National and regional population attributable fractions for anemia risk factors (iron, folate, and vitamin B12) in Belize: potential impact of fortification.

Objective: To estimate the national and regional population attributable fraction (PAF) and potential number of preventable anemia cases for three nutritional risk factors (iron, red blood cell folate [RBCF], and vitamin B12 deficiencies) among women of childbearing age in Belize. Methods: A national probability-based household and micronutrient survey capturing sociodemographic and health information was conducted among 937 nonpregnant Belizean women aged 15-49 years. Blood samples were collected to determine hemoglobin, ferritin, alpha-1-glycoprotein (AGP), RBCF, and vitamin B12 status. All analyses used sample weights and design variables to reflect a complex sample survey. Logistic regression was used to determine adjusted prevalence risk (aPR) ratios, which were then used to estimate national and regional PAF for anemia. Results: The overall prevalence of anemia (hemoglobin <12 g/dL) was 21.2% (95% CI [18.7, 25.3]). The prevalence of anemia was significantly greater among women with iron deficiency (59.5%, 95% CI [48.7, 69.5]) compared to women without iron deficiency (15.2%, 95% CI [12.2, 18.3]; aPR 3.9, 95% CI [2.9, 5.1]). The three nutritional deficiencies examined contributed to 34.6% (95% CI [22.1, 47.1]) of the anemia cases. If all these nutritional deficiencies could be eliminated, then an estimated 5 953 (95% CI [3 807, 8 114]) anemia cases could be prevented. Conclusions: This study suggests that among women of child-bearing age in Belize, anemia cases might be reduced by a third if three modifiable nutritional risk factors (iron, RBCF, and vitamin B12 deficiencies) could be eliminated. Fortification is one potential strategy to improve nutritional status and reduce the burden of anemia in this population.

Associations between Genetic Variants and Blood Biomarkers of One-Carbon Metabolism in Postmenopausal Women from the Women's Health Initiative Observational Study.

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

Associations between Plasma Choline Metabolites and Genetic Polymorphisms in One-Carbon Metabolism in Postmenopausal Women: The Women's Health Initiative Observational Study.

BACKGROUND: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites. OBJECTIVES: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites. METHODS: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined. RESULTS: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration. CONCLUSIONS: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

Fracture in drug-eluting stents increases focal intimal hyperplasia in the atherosclerosed rabbit iliac artery.

OBJECTIVES: Drug-eluting stent (DES) strut fracture (SF) is associated with higher incidence of In-stent restenosis (ISR)-return of blockage in a diseased artery post stenting-than seen with bare metal stents (BMS). We hypothesize that concomitance of drug and SF leads to greater neointimal response. BACKGROUND: Controlled release of therapeutic agents, such as sirolimus and its analogs, or paclitaxel from has reduced tissue based DES failure modes compared to BMS. ISR is dramatically reduced and yet the implications of mechanical device failure is magnified. METHODS: Bilateral Xience Everolimus-eluting stents (EES) were implanted in 20 New Zealand White rabbits on normal (n = 7) or high fat (HF)/high cholesterol (HC) (n = 13) diets. Implanted stents were intact or mechanically fractured. Everolimus concentration was as packaged or pre-eluted. After 21 days, stented vessels were explanted, resin embedded, MicroCT scanned, and analyzed histomorphometrically. RESULTS: Fractured EES were associated with significant (P < 0.05) increases in arterial stenosis and neointimal formation and lower lumen-to-artery area ratios compared to intact EES. Hyperlipidemic animals receiving pre-eluted EES revealed no significant difference between intact and fracture groups. CONCLUSIONS: SF increases intimal hyperplasia, post EES implant, and worse with more advanced disease. Pre-eluted groups, reflective of BMS, did not show significant differences, suggesting a synergistic effect of everolimus and mechanical injury, potentially explaining the lack of SF reports for BMS. Here, we report that ISR has a higher incidence with SF in EES, the clinical implication is that patients with SF after DES implantation merit careful follow-up.

Percutaneous Hepatic Perfusion With Filtered Melphalan for Localized Treatment of Metastatic Hepatic Disease: A Risk Assessment.

Regional therapies for metastatic liver disease have garnered interest in recent years due to technological advances in drug delivery. A percutaneous hepatic perfusion (PHP) using a newly developed generation 2 (GEN2) filtration system was designed to mitigate systemic toxicity and cardiovascular risk associated with hepatic blood filtration during hepatic artery infusion of the chemotherapy drug melphalan. The GEN2 system was evaluated in healthy swine, and plasma samples were assessed for clinical chemistry, melphalan toxicokinetics (TK), inflammatory cytokines, catecholamines, hematological, and cardiac biomarkers. Cardiovascular safety was assessed by echocardiography, electrocardiogram, and telemetry. Toxicology parameters included clinical signs, body weight, gross pathology, and histopathology. There were no treatment-related deaths associated with the PHP procedure with GEN2 filtration, and all animals survived to scheduled necropsy. Assessment of the pharmacokinetic/TK plasma concentrations of melphalan demonstrated that the GEN2 filter was able to extract melphalan from blood with high efficiency and reduce melphalan exposure in the systemic circulation. The hemodynamic, immunosuppressive, immunotoxic, cardiotoxic, and histopathologic effects of melphalan were limited. The significant hemodynamic challenge imposed by filtration resulted in a compensatory tachycardia with supranormal left ventricular function, although no wall motion abnormalities were detected and left ventricular function remained normal. Catecholamines decreased and then quickly rebounded during washout. Transient and reversible effects of treatment on cardiac enzymes, catecholamines, and cytokines and reversible hemodynamic effects without cardiac damage indicated that PHP with melphalan was not cardiotoxic or immunotoxic under the conditions tested, due to high efficiency of the filtration system limiting exposure of melphalan to the systemic circulation.

Folate Deficiency Is Prevalent in Women of Childbearing Age in Belize and Is Negatively Affected by Coexisting Vitamin B-12 Deficiency: Belize National Micronutrient Survey 2011.

Background: Folate deficiency, vitamin B-12 deficiency, and anemia can have adverse effects on birth outcomes. Also, low vitamin B-12 reduces the formation of metabolically active folate.Objectives: We sought to establish the baseline prevalence of and factors associated with folate deficiency and insufficiency, vitamin B-12 deficiency, and anemia among women of childbearing age (WCBA) in Belize.Methods: In 2011, a national probability-based survey was completed among Belizean nonpregnant WCBA aged 15-49 y. Blood samples for determination of hemoglobin, folate (RBC and serum), and vitamin B-12 (plasma) and sociodemographic and health information were collected from 937 women. RBC and serum folate concentrations were measured by microbiologic assay (MBA). Folate status was defined based on both the WHO-recommended radioproteinbinding assay and the assay adjusted for the MBA.Results: The national prevalence estimates for folate deficiency in WCBA, based on serum and RBC folate concentrations by using the assay-matched cutoffs, were 11.0% (95% CI: 8.6%, 14.0%) and 35.1% (95% CI: 31.3%, 39.2%), respectively. By using the assay-matched compared with the WHO-recommended cutoffs, a substantially higher prevalence of folate deficiency was observed based on serum (6.9% absolute difference) and RBC folate (28.9% absolute difference) concentrations. The prevalence for RBC folate insufficiency was 48.9% (95% CI: 44.8%, 53.1%). Prevalence estimates for vitamin B-12 deficiency and marginal deficiency and anemia were 17.2% (95% CI: 14.2%, 20.6%), 33.2% (95% CI: 29.6%, 37.1%), and 22.7% (95% CI: 19.5%, 26.2%), respectively. The adjusted geometric means of the RBC folate concentration increased significantly (P-trend < 0.001) in WCBA who had normal vitamin B-12 status relative to WCBA who were vitamin B-12 deficient.Conclusions: In Belize, the prevalence of folate and vitamin B-12 deficiencies continues to be a public health concern among WCBA. Furthermore, low folate status co-occurred with low vitamin B-12 status, underlining the importance of providing adequate vitamin B-12 and folic acid intake through approaches such as mandatory food fortification.

DNA Methylation Changes in Whole Blood and CD16+ Neutrophils in Response to Chronic Folic Acid Supplementation in Women of Childbearing Age.

Folate, a water-soluble vitamin, is a key source of one-carbon groups for DNA methylation, but studies of the DNA methylation response to supplemental folic acid yield inconsistent results. These studies are commonly conducted using whole blood, which contains a mixed population of white blood cells that have been shown to confound results. The objective of this study was to determine if CD16+ neutrophils may provide more specific data than whole blood for identifying DNA methylation response to chronic folic acid supplementation. The study was performed in normal weight (BMI 18.5 - 24.9 kg/m2) women (18 - 35 y; n = 12), with blood samples taken before and after 8 weeks of folic acid supplementation at 800 µg/day. DNA methylation patterns from whole blood and isolated CD16+ neutrophils were measured across >485,000 CpG sites throughout the genome using the Infinium HumanMethylation450 BeadChip. Over the course of the 8-week supplementation, 6746 and 7513 CpG sites changed (p < 0.05) in whole blood and CD16+ neutrophils, respectively. DNA methylation decreased in 68.4% (whole blood) and 71.8% (CD16+ neutrophils) of these sites. There were only 182 CpG sites that changed in both the whole blood and CD16+ neutrophils, 139 of which changed in the same direction. These results suggest that the genome-wide DNA methylation response to chronic folic acid supplementation is different between whole blood and CD16+ neutrophils and that a single white blood cell type may function as a more specific epigenetic reporter of folate status than whole blood.

Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study.

BACKGROUND: Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations. METHODS: Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations. RESULTS: Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-ß-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3ß (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS). CONCLUSIONS: Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.

Biomarkers of Nutrition for Development-Folate Review.

The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.

Two Blades-Up Runs Using the JetStream Navitus Atherectomy Device Achieve Optimal Tissue Debulking of Nonocclusive In-Stent Restenosis: Observations From a Porcine Stent/Balloon Injury Model.

PURPOSE: To determine the number of runs with blades up (BU) using the JetStream Navitus to achieving optimal debulking in a porcine model of femoropopliteal artery in-stent restenosis (ISR). METHODS: In this porcine model, 8 limbs were implanted with overlapping nitinol self-expanding stents. ISR was treated initially with 2 blades-down (BD) runs followed by 4 BU runs (BU1 to BU4). Quantitative vascular angiography (QVA) was performed at baseline, after 2 BD runs, and after each BU run. Plaque surface area and percent stenosis within the treated stented segment were measured. Intravascular ultrasound (IVUS) was used to measure minimum lumen area (MLA) and determine IVUS-derived plaque surface area. RESULTS: QVA showed that plaque surface area was significantly reduced between baseline (83.9%±14.8%) and 2 BD (67.7%±17.0%, p=0.005) and BU1 (55.4%±9.0%, p=0.005) runs, and between BU1 and BU2 runs (50.7%±9.7%, p<0.05). Percent stenosis behaved similarly with no further reduction after BU2. There were no further reductions in plaque surface area or percent stenosis with BU 3 and 4 runs (p=0.10). Similarly, IVUS (24 lesions) confirmed optimal results with BU2 runs and no additional gain in MLA or reduction in plaque surface area with BU3 and 4. IVUS confirmed no orbital cutting with JetStream Navitus. There were no stent strut discontinuities on high-resolution radiographs following atherectomy. CONCLUSION: JetStream Navitus achieved optimal tissue debulking after 2 BD and 2 BU runs with no further statistical gain in debulking after the BU2 run. Operators treating ISR with JetStream Navitus may be advised to limit their debulking to 2 BD and 2 BU runs to achieve optimal debulking.

Biomarkers of one-carbon metabolism are associated with biomarkers of inflammation in women.

Folate-mediated one-carbon metabolism is essential for DNA synthesis, repair, and methylation. Perturbations in one-carbon metabolism have been implicated in increased risk of some cancers and may also affect inflammatory processes. We investigated these interrelated pathways to understand their relation. The objective was to explore associations between inflammation and biomarkers of nutritional status and one-carbon metabolism. In a cross-sectional study in 1976 women selected from the Women's Health Initiative Observational Study, plasma vitamin B-6 [pyridoxal-5'-phosphate (PLP)], plasma vitamin B-12, plasma folate, and RBC folate were measured as nutritional biomarkers; serum C-reactive protein (CRP) and serum amyloid A (SAA) were measured as biomarkers of inflammation; and homocysteine and cysteine were measured as integrated biomarkers of one-carbon metabolism. Student's t, chi-square, and Spearman rank correlations, along with multiple linear regressions, were used to explore relations between biomarkers; additionally, we tested stratification by folic acid fortification period and multivitamin use. With the use of univariate analysis, plasma PLP was the only nutritional biomarker that was modestly significantly correlated with serum CRP and SAA (ρ = -0.22 and -0.12, respectively; P < 0.0001). Homocysteine (µmol/L) showed significant inverse correlations with all nutritional biomarkers (ranging from ρ = -0.30 to ρ = -0.46; all P < 0.0001). With the use of multiple linear regression, plasma PLP, RBC folate, homocysteine, and cysteine were identified as independent predictors of CRP; and PLP, vitamin B-12, RBC folate, and homocysteine were identified as predictors of SAA. When stratified by folic acid fortification period, nutrition-homocysteine correlations were generally weaker in the postfortification period, whereas associations between plasma PLP and serum CRP increased. Biomarkers of inflammation are associated with PLP, RBC folate, and homocysteine in women. The connection between the pathways needs to be further investigated and causality established. The trial is registered at clinicaltrials.gov as NCT00000611.

Does obesity modify the association of supplemental folic acid with folate status among nonpregnant women of childbearing age in the United States?

BACKGROUND: Obesity is associated with an increased risk of having a pregnancy affected by a neural tube defect (NTD). It is not clear whether the amount of folic acid required by obese women to protect against NTDs is the same as that for nonobese women. METHODS: We analyzed data from the National Health and Nutrition Examination Survey, representative of the noninstitutionalized civilian U.S. population, to assess whether body mass index (BMI; normal weight, overweight, and obese categories) modified the association between supplemental folic acid intake and folate status. We estimated the geometric mean concentration among nonpregnant women of childbearing age (15-44 years) during the postfortification period of: serum folate (2003-2008); red blood cell (RBC) folate (2007-2008); and plasma total homocysteine (tHcy; 2003-2006), adjusted for age, race and ethnicity, and total dietary folate expressed as dietary folate equivalents for strata of supplement use and BMI. RESULTS: BMI was inversely associated with serum folate among women who did not use supplements containing folic acid; no differences between women in different BMI categories were observed among supplement users. Regardless of supplement use, obese women had the highest RBC folate concentrations. There were no differences in tHcy by BMI, regardless of supplement use. CONCLUSIONS: These results do not support a straightforward modification of the relationship between supplemental folic acid intake and folate status by BMI. In this population, BMI may affect the body distribution of folate, as reflected by lower serum and higher RBC folate levels in obese women who do not use supplements.

Assessment of vitamin B(12) absorption based on the accumulation of orally administered cyanocobalamin on transcobalamin.

BACKGROUND: Vitamin B(12), or cobalamin (Cbl), is absorbed in the intestine and transported to the cells bound to transcobalamin (TC). We hypothesize that cyanocobalamin (CNCbl) is absorbed unchanged, thereby allowing measurement of the complex of CNCbl bound to TC (TC-CNCbl) to be used for studying the absorption of the vitamin. METHODS: TC was immunoprecipitated from serum samples obtained from healthy donors at baseline and at 24 h after oral administration of three 9-microg CNCbl doses over 1 day. Cbl was released by treatment with subtilisin Carlsberg. The different forms of Cbl were isolated by HPLC and subsequently quantified with an ELISA-based Cbl assay. RESULTS: At baseline, the median TC-CNCbl concentration was 1 pmol/L (range, 0-10 pmol/L); the intraindividual variation (SD) was 1.6 pmol/L (n = 31). After CNCbl administration, the TC-CNCbl concentration increased significantly (P = 0.0003, paired t-test), whereas no major changes were observed in any of the other Cbl forms bound to TC (n = 10). Only a moderate additional increase in TC-CNCbl was observed with prolonged (5 days) CNCbl administration (n = 10). We designed an absorption test based on measuring TC-CNCbl at baseline and 24 h after CNCbl intake and established a reference interval for the increase in TC-CNCbl (n = 78). The median absolute increase was 23 pmol/L (range, 6-64 pmol/L), and the relative increase was >3-fold. CONCLUSIONS: Our data demonstrate that CNCbl is absorbed unchanged and accumulates on circulating TC. We suggest that measuring TC-CNCbl will improve the assessment of vitamin B(12) absorption.

MTHFR, TGFB3, and TGFA polymorphisms and their association with the risk of non-syndromic cleft lip and cleft palate in China.

Our previous results indicated a moderate association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C-T variant and an increased risk of non-syndromic cleft lip with or without cleft palate (nsCL/P) among the northern but not southern population in China, suggesting possible genetic heterogeneity in the etiology of nsCL/P between these two populations. It remains unknown whether the transforming growth factor alpha (TGFA) gene TaqI polymorphism and transforming growth factor beta 3 (TGFB3) gene CA repeats influence the risk of nsCL/P differently between the northern and southern Chinese populations. In this study of 188 Chinese case-parent triads, we found an independent association between the TGFB3 variant and risk of nsCL/P (OR = 2.10, 95% CI: 1.25-3.54 for heterozygotes; OR = 1.78, 95% CI: 0.83-3.83 for homozygotes). The MTHFR variant was associated with an increased risk of nsCL/P among children in the north (OR = 3.11, 95% CI: 1.18-8.23 for heterozygotes; OR = 3.36, 95%CI: 1.14-9.93 for homozygotes) and appear to interact marginally with the TGFB3 variant in the occurrence of nsCL/P among southern subjects (OR = 0.26, 95% CI: 0.06-1.07). No association was found between the TGFA variant and risk of nsCL/P in our data. Our results suggest that the TGFB3 gene variant may be an important genetic risk factor for nsCL/P occurrence in Chinese children, and we found no evidence of heterogeneity between northern and southern Chinese populations in the associations between TGFB3 and TGFA variants and risk of nsCL/P, but these results warrant further investigation.

Iron, folate, and B(12) deficiencies and their associations with anemia among women of childbearing age in a rural area in Northern China.

OBJECTIVE: To assess the prevalence of folate, vitamin B(12), and iron deficiencies and their associations with anemia among women of childbearing age in northern China, an area with a reported high incidence of neural tube defects. METHODS: Plasma folate, vitamin B(12), ferritin, and hemoglobin levels were measured among 1,671 non-pregnant women of childbearing age from Xianghe County, Hebei Province, China in June 2004. RESULTS: Geometric means [95 % confidence interval (CI)] of plasma concentrations were 9.3 (4.0, 21.6) nmol/L for folate, 213.1 (82.4, 550.9) pmol/L for vitamin B(12), 17.4 (1.1, 278.6) microg/L for ferritin, and 129.9 (104.6, 161.4) g/L for hemoglobin (Hb). Approximately 24 % of women had biochemical evidence of folate deficiency (<6.8 nmol/L), 21.4 % were deficient (<148 pmol/L) in vitamin B(12), 30.2 % had iron depletion (<15 microg/L), and anemia (Hb < 120 g/L) was detected among 15.4 % of women. Of the three nutrients, only iron depletion (ferritin < 15 microg/L) was independently associated with anemia (adjusted odds ratio = 6.4, 95 % CI 4.8, 8.6). CONCLUSIONS: Although there were substantial proportions of folate and vitamin B(12) deficiencies among women of childbearing age in northern China, iron deficiency was the most important contributor to anemia.

Fortification of flour with folic acid.

BACKGROUND: After randomized, controlled trials established that consumption of folic acid before pregnancy and during the early weeks of gestation reduces the risk of a neural tube defect (NTD)-affected pregnancy, the United States Public Health Service recommended in 1992 that all women capable of becoming pregnant consume 400 microg folic acid daily. In 1998, folic acid fortification of all enriched cereal grain product flour was fully implemented in the United States and Canada. OBJECTIVE: To provide guidance on national fortification of wheat and maize flours to prevent 50 to 70% of the estimated 300,000 NTD-affected pregnancies worldwide. METHODS: An expert workgroup reviewed the latest evidence of effectiveness of folic acid flour fortification and the safety of folic acid. RESULTS: Recent estimates show that in the United States and Canada, the additional intake of about 100 to 150 microg/day of folic acid through food fortification has been effective in reducing the prevalence of NTDs at birth and increasing blood folate concentrations in both countries. Most potential adverse effects associated with folic acid are associated with extra supplement use not mandatory fortification. Fortification of wheat flour has a proven record of prevention in other developed countries. In 2009, 51 countries had regulations written for mandatory wheat flour fortification programs that included folic acid. CONCLUSIONS: NTDs remain an important cause of perinatal mortality and infantile paralysis worldwide. Mandatory fortification of flour with folic acid has proved to be one of the most successful public health interventions in reducing the prevalence of NTD-affected pregnancies. Most developing countries have few, if any, common sources of folic acid, unlike many developed countries, which have folic acid available from ready-to-eat cereals and supplements. Expanding the number of developed and developing countries with folic acid flour fortification has tremendous potential to safely eliminate most folic acid-preventable NTDs.

Preclinical evaluation of the ANCD thrombectomy device: safety and efficacy in a swine clot model.

BACKGROUND: The Advanced Thrombectomy System (ANCD) provides a new funnel component designed to reduce clot fragmentation and facilitate retrieval in patients with stroke by locally restricting flow, allowing distal aspiration in combination with a stent retriever (SR). OBJECTIVE: To evaluate the preclinical efficacy and safety of the ANCD in a swine clot model. METHODS: Soft and firm clots were implanted in the lingual and cervical arteries of 11 swine to obtain Thrombolysis in Cerebral Infarction (TICI) 0 blood flow. Mechanical thrombectomy was performed with either a balloon guide catheter+Solitaire 2 stent retriever (BGC+SR, n=13) or ANCD+SR (n=13). TICI flow was evaluated and successful revascularization was defined as TICI 3 (normal perfusion). To characterize safety, a total of 3 passes were performed in each vessel independent of recanalization. Tissues were explanted for histopathological analysis after 3 and 30 days, respectively. RESULTS: First pass reperfusion rates were ANCD+SR: 69% and BGC+SR: 46%. Reperfusion increased after the third pass in both groups (ANCD+SR: 100%, vs BGC+SR: 77%). Recanalization was achieved after an average of 1.4 and 1.9 passes in ANCD+SR and BGC+SR (p=0.095), respectively. Vessel injury was comparable in both groups; endothelial loss at 3 days was the most common injury seen (ANCD+SR: 1.78±1.22; BGC+SR: 2.03±1.20; p=0.73), while other histopathological markers were absent or minimal. Tissues downstream from targeted vessels also showed absence or minimal lesions across both groups. CONCLUSIONS: Results in a swine clot model support the high efficacy of the ANCD+SR without causing clinically significant vessel injury potentially related to the new funnel component.

Phytotoxicity of constituents of glandular trichomes and the leaf surface of camphorweed, Heterotheca subaxillaris.

Camphorweed, Heterotheca subaxillaris (Lam.) Britt. & Rusby, has a camphor-like odor, and its leaf surfaces contain glandular trichomes of the type shown to contain high levels of isoprenoids in other species. Borneol (1), the phytotoxic calamenene-type sesquiterpenes (2-5, 9-11), and methylated flavones (12-15) were isolated from the dichloromethane rinsate of camphorweed aerial tissues. The strongest plant growth inhibitor against Agrostis stolonifera and Lactuca sativa seedlings, as well as duckweed (Lemna pausicostata), was 2-methoxy-calamenene-14-carboxylic acid (2). Esterification of calamenene carboxylic acids decreased their biological activity.

National and regional population attributable fractions for anemia risk factors (iron, folate, and vitamin B12) in Belize: potential impact of fortification / Fracciones atribuibles poblacionales nacionales y regionales de factores de riesgo de anemia (hierro, folato y vitamina B12) en Belice: posible impacto del enriquecimiento de los alimentos con suplementos / Frações atribuíveis populacionais nacionais e regionais de fatores de risco para anemia (ferro, ácido fólico e vitamina B12) em Belize: potencial impacto da fortificação

[ABSTRACT]. Objective. To estimate the national and regional population attributable fraction (PAF) and potential number of preventable anemia cases for three nutritional risk factors (iron, red blood cell folate [RBCF], and vitamin B12 deficiencies) among women of childbearing age in Belize. Methods. A national probability-based household and micronutrient survey capturing sociodemographic and health information was conducted among 937 nonpregnant Belizean women aged 15–49 years. Blood samples were collected to determine hemoglobin, ferritin, alpha-1-glycoprotein (AGP), RBCF, and vitamin B12 status. All analyses used sample weights and design variables to reflect a complex sample survey. Logistic regression was used to determine adjusted prevalence risk (aPR) ratios, which were then used to estimate national and regional PAF for anemia. Results. The overall prevalence of anemia (hemoglobin <12 g/dL) was 21.2% (95% CI [18.7, 25.3]). The prevalence of anemia was significantly greater among women with iron deficiency (59.5%, 95% CI [48.7, 69.5]) compared to women without iron deficiency (15.2%, 95% CI [12.2, 18.3]; aPR 3.9, 95% CI [2.9, 5.1]). The three nutritional deficiencies examined contributed to 34.6% (95% CI [22.1, 47.1]) of the anemia cases. If all these nutritional deficiencies could be eliminated, then an estimated 5 953 (95% CI [3 807, 8 114]) anemia cases could be prevented. Conclusions. This study suggests that among women of child-bearing age in Belize, anemia cases might be reduced by a third if three modifiable nutritional risk factors (iron, RBCF, and vitamin B12 deficiencies) could be eliminated. Fortification is one potential strategy to improve nutritional status and reduce the burden of anemia in this population.

[RESUMEN]. Objetivo. Calcular la fracción atribuible poblacional a nivel nacional y regional y el número de casos de anemia que podrían prevenirse para tres factores de riesgo nutricional (deficiencia de hierro, folato eritrocitario y vitamina B12) en las mujeres en edad reproductiva en Belice. Metodología. Se llevó a cabo una encuesta probabilística nacional sobre características de los hogares y micronutrientes en la que se recopiló información sociodemográfica y de salud de 937 mujeres beliceñas no embarazadas de entre 15 y 49 años. Se extrajeron muestras de sangre para determinar los niveles de hemoglobina, ferritina, alfa–1–glucoproteína, folato eritrocitario y vitamina B12. En todos los análisis se emplearon ponderaciones muestrales y variables calculadas para tener en cuenta que se trataba de una encuesta con una muestra compleja. Se estimaron mediante regresión logística las razones de riesgos de prevalencia ajustados, que posteriormente se utilizaron para calcular la fracción atribuible poblacional con respecto a la anemia a nivel nacional y regional. Resultados. La prevalencia global de la anemia (hemoglobina <12 g/dl) fue del 21,2% (IC del 95%: 18,7– 25,3). La prevalencia de la anemia fue significativamente mayor en las mujeres con ferropenia (59,5%, IC del 95%: 48,7–69,5) que en las que no tenían ferropenia (15,2%, IC del 95%: 12,2, 18,3); razón de riesgos de prevalencia ajustados = 3.9, IC del 95%; 2,9–5,1). Las tres deficiencias nutricionales examinadas explicaban al 34,6% (IC del 95%: 22,1–47,1) de los casos de anemia. Se estima que si pudieran eliminarse todas estas deficiencias nutricionales, se prevendrían unos 5953 (IC del 95%: 3807–8114) casos de anemia. Conclusiones. Los resultados de este estudio sugieren que los casos de anemia en las mujeres en edad reproductiva de Belice podrían reducirse en un tercio si se pudieran eliminar tres factores de riesgo nutricionales modificables (deficiencias de hierro, folato eritrocitario y vitamina B12). Una posible estrategia para mejorar el estado nutricional y reducir la carga de la anemia en este grupo poblacional es en el enriquecimiento de los alimentos con suplementos.

[RESUMO]. Objetivo. Estimar a fração atribuível populacional (FAP) nacional e regional e o potencial número de casos preveníveis de anemia para três fatores de risco nutricionais (deficiência de ferro, ácido fólico eritrocitário e vitamina B12) entre mulheres em idade fértil em Belize. Métodos. Realizou-se um inquérito probabilístico domiciliar nacional sobre micronutrientes, que coletou informações sociodemográficas e de saúde de 937 mulheres belizenhas não grávidas com idade entre 15 e 49 anos. Coletaram-se amostras de sangue para dosagem de hemoglobina, ferritina, alfa-1-glicoproteína (AGP), ácido fólico eritrocitário e vitamina B12. Todas as análises usaram variáveis de delineamento e ponderações amostrais para refletir um inquérito amostral complexo. Aplicou-se regressão logística para determinar razões ajustadas de risco de prevalência (RPa), que foram usadas para estimar a FAP nacional e regional para anemia. Resultados. A prevalência geral de anemia (hemoglobina <12 g/dL) foi de 21,2% (IC 95% [18,7–25,3]). A prevalência de anemia foi significativamente maior em mulheres com deficiência de ferro (59,5%, IC 95% [48,7–69,5]) que em mulheres sem deficiência de ferro (15,2%, IC 95% [12,2–18,3]); RPa 3,9, IC 95% [2,9– 5,1]). As três deficiências nutricionais analisadas contribuíram para 34,6% (IC 95% [22,1–47,1]) dos casos de anemia. Caso se eliminassem todas essas deficiências nutricionais, seria possível evitar cerca de 5.953 (IC 95% [3.807–8.114]) casos de anemia. Conclusões. Este estudo sugere que, nas mulheres belizenhas em idade fértil, os casos de anemia poderiam ser reduzidos em um terço caso fosse possível eliminar três fatores de risco nutricionais modificáveis (deficiência de ferro, ácido fólico eritrocitário e vitamina B12). A fortificação é uma possível estratégia para melhorar o estado nutricional e reduzir a carga de anemia nessa população.

Folate status in women of reproductive age as basis of neural tube defect risk assessment.

Reliable folate status data for women of reproductive age (WRA) to assess global risk for neural tube defects (NTDs) are needed. We focus on a recent recommendation by the World Health Organization that a specific "optimal" red blood cell (RBC) folate concentration be used as the sole indicator of NTD risk within a population and discuss how to best apply this guidance to reach the goal of assessing NTD risk globally. We also emphasize the importance of using the microbiologic assay (MBA) as the most reliable assay for obtaining comparable results for RBC folate concentration across time and countries, the need for harmonization of the MBA through use of consistent key reagents and procedures within laboratories, and the requirement to apply assay-matched cutoffs for folate deficiency and insufficiency. To estimate NTD risk globally, the ideal scenario would be to have country-specific population-based surveys of RBC folate in WRA determined utilizing a harmonized MBA, as was done in recent studies in Guatemala and Belize. We conclude with guidance on next steps to best navigate the road map toward the goal of generating reliable folate status data on which to assess NTD risk in WRA in low- and middle-income countries.