregnant rats were randomly divided into two groups, according to the diet: group 1, (control) standard diet (2 mg/kg diet of folic acid) and group 2, supplemented diet with 4 mg/kg diet of folic acid. Throughout the gestational period, the pregnant rats received experimental diets. Results show that folic acid supplementation did not impair the mother-pup relationship. We showed that supplemented diet with 4 mg/kg diet of folic acid during pregnancy impairs memory and motricity of the offspring when compared with standard diet. It was also observed an increase in anxiety- and depression-like behavior in this group. Nitrative stress and neuroinflammation parameters were increased in the cerebral cortex of the offspring. ROS, reactive oxygen species.

Prevalence and Disparities in Folate and Vitamin B12 Deficiency Among Preschool Children in Guatemala.

BACKGROUND AND OBJECTIVE: Folate and vitamin B12 deficiencies can impair proper growth and brain development in children. Data on the folate and vitamin B12 status of children aged 6-59 months in Guatemala are scarce. Identification of factors associated with higher prevalence of these micronutrient deficiencies within the population is needed for national and regional policymakers. OBJECTIVE: To describe national and regional post-fortification folate and vitamin B12 status of children aged 6-59 months in Guatemala. METHODS: A multistage, cluster probability study was carried out with national and regional representation of children aged 6-59 months. Demographic and health information was collected for 1246 preschool children, but blood samples for red blood cell (RBC) folate and vitamin B12 were collected and analyzed for 1,245 and 1143 preschool children, respectively. We used the following deficiency criteria as cutoff points for the analyses: < 305 nmol/L for RBC folate, < 148 pmol/L for vitamin B12 deficiency, and 148-221 pmol/L for marginal vitamin B12 deficiency. Prevalence of RBC folate deficiency and vitamin B12 deficiency and marginal deficiency were estimated. Prevalence risk ratios of RBC folate and vitamin B12 deficiency were estimated comparing subpopulations of interest. RESULTS: The national prevalence estimates of RBC folate deficiency among children was 33.5% [95% CI 29.1, 38.3]. The prevalence of RBC folate deficiency showed wide variation by age (20.3-46.6%) and was significantly higher among children 6-11 months and 12-23 months (46.6 and 37.0%, respectively), compared to older children aged 48-59 months (20.3%). RBC folate deficiency also varied widely by household wealth index (22.6-42.0%) and geographic region (27.2-46.7%) though the differences were not statistically significant. The national geometric mean for RBC folate concentrations was 354.2 nmol/L. The national prevalences of vitamin B12 deficiency and marginal deficiency among children were 22.5% [95% CI 18.2, 27.5] and 27.5% [95% CI 23.7, 31.7], respectively. The prevalence of vitamin B12 deficiency was significantly higher among indigenous children than among non-indigenous children (34.5% vs. 13.1%, aPRR 2.1 95% CI 1.4, 3.0). The prevalence of vitamin B12 deficiency also significantly varied between the highest and lowest household wealth index (34.3 and 6.0%, respectively). The national geometric mean for vitamin B12 concentrations was 235.1 pmol/L. The geometric means of folate and B12 concentrations were significantly lower among children who were younger, had a lower household wealth index, and were indigenous (for vitamin B12 only). Folate and vitamin B12 concentrations showed wide variation by region (not statistically significant), and the Petén and Norte regions showed the lowest RBC folate and vitamin B12 concentrations, respectively. CONCLUSIONS: In this study, a third of all children had RBC folate deficiency and half were vitamin B12 deficient. Folate deficiency was more common in younger children and vitamin B12 deficiency was more common in indigenous children and those from the poorest families. These findings suggest gaps in the coverage of fortification and the need for additional implementation strategies to address these gaps in coverage to help safeguard the health of Guatemalan children.

Thyroid Dysfunction, Vitamin B12, and Folic Acid Deficiencies Are Not Associated With Cognitive Impairment in Older Adults in Lima, Peru.

Background: Reversible etiologies of cognitive impairment are common and treatable, yet the majority of mild cognitive impairment (MCI) and dementia research in Latin America has focused on irreversible, neurodegenerative etiologies. Objective: We sought to determine if thyroid dysfunction and vitamin B12 and folate deficiencies are associated with cognitive disorders among older adults with memory complaints in Lima, Peru. Methods: This was a retrospective review of patients who presented for cognitive evaluations to a multidisciplinary neurology clinic in Lima, Peru from January 2014 to February 2020. We included individuals aged ≥60 years, native Spanish-speakers, with at least a primary school educational level and a complete clinical assessment. Patients had either subjective cognitive decline (SCD), MCI, or dementia. One-way ANOVA and multiple logistic regression analyses were performed. Results: We included 720 patients (330 SCD, 154 MCI, and 236 dementia); the dementia group was significantly older [mean age SCD 69.7 ± 4.1, dementia 72.4 ± 3.7 (p = 0.000)] and had lower folate levels than SCD patients. The MCI group had higher free T3 levels compared with SCD patients. Those with lower TSH had greater dementia risk (OR = 2.91, 95%CI: 1.15-6.86) but not MCI risk in unadjusted models. B12 deficiency or borderline B12 deficiency was present in 34% of the dementia group, yet no clear correlation was seen between neuropsychological test results and B12 levels in our study. There was no association between MCI or dementia and thyroid hormone, B12 nor folate levels in adjusted models. Conclusion: Our findings do not support an association between metabolic and endocrine disorders and cognitive impairment in older Peruvians from Lima despite a high prevalence of B12 deficiency. Future work may determine if cognitive decline is associated with metabolic or endocrine changes in Latin America.

Effects of maternal folic acid supplementation on nuclear methyltransferase activity of adult rats subjected to an animal model of schizophrenia.

INTRODUCTION: Schizophrenia is considered one of the most disabling and severe human diseases worldwide. The etiology of schizophrenia is thought to be multifactorial and evidence suggests that DNA methylation can play an important role in underlying pivotal neurobiological alterations of this disorder. Some studies have demonstrated the effects of dietary supplementation as an alternative approach to the prevention of schizophrenia, including folic acid. However, no study has ever investigated the role of such supplementation in altering the DNA methylation system in the context of schizophrenia. OBJECTIVES: The present study aims to investigate the effects of maternal folic acid supplementation at different doses on nuclear methyltransferase activity of adult rat offspring subjected to an animal model schizophrenia induced by ketamine. METHODS: Adult female Wistar rats, (60 days old) received folic acid-deficient diet, control diet, or control diet plus folic acid supplementation (at 5, 10, or 50 mg/kg) during pregnancy and lactation. After reaching adulthood (60 days), the male offspring of these dams were subjected to the animal model of schizophrenia induced by 7 days of ketamine intraperitoneal injection (25 mg/kg). After the 7-day protocol, the activity of nuclear methyltransferase was evaluated in the brains of the offspring. RESULTS: Maternal folic acid supplementation at 50 mg/kg increased methyltransferase activity in the frontal cortex, while 10 mg/kg increased methyltransferase activity in the hippocampus. In the striatum of offspring treated with ketamine, maternal deficient diet, control diet, and folic acid supplementation at 5 mg/kg decreased methyltransferase activity compared to the control group. The folic acid supplementation at 10 and 50 mg/kg reversed this ketamine effect. CONCLUSIONS: Maternal FA deficiency could be related to schizophrenia pathophysiology, while FA supplementation could present a protective effect since it demonstrated persistent effects in epigenetic parameters in adult offspring.

Inhibition of MTOR signaling impairs rat embryo organogenesis by affecting folate availability.

Mechanistic target of rapamycin (MTOR) is essential for embryo development by acting as a nutrient sensor to regulate cell growth, proliferation and metabolism. Folate is required for normal embryonic development and it was recently reported that MTOR functions as a folate sensor. In this work, we tested the hypothesis that MTOR functions as a folate sensor in the embryo and its inhibition result in embryonic developmental delay affecting neural tube closure and that these effects can be rescued by folate supplementation. Administration of rapamycin (0.5 mg/kg) to rats during early organogenesis inhibited embryonic ribosomal protein S6, a downstream target of MTOR Complex1, markedly reduced embryonic folate incorporation (-84%, P < 0.01) and induced embryo developmental impairments, as shown by an increased resorption rate, reduced embryo somite number and delayed neural tube closure. These alterations were prevented by folic acid administered to the dams. Differently, although an increased rate of embryonic rotation defects was observed in the rapamycin-treated dams, this alteration was not prevented by maternal folic acid supplementation. In conclusion, MTOR inhibition during organogenesis in the rat resulted in decreased folate levels in the embryo, increased embryo resorption rate and impaired embryo development. These data suggest that MTOR signaling influences embryo folate availability, possibly by regulating the transfer of folate across the maternal-embryonic interface.

Folic Acid Supplementation in the Gestational Phase of Female Rats Improves Age-Related Memory Impairment and Neuroinflammation in Their Adult and Aged Offspring.

Folic acid (FA) supplementation is important during pregnancy to avoid malformations in the offspring. However, it is unknown if it can affect the offspring throughout their lives. To evaluate the offspring, female mother rats (dams) were separated into 5 groups: Four groups received the AIN-93 diet, divided into control and FA (5, 10, and 50 mg/kg), and an additional group received a FA-deficient diet, and the diet was performed during pregnancy and lactation. We evaluated the female offspring of these dams (at 2 and 18 months old). The aged offspring fed with FA-deficient diet presented habituation, spatial and aversive memory impairment and the FA maternal supplementation prevented this. The natural aging caused an increase in the TNF-α and IL-1ß levels in the hippocampus from 18-month-old offspring. FA maternal supplementation was able to prevent the increase of these cytokines. IL-4 levels decreased in the prefrontal cortex from aged control rats and FA prevented it. FA deficiency decreased the levels of IL-4 in the hippocampus of the young offspring. In addition, natural aging and FA deficiency decreased brain-derived neurotrophic factor levels in the hippocampus and nerve growth factor levels in the prefrontal cortex and FA supplementation prevented it. Thus, the present study shows for the first time the effect of FA maternal supplementation on memory, cytokines, and neurotrophins in the aged offspring.

Zinc deficiency associated with anaemia among young children in rural Guatemala.

One in four children younger than age five in Guatemala experiences anaemia (haemoglobin <11.0 g/dl). This study characterized the factors and micronutrient deficiencies associated with anaemia in a baseline cross-sectional sample of 182 Guatemalan infants/toddlers and 207 preschoolers, using generalized linear mixed models. Associations between anaemia and maternal, child and household variables, and biomarkers (soluble transferrin receptor, ferritin, zinc, folate, vitamin B12, C-reactive protein, and α1-acid glycoprotein) were explored. Rates of anaemia were 56% among infants/toddlers and 12.1% among preschoolers. In children with anaemia, rates of iron deficiency (low ferritin based on inflammation status, and/or high soluble transferrin receptor, ≥1.97 mg/L) and zinc deficiency (serum zinc <65 µg/dl) were 81.1% and 53.7%, respectively. Folate deficiency (either plasma folate <3 ng/ml or erythrocyte folate <100 ng/ml) was 3.3%. Vitamin B12 deficiency (plasma vitamin B12 <148 pmol/L) was 7.5%. For infants and toddlers (<24 months), the odds ratio of anaemia was lower when higher number of adults lived in the household (OR = 0.69; 95% CI [0.53, 0.90]), and higher when children were zinc deficient (OR = 3.40; 95% CI [1.54, 7.47]). For preschoolers (36-60 months), the odds ratio of anaemia was lower for every additional month of age (OR = 0.90; 95% CI [0.81, 1.00]). Findings suggest that micronutrient deficiencies coexist in Guatemalan rural children, and zinc deficiency is associated with anaemia in children <24 months, highlighting the need of continued multidisciplinary interventions with multiple micronutrients. Further research examining how household composition, feeding practices, and accessibility to micronutrient supplements and to animal source foods is needed to incorporate strategies to improve the nutritional status of Guatemalan children.

Quinoa pasta fermented with lactic acid bacteria prevents nutritional deficiencies in mice.

In recent years, quinoa (Chenopodium quinoa Willd), an ancestral crop of the Andean region of South America, has gained worldwide attention due to its high nutritional value. This grain is a good source of several vitamins and minerals; however, their bioavailability is decreased by the presence of antinutritional factors such as phytic acid. These compounds can be reduced using lactic acid bacteria (LAB), that have a GRAS (Generally Recognized as Safe) status and have traditionally been associated with food fermentation due to their biosynthetic capacity and metabolic versatility. The objective of this study was to evaluate the effectiveness of a pasta made with quinoa sourdough fermented by L. plantarum strains producing vitamins B2 and B9 and phytase to prevent vitamins and minerals deficiency using an in vivo mouse model. The results showed that the pasta fermented with the mixed culture containing L. plantarum CRL 2107 + L. plantarum CRL 1964 present increased B2 and B9 levels in mice blood. Likewise, higher concentrations of P, Ca+2, Fe+2, Mg+2 (18.75, 10.70, 0.37, 4.85 mg/dL, respectively) were determined with respect to the deficient group (DG) (9.85, 9.90, 0.26, 3.34 mg/dL, respectively). Hematological studies showed an increase in hemoglobin (14.4 ±â€¯0.6 g/dL), and hematocrit (Htc, 47.0 ±â€¯0.6%) values, compared to the DG (Hb: 12.6 ±â€¯0.5 g/dL, Hto: 39.9 ±â€¯1.1%). Furthermore, histological evaluations of the intestines showed an increase of the small intestine villi length in this latter group. The results allow us to conclude that bio-enrichment of quinoa pasta using LAB could be a novel strategy to increase vitamin and minerals bioavailability in cereal/pseudocereal - derived foods.

Validación de un cuestionario sobre factores de riesgo para defectos congénitos / Validation of a questionnaire about risk factors for congenital defects

Introducción: Los defectos congénitos constituyen la primera causa de muerte infantil en los países desarrollados y la segunda en muchos países en vías de desarrollo. Objetivo: Validar un cuestionario sobre factores de riesgo para defectos congénitos relacionados con la deficiencia de ácido fólico. Métodos: El proceso de validación se basó en un proceso dinámico de retroalimentación y toma de decisiones cambiante, de acuerdo al criterio de expertos, para lo que se utilizó el método Delphi, el cual constó de tres etapas: selección de los expertos, análisis y validación de cada uno de los ítems por parte de los expertos y su posterior reevaluación y, por último, la realización de un estudio piloto. En el proceso de validación del cuestionario se calculó el coeficiente de concordancia de Kendall y Friedman con el objetivo de determinar concordancia o similitudes de las respuestas de los evaluadores respectivamente. Resultados: Se seleccionaron 18 expertos con altos niveles de competencia de acuerdo al cálculo de los coeficientes de conocimiento y argumentación. En la segunda versión del cuestionario existió similitud en las respuestas de los expertos a favor de la categoría superior de muy bien, así como concordancia en el nivel de respuesta de los expertos. Conclusiones: El cuestionario diseñado dispone de niveles óptimos de validez de contenido y factibilidad para identificar los factores de riesgo para defectos congénitos sensibles a la deficiencia de ácido fólico(AU)

Introduction: Congenital defects are the leading cause of child mortality in developed countries and the second in many developing countries. Objective: Validate a questionnaire about risk factors for congenital defects related to folic acid deficiency. Methods: Validation was based on a dynamic process of feedback and changing decision-making geared by expert criteria for which use was made of the Delphi method in three stages: selection of experts, analysis and validation of each item by the experts and further re-evaluation, and conduct of a pilot study. Kendall and Friedman's coefficient of concordance was estimated to determine the agreement or similarities between the answers provided by the evaluators. Results: Eighteen highly-qualified experts were selected based on the knowledge and argumentation coefficients estimated. In the second version of the questionnaire the answers provided by experts coincided in awarding the higher category of 'very good', and there was concordance in the experts' response level. Conclusions: The questionnaire designed is characterized by optimal levels of content validity and feasibility to identify risk factors for congenital defects related to folic acid deficiency(AU)

Estomatitis aftosa recurrente y deficiencias nutricionales: Reporte de tres casos y revisión de literatura / Recurrent Aphthous Stomatitis and Nutritional Deficiencies: Report of Three Cases with Literature Review

RESUMEN Introducción: La estomatitis aftosa recurrente (EAR) es la enfermedad ulcerativa más común que afecta la mucosa oral no queratinizada. La etiología aún se desconoce, pero se han propuesto varios factores locales y sistémicos como agentes causales. Descripción del caso: se informa tres pacientes con presencia de EAR asociada a deficiencias nutricionales, debidas a dietas de restricción alimentaria. El primer caso, una mujer de 19 años con deficiencia de hierro, refirió tomar té verde a diario y consumir poca cantidad de carbohidratos, grasas y carne. El segundo caso, un hombre de 32 años con deficiencia de hierro y vitamina B12 asociada a dieta tipo vegana, aunque a veces si consumía carne. El tercer caso, hombre de 50 años, vegano y exfumador desde hace un año, presentó deficiencia de hierro, vitamina B12 y ácido fólico. En los tres casos un detallado interrogatorio, examen clínico y análisis sanguíneo completo, permitió establecer un adecuado diagnóstico, manejo odontológico y derivación con un nutricionista, con el fin de tratar la patología de base y no sólo brindarles un tratamiento sintomático de las lesiones. Discusión: Ante un cuadro de EAR es recomendable realizar un análisis que incluya hemograma, ácido fólico, hierro y vitamina B12, para descartar posibles causas sistémicas y eventualmente tratarlas. El manejo clínico tiene como objetivo mejorar la función del paciente y la calidad de vida mediante terapias tópicas y sistémicas; sin embargo, es fundamental identificar y controlar los factores causales que contribuyen; así como, la exclusión o tratamiento de la enfermedad sistémica subyacente.

ABSTRACT Introduction: Recurrent aphthous stomatitis (RAS) is the most common ulcerative disease that affects the non-keratinized oral mucosa. The etiology is still unknown, but several local and systemic factors have been proposed as causal agents. Case description: three patients are reported with RAS associated with nutritional deficiencies, due to dietary restriction diets. The first case, a 19-year- old woman with iron deficiency, reported taking green tea daily and consuming a small amount of carbohydrates, fats and meat. The second case, a 32-year-old man with iron deficiency and vitamin B12 associated with vegan diet, although sometimes if he consumed meat. The third case, man of 50 years, vegan and ex-smoker for a year, presented deficiency of iron, vitamin B12 and folic acid. In all three cases a detailed questioning, clinical examination and complete blood analysis allowed to establish an adequate diagnosis, dental management and referral with a nutritionist, in order to treat the underlying pathology and not only provide a symptomatic treatment of the injuries. Discussion: In the setting of RAS, it is advisable to perform an analysis that includes a blood count, folic acid, iron and vitamin B12, to rule out possible systemic causes and eventually treat them. Clinical management aims to improve patient function and quality of life through topical and systemic therapies; however, it is essential to identify and control the causal factors that contribute; as well as, the exclusion or treatment of the underlying systemic disease.

Non-alcoholic fatty liver disease and neurological defects.

INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) can be considered one of the most common causes of liver disease in our days and is regarded as one of the newest vascular risk factors for cerebrovascular and other neurological diseases. MATERIALS AND METHODS: We studied a group of neurological outpatients, divided into two homogenous groups based on the presence or absence of NAFLD. RESULTS AND CONCLUSIONS: We testified an independent relationship between NAFLD and common vascular risk factors (age, sex, educational level, BMI, cholesterol and lipid assessment, Hb1ac). At the same time, we ascertained an independent relationship between NAFLD and more recently recognized vascular risk factors, such as lack of folate, vitamin B12 and vitamin D-OH25, and increased levels of homocysteine. Finally, we have documented that NAFLD showed worse executive and frontal functions, and behavioral changes, such as depressive mood and anxiety, and apathy.

Concentrations of Intra-erythrocyte Folate, Serum Vitamin B12, and Hemoglobin in Women of Childbearing Age and Associated Factors.

Objective: The aim was to verify the relations among intra-erythrocyte folate, serum vitamin B12, and hemoglobin concentrations in women of childbearing age and their association with several socioeconomic and demographic variables, nutritional status, and food consumption in the city of Recife, Northeastern Brazil.Methods: This was a cross-sectional study with a random sample of 1,210 women of childbearing age from the city of Recife. Concentrations of serum vitamin B12 and intra-erythrocyte folate were analyzed by immunoassay and hemoglobin concentrations by automated determination. A questionnaire was used to collect socioeconomic and demographic data of nutritional status and a food frequency questionnaire was used to evaluate food consumption.Results: Reductions in hemoglobin concentrations were found in 141 women (12.0%; 95% confidence interval (CI), 10.3-13.9), serum vitamin B12 in 81 women (7.0%; 95% CI, 5.7-8.6), and only 1 woman had a reduction in intra-erythrocyte folate concentrations. No women had a concomitant reduction of intra-erythrocyte folate, serum vitamin B12, and hemoglobin concentrations. However, 13 women (1.1%; 95% CI, 0.6-1.9) had a concomitant deficiency of hemoglobin and vitamin B12. Intra-erythrocyte folate concentrations were higher in women of a higher age and income. Hemoglobin concentrations were lower in smokers, and serum vitamin B12 concentrations did not show a significant variation in relation to socioeconomic, demographic, and anthropometric parameters. There was no strong correlation between food consumption and biochemical concentrations evaluated.Conclusion: Despite the strategies to eradicate anemia, this nutritional deficiency was dominant. Serum vitamin B12 deficiency outpacing intra-erythrocyte folate is worrying due to the lack of programs to fight against vitamin B12 insufficiency. Age and income were directly related to intra-erythrocyte folate concentrations. Food consumption suggests that there is a homeostatic control to maintain equilibrium at biochemical concentrations.

Serum folate and vitamin B12 status in young Brazilian children.

OBJECTIVE: To assess the nutritional status of folate and vitamin B12 with anaemia in young children. DESIGN: A cross-sectional study was conducted at the primary health-care centres of four Brazilian cities. Folate and vitamin B12 were assessed by fluoroimmunoassay. Multilevel Poisson regression models were used to explore the association of folate and vitamin B12 status in relation to anaemia in young children. SETTING: Brazil.ParticipantsChildren (n 460) aged 11 to 15 months. RESULTS: The median (interquartile range) of serum folate was 39·7 (28·8-55·3) nmol/l and only four children presented with folate deficiency (<10 nmol/l). Surprisingly, 30·9 % of children presented with serum folate concentrations above the upper limit of detectable values by the commercial kit used for analysis. The frequency of vitamin B12 deficiency (<148 pmol/l) was 15 % and it was inversely associated with the highest tertile of serum folate concentrations (P<0·001). Having high serum folate concentration (≥50·1 nmol/l) and vitamin B12≥148 pmol/l was associated with lower frequency of anaemia in these children (prevalence ratio=0·53; 95% CI 0·30, 0·92). CONCLUSIONS: High frequency of elevated serum concentration of folate was found among young Brazilian children and 15 % of them had vitamin B12 deficiency. The combination of high serum folate and normal vitamin B12 status was associated with a lower frequency of anaemia in these children. Improvements in the current strategies to promote healthy food-based complementary feeding along with prevention and control of micronutrient deficiencies are recommended to improve children's health.

Dried blood spot microbiological assay indicates high prevalence of folate deficiency in rural adult men and women in the Haitian Central Plateau.

BACKGROUND: Although folate deficiency is linked to adverse health effects, limited data exist characterizing the problem in rural settings. This study determined the prevalence of folate deficiency and anemia in rural adults in the Haitian Central Plateau using combined laboratory methods. METHODS: Dried blood spots (DBSs) and hemoglobin measurements were collected from adult men and women selected by cluster random sampling in Haiti's Central Plateau. DBSs were analyzed for folate using a microbiological assay. Hemoglobin levels were determined using both a HemoCue photometer and the sodium lauryl sulfate microplate method. Red cell folate (RCF) levels were determined by normalizing DBS folate to hemoglobin. RESULTS: Of the 197 subjects assessed for hemoglobin, 11.4% of males and 21.0% of females were anemic (male: hemoglobin<12 g/dL; female: hemoglobin<11 g/dL). Of the 173 subjects assessed for RCF, 27.9% of men and 14.9% of women were folate deficient (RCF<340 nmol/L). Among reproductive-age women, 83.6% had RCF levels associated with a risk of neural tube defects of >14 per 10 000 live births (RCF≤699 nmol/L). CONCLUSIONS: Adults in the Haitian Central Plateau suffer from high rates of anemia and folate deficiency, putting the population at elevated risk for disease. DBSs and microbiological assay make folate evaluation feasible, even in low-resource regions.

Seleção e aplicação de bactérias láticas produtoras de folato para obtenção de um leite fermentado bioenriquecido e avaliação de biodisponibilidade do folato produzido / Screening and application of folate-producing lactic acid bacteria for production of bioenriched fermented milk and evaluation of the bioavaliability of the produced folate

A deficiência de folato é um problema de saúde pública que vem sendo combatido através da fortificação obrigatória de ácido fólico. Entretanto, a ingestão excessiva pode causar efeitos colaterais indesejados. A forma natural da vitamina produzida por algumas cepas de bactérias láticas pode ser uma alternativa segura para aumentar a ingestão de folato pela população. Este trabalho visou selecionar as melhores cepas de BAL produtoras de folato, identificar as melhores condições para a produção da vitamina e avaliar a biodisponibilidade do folato produzido pelas cepas no leite fermentado, empregando-se testes em modelos animais. O estudo foi desenvolvido com cinco cepas de Streptococcus thermophilus (34v, 170v, 268v, 361v e 341 pc) e um cepa de Lactobacillus plantarum (16cv), todas boas produtoras de folato. As condições de produção e a combinação de cepas que resultaram na melhor produção folato foram utilizadas para produzir um leite biofermentado (BFM), avaliando-se a biodisponibilidade da vitamina produzida empregando-se um modelo animal de depleção/repleção, com camundongos Balb/c submetidos a 14 dias de depleção, seguido de 21 dias de repleção da vitamina. Após os 35 dias, os animais foram sacrificados, retirando-se sangue, rins, fígado, baço e intestino para quantificação de folato e avaliação histológica da mucosa intestinal. Todas as quantificações de folato foram feitas pelo método microbiológico. A melhor combinação de cepas (St. Thermophilus 34v + Lb. Plantarum 16cv) resultou na produção de 300 ng/mL de folato, sendo a temperatura de 42ºC melhor que 37ºC para a produção da vitamina. A produção de folato no leite na fermentação em pH controlado 6,0 foi 35% superior à observada no leite fermentado em pH livre. As concentrações de folato no baço e glóbulos vermelhos foram mais altas nos camundongos que ingeriram leite fermentado bioenriquecido (BFM) em relação aos demais grupos de animais. A relação vilosidade/cripta nos camundongos dos grupos BFM foi igual à observada nos animais que receberam leite suplementado com ácido fólico. Houve aumento da hemoglobina, hematócrito e hemácias nos camundongos que ingeriram BFM, evidenciando a bioeficácia do folato produzido. Esses resultados indicam que a produção de folato por bactérias láticas selecionadas em produtos fermentados pode ser uma boa alternativa para aumentar a ingestão de vitamina B9 pela população

A deficiência de folato é um problema de saúde pública que vem sendo combatido através da fortificação obrigatória de ácido fólico. Entretanto, a ingestão excessiva pode causar efeitos colaterais indesejados. A forma natural da vitamina produzida por algumas cepas de bactérias láticas pode ser uma alternativa segura para aumentar a ingestão de folato pela população. Este trabalho visou selecionar as melhores cepas de BAL produtoras de folato, identificar as melhores condições para a produção da vitamina e avaliar a biodisponibilidade do folato produzido pelas cepas no leite fermentado, empregando-se testes em modelos animais. O estudo foi desenvolvido com cinco cepas de Streptococcus thermophilus (34v, 170v, 268v, 361v e 341 pc) e um cepa de Lactobacillus plantarum (16cv), todas boas produtoras de folato. As condições de produção e a combinação de cepas que resultaram na melhor produção folato foram utilizadas para produzir um leite biofermentado (BFM), avaliando-se a biodisponibilidade da vitamina produzida empregando-se um modelo animal de depleção/repleção, com camundongos Balb/c submetidos a 14 dias de depleção, seguido de 21 dias de repleção da vitamina. Após os 35 dias, os animais foram sacrificados, retirando-se sangue, rins, fígado, baço e intestino para quantificação de folato e avaliação histológica da mucosa intestinal. Todas as quantificações de folato foram feitas pelo método microbiológico. A melhor combinação de cepas (St. Thermophilus 34v + Lb. Plantarum 16cv) resultou na produção de 300 ng/mL de folato, sendo a temperatura de 42ºC melhor que 37ºC para a produção da vitamina. A produção de folato no leite na fermentação em pH controlado 6,0 foi 35% superior à observada no leite fermentado em pH livre. As concentrações de folato no baço e glóbulos vermelhos foram mais altas nos camundongos que ingeriram leite fermentado bioenriquecido (BFM) em relação aos demais grupos de animais. A relação vilosidade/cripta nos camundongos dos grupos BFM foi igual à observada nos animais que receberam leite suplementado com ácido fólico. Houve aumento da hemoglobina, hematócrito e hemácias nos camundongos que ingeriram BFM, evidenciando a bioeficácia do folato produzido. Esses resultados indicam que a produção de folato por bactérias láticas selecionadas em produtos fermentados pode ser uma boa alternativa para aumentar a ingestão de vitamina B9 pela população

Prevalence of low folate deficiency after wheat flour supplementation - should we still measure serum folate?

ABSTRACT Objectives: To determine the frequency of folic acid deficiency in consecutive serum folate determinations and to determine whether there was a significant decrease in serum folate deficiency after folate was added to wheat flour. Methods: A retrospective descriptive observational study was performed of consecutive folate measurements at the Hospital Privado Universitario, Cordoba, Argentina. Results: Two cohorts were analyzed: 1197 folate measurements between 2001 and 2008 (before supplementation) and 3335 folate measurements from 2009 to 2014 (after supplementation). Folate deficiency was found in 84/1197 (7%) subjects in the pre-supplementation group and in 58/3335 (1.73%) after supplementation. The prevalence of folate deficiency was 12% between 2001 and 2003 when folate was not added to flour compared to 4% in 2004-2007 (p-value < 0.0001) when folate was added to the flour but no widespread use was documented. Conclusions: In the studied population, the prevalence of serum folic acid deficiency after folate supplementation was low at 1.73%. There was a significant decrease in folate deficiency after folate was added to wheat flour. Given the low prevalence of folic acid deficiency observed in this and similar studies, and the observed change with supplementation, we conclude that routine measurement of serum folate is of limited clinical use.

Folate deficiency prevents neural crest fate by disturbing the epigenetic Sox2 repression on the dorsal neural tube.

Folate deficiency has been known to contribute to neural tube and neural crest defects, but why these tissues are particularly affected, and which are the molecular mechanisms involved in those abnormalities are important human health questions that remain unanswered. Here we study the function of two of the main folate transporters, FolR1 and Rfc1, which are robustly expressed in these tissues. Folate is the precursor of S-adenosylmethionine, which is the main donor for DNA, protein and RNA methylation. Our results show that knockdown of FolR1 and/or Rfc1 reduced the abundance of histone H3 lysine and DNA methylation, two epigenetic modifications that play an important role during neural and neural crest development. Additionally, by knocking down folate transporter or pharmacologically inhibiting folate transport and metabolism, we observed ectopic Sox2 expression at the expense of neural crest markers in the dorsal neural tube. This is correlated with neural crest associated defects, with particular impact on orofacial formation. By using bisulfite sequencing, we show that this phenotype is consequence of reduced DNA methylation on the Sox2 locus at the dorsal neural tube, which can be rescued by the addition of folinic acid. Taken together, our in vivo results reveal the importance of folate as a source of the methyl groups necessary for the establishment of the correct epigenetic marks during neural and neural crest fate-restriction.