A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants.

We recently showed that riboflavin is a selected substrate of breast cancer resistance protein (BCRP) over P-glycoprotein (P-gp) and demonstrated its prediction performance in preclinical drug-drug interaction (DDI) studies. The aim of this study was to investigate the suitability of riboflavin to assess BCRP inhibition in humans. First, we assessed the substrate potential of riboflavin toward other major drug transporters using established transfected cell systems. Riboflavin is a substrate for organic anion transporter (OAT)1, OAT3, and multidrug and toxin extrusion protein (MATE)2-K, with uptake ratios ranging from 2.69 to 11.6, but riboflavin is not a substrate of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)2, and MATE1. The effects of BMS-986371, a potent in vitro inhibitor of BCRP (IC 50 0.40 µM), on the pharmacokinetics of riboflavin, isobutyryl carnitine, and arginine were then examined in healthy male adults (N = 14 or 16) after oral administration of methotrexate (MTX) (7.5 mg) and enteric-coated (EC) sulfasalazine (SSZ) (1000 mg) alone or in combination with BMS-986371 (150 mg). Oral administration of BMS-986371 increased the area under the plasma concentration-time curves (AUCs) of rosuvastatin and immediate-release (IR) SSZ to 1.38- and 1.51-fold, respectively, and significantly increased AUC(0-4h), AUC(0-24h), and C max of riboflavin by 1.25-, 1.14-, and 1.11-fold (P-values of 0.003, 0.009, and 0.025, respectively) compared with the MTX/SSZ EC alone group. In contrast, BMS-986371 did not significantly influence the AUC(0-24h) and C max values of isobutyryl carnitine and arginine (0.96- to 1.07-fold, respectively; P > 0.05). Overall, these data indicate that plasma riboflavin is a promising biomarker of BCRP that may offer a possibility to assess drug candidate as a BCRP modulator in early drug development. SIGNIFICANCE STATEMENT: Endogenous compounds that serve as biomarkers for clinical inhibition of breast cancer resistance protein (BCRP) are not currently available. This study provides the initial evidence that riboflavin is a promising BCRP biomarker in humans. For the first time, the value of leveraging the substrate of BCRP with acceptable prediction performance in clinical studies is shown. Additional clinical investigations with known BCRP inhibitors are needed to fully validate and showcase the utility of this biomarker.

Circulating trimethyllysine and risk of acute myocardial infarction in patients with suspected stable coronary heart disease.

BACKGROUND: The carnitine precursor trimethyllysine (TML) is associated with progression of atherosclerosis, possibly through a relationship with trimethylamine-N-oxide (TMAO). Riboflavin is a cofactor in TMAO synthesis. We examined prospective relationships of circulating TML and TMAO with acute myocardial infarction (AMI) and potential effect modifications by riboflavin status. METHODS: By Cox modelling, risk associations were examined amongst 4098 patients (71.8% men) with suspected stable angina pectoris. Subgroup analyses were performed according to median plasma riboflavin. RESULTS: During a median follow-up of 4.9 years, 336 (8.2%) patients experienced an AMI. The age- and sex-adjusted hazard ratio (HR) (95% CI) comparing the 4th vs. 1st TML quartile was 2.19 (1.56-3.09). Multivariable adjustment for traditional cardiovascular risk factors and indices of renal function only slightly attenuated the risk estimates [HR (95% CI) 1.79 (1.23-2.59)], which were particularly strong amongst patients with riboflavin levels above the median (Pint  = 0.035). Plasma TML and TMAO were strongly correlated (rs  = 0.41; P < 0.001); however, plasma TMAO was not associated with AMI risk in adjusted analyses [HR (95% CI) 0.81 (0.58-1.14)]. No interaction between TML and TMAO was observed. CONCLUSION: Amongst patients with suspected stable angina pectoris, plasma TML, but not TMAO, independently predicted risk of AMI. Our results motivate further research on metabolic processes determining TML levels and their potential associations with cardiovascular disease. We did not adjust for multiple comparisons, and the subgroup analyses should be interpreted with caution.

The Homozygous Hemoglobin EE Variant Is Associated with Poorer Riboflavin Status in Cambodian Women of Reproductive Age.

BACKGROUND: Riboflavin is required for erythropoiesis, which is increased in people with hemoglobinopathies due to increased hemolysis and erythrocyte turnover. Dietary intake and status of riboflavin is poor in Cambodia, where hemoglobinopathies are common. OBJECTIVE: We assessed the association between genetic hemoglobin disorders and riboflavin status in women of reproductive age in Cambodia. METHODS: Venous blood samples from 515 Cambodian women of reproductive age, 18-45 y, were analyzed for biomarker status of riboflavin [erythrocyte glutathione reductase activation coefficient (EGRac)], genetic hemoglobin (Hb) disorders, and hematological indices. Linear regression analysis was used to estimate the association between EGRac with Hb, ferritin, and Hb genotypes. EGRac was log transformed in the analyses, and the regression coefficients represent the geometric mean differences. RESULTS: Genetic Hb disorders were present in 57% of the population, with the homozygous hemoglobin E variant (Hb EE) occurring in ∼10% of women (n = 53). Deficient (EGRac ≥1.40) or marginal riboflavin status (EGRac ≥1.30 and <1.40) was observed in 92% (n = 475) of women. The variant Hb EE genotype was associated with 18% (95% CI: 9%, 28%) higher geometric mean EGRac values than the normal Hb AA genotype (P < 0.001). CONCLUSIONS: Although riboflavin biomarker deficiency or marginal status is widely prevalent in Cambodian women, lower riboflavin status was observed more frequently in women with the Hb EE genotype than in women with normal Hb AA. The relation between genetic Hb disorders and riboflavin warrants further investigation. This trial was registered at clinicaltrials.gov as NCT01593423 and NCT02481375.

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

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

[The association between the whole blood riboflavin level and the occurrence, development and prognosis of esophageal squamous cell carcinoma].

Objective: To investigate the association between the whole blood riboflavin level and the occurrence, development and prognosis of esophageal squamous cell carcinoma (ESCC) in China. Methods: From March 2014 to September 2018, ESCC patients from three hospitals (the Affiliated Hospital of Medical College of Shantou University, Shantou Central Hospital in Southern Chaoshan area and First Affiliated Hospital of Zhengzhou University in Northern Taihang Mountain) were selected as a case group; non-esophageal patients who had a physical examination were selected as a control group. The case and control group were paired by age (±5 years) and a 1:1 ration. A total of 1 528 subjects were enrolled including 764 patients in the case group and 764 patients in the control group. About 3-5 ml venous blood samples were collected, and the erythrocyte glutathione reductase activity coefficient (GRAC) was measured to assess the whole blood riboflavin level. A multivariate conditional logistic regression model was used to analyze the association between the GRAC and the risk of ESCC. The association between the GRAC and the prognosis of ESCC was analyzed by using Cox proportional risk regression model based on 288 patients with complete survival data. They were divided into two groups, the high GRAC group (GRAC≥7.87) group and the low GRAC group (GRAC<7.87) according to the strongest correlation between the total survival time, survival outcome and GRAC (GRAC=7.87). Results: Among the 1 528 patients, 958 patients were from Southern Chaoshan area, including 479 patients in the case group with an average age about (59.90±9.34) years and 479 patients in the control group with an average age about (59.55±8.77) years. Other 570 patients were from Northern Taihang Mountain area, including 285 patients in the case group with an average age (58.39±5.19) years and 285 patients in the control group with an average age about (58.74±4.57) years. The multivariate conditional logistic regression showed that the OR (95%CI) of the GRAC and the risk of ESCC was 1.009 (0.998-1.019). The Cox proportional hazard regression model analysis showed that the HR (95%CI) of the high GRAC group was 1.712 (1.034-2.824) compared with the low GRAC group in the 50-70 years group. Conclusion: The whole blood riboflavin level might not be associated with the occurrence of ESCC. The high whole blood riboflavin level would be more beneficial to the prognosis of ESCC patients aged 50-70 years.

[Magnesium and vitamin B2 status of children with bronchial asthma and obesity].

Insufficiency or deficiency of some micronutrients may be additional modifying factors that influence the pathogenesis of the disease and the effectiveness of standard pharmacotherapy. The aim of the study - to evaluate the level of magnesium and vitamin B2 in blood serum of patients with bronchial asthma and obesity in order to develop methods for individual correction of deficiency. Material and methods. The study included 51 children aged 12-17 years. The first group included 23 patients (12 girls and 11 boys) with asthma with comorbidities (obesity), and the second group consisted of 28 children (10 girls and 18 boys) with obesity. The concentration of magnesium in blood serum was determined by a colorimetric method without deproteinization, and vitamin B2 - by an immunological microbiological method. Results and discussion. When analyzing the concentration of magnesium in blood serum of the examined children, it was found that in patients with bronchial asthma and obesity, a reduced content of this mineral was observed in 15 (65.2%) patients. The average magnesium concentration was 0.66±0.02 mmol/l at a rate of 0.7-1.2 mmol/l. A statistically significant decrease in the magnesium level in children suffering from asthma and obesity was noted, compared with the level in children with obesity (0.66 [0.57; 0.73] vs 0.71 [0.67; 0.73] mmol/l, р<0.05). Low serum magnesium levels in obese patients were detected more rarely (р<0.05) - only in 6 (21.4%) children, mostly in patients with grade III obesity. The remaining 22 (78.6%) children had magnesium level within the normal range. Patients with low serum magnesium levels showed increased irritability, sleep disturbance, loss of memory and concentration. Vitamin B2 levels in all examined children were within the normal range (137-370 ng/ml). Conclusion. The results indicate a decrease in the concentration of magnesium and normal levels of vitamin B2 in serum in patients with bronchial asthma and obesity. Low serum magnesium levels were observed in children with low bronchial asthma control. To increase the effectiveness of therapy and control the symptoms of bronchial asthma, especially when combined with obesity, correction of the accompanying magnesium deficiency is necessary.

Low vitamin B12 increases risk of gastric cancer: A prospective study of one-carbon metabolism nutrients and risk of upper gastrointestinal tract cancer.

Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed prediagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988. We conducted a nested case-control study including 127 noncardia gastric adenocarcinoma (NCGA), 41 esophagogastric junctional adenocarcinoma and 60 esophageal squamous cell carcinoma incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower prediagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7-12.6 for lowest compared to highest quartile, p-trend <0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population. As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen.

Plasma Riboflavin Level is Associated with Risk, Relapse, and Survival of Esophageal Squamous Cell Carcinoma.

Riboflavin is an essential micronutrient for normal cellular activity, and deficiency may result in disease, such as cancer. We performed a case-control study to explore the association of riboflavin levels with risk and prognosis of esophageal squamous cell carcinoma (ESCC). Plasma riboflavin levels, as measured by enzyme-linked immunosorbent assay (ELISA), in ESCC patients were significantly lower than in those of healthy controls (7.04 ± 6.34 ng/ml vs. 9.32 ± 12.40 ng/ml; P < 0.05). Moreover, there was an inverse relationship between riboflavin level and risk of ESCC (odds ratio (OR) = 0.97, 95% confidence interval (CI) = 0.95-0.99, P =  0.02). The 5-year relapse-free and overall survival rates were significantly lower when riboflavin levels were ≤0.8 ng/ml than >0.8 ng/ml (relapse-free survival rate: 29.4% vs. 54.8%; overall survival rate: 28.6% vs. 55.6%). Plasma riboflavin level was an independent protective factor for both relapse-free (hazard ratio (HR) = 0.325, 95% CI = 0.161-0.657, P = 0.002) and overall survival of ESCC patients (HR = 0.382, 95% CI = 0.190-0.768, P = 0.007). In conclusion, plasma riboflavin levels are significantly related to risk and prognosis of ESCC patients, suggesting that moderate supplementation of riboflavin will decrease risk and prevent recurrence of ESCC and also improve prognosis of ESCC patients.

Severe riboflavin deficiency induces alterations in the hepatic proteome of starter Pekin ducks.

Suboptimal vitamin B2 status is encountered globally. Riboflavin deficiency depresses growth and results in a fatty liver. The underlying mechanisms remain to be established and an overview of molecular alterations is lacking. We investigated hepatic proteome changes induced by riboflavin deficiency to explain its effects on growth and hepatic lipid metabolism. In all, 360 1-d-old Pekin ducks were divided into three groups of 120 birds each, with twelve replicates and ten birds per replicate. For 21 d, the ducks were fed ad libitum a control diet (CAL), a riboflavin-deficient diet (RD) or were pair-fed with the control diet to the mean daily intake of the RD group (CPF). When comparing RD with CAL and CPF, growth depression, liver enlargement, liver lipid accumulation and enhanced liver SFA (C6 : 0, C12 : 0, C16 : 0, C18 : 0) were observed. In RD, thirty-two proteins were enhanced and thirty-one diminished (>1·5-fold) compared with CAL and CPF. Selected proteins were confirmed by Western blotting. The diminished proteins are mainly involved in fatty acid ß-oxidation and the mitochondrial electron transport chain (ETC), whereas the enhanced proteins are mainly involved in TAG and cholesterol biosynthesis. RD causes liver lipid accumulation and growth depression probably by impairing fatty acid ß-oxidation and ETC. These findings contribute to our understanding of the mechanisms of liver lipid metabolic disorders due to RD.

Vitamin B2, vitamin B12 and total homocysteine status in children and their associations with dietary intake of B-vitamins from different food groups: the Healthy Growth Study.

PURPOSE: To examine the associations between the dietary intakes of certain B-vitamins from different food sources with the relevant plasma status indices in children. METHODS: A representative subsample of 600 children aged 9-13 years from the Healthy Growth Study was selected. Dietary intakes of vitamins B2, B12, B6 and folate derived from different food sources were estimated. Plasma levels of vitamin B2 (or riboflavin), methylmalonic acid (MMA) and total homocysteine (tHcy) were also measured. RESULTS: Plasma concentrations of vitamin B2 below 3 µg/L were found in 22.8 % of the children. Children in the lower quartile of dietary vitamin B2 intake were found to have the lowest plasma vitamin B2 levels compared to children in the upper three quartiles (5.06 ± 7.63 vs. 6.48 ± 7.88, 6.34 ± 7.63 and 6.05 ± 4.94 µg/L respectively; P = 0.003). Regarding vitamin B12 children in the lower quartile of dietary intake had higher mean plasma tHcy levels compared to children in the upper two quartiles, respectively (6.00 ± 1.79 vs. 5.41 ± 1.43 and 5.46 ± 1.64 µmol/L; P = 0.012). Positive linear associations were observed between plasma vitamin B2 levels and dietary vitamin B2 derived from milk and fruits (ß = 0.133; P = 0.001 and ß = 0.086; P = 0.037). Additionally, nonlinear associations were also observed between plasma vitamin B2 levels and vitamin B2 derived from red meat, as well as between tHcy levels and vitamins B12 and B6 derived from milk; vitamins B12, B6 and folate derived from cereal products and folate derived from fruits. CONCLUSION: A considerably high prevalence of poor plasma vitamin B2 status was observed in children. The intake of milk, fruits and cereals was associated with more favorable tHcy levels, while the intake of milk and fruits with more favorable plasma B2 levels. However, these findings need to be further confirmed from controlled dietary intervention studies examining the modulation of biomarkers of B-vitamins.

The role of vitamin B1-B2 and plasma lipid profile in intrahepatic cholestasis of pregnancy.

AIM: The present study aimed to determine the levels of total cholesterol, triglycerides (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and vitamins B1 and B2 in intrahepatic cholestasis of pregnancy (ICP) patients, and to evaluate if these were involved in the pathophysiology of the disease. METHODS: The prospective randomized study included 35 pregnant patients who were admitted to the Gynecology and Obstetrics Polyclinic, Faculty of Medicine at Dicle University and who were diagnosed with ICP (Group 1), and 40 healthy pregnant women who were admitted in the same period and who had no systemic diseases that might complicate the pregnancy during the pregnancy follow-up (Group 2). Serum lipid levels and vitamins B1 and B2 were determined and compared, and statistical comparisons of the groups were made. RESULTS: There was no difference between the TG levels of the two groups (P=0.631). Total cholesterol, LDL, HDL, and vitamin B1 and B2 levels were higher in Group 1 than in Group 2 (P=0.001, P=0.001, P=0.001, P=0.001, and P=0.032, respectively). CONCLUSIONS: Increased levels of vitamins B1 and B2 may indicate a need for increased energy metabolism at the fetus. So we believe that new studies are required, which will be supported by the placental analyses of the pyruvate and lactate levels in maternal blood at delivery and fetal cord blood in order to develop a better understanding on the fetal effects of energy metabolism.

[Dietary vitamins intakes status of elderly people of 6 minitoring areas in Zhejiang Province in 2010-2012].

OBJECTIVE: To assess the situations of dietary vitamins intakes among aged 60 years old adults in different areas of Zhejiang Province, and analyze the food sources of vitamins. METHODS: Data were obtained from the 2010-2012 Chinese National Nutrition and Health Survey in Zhejiang Province. Dietary intakes among elderly people of vitamin A, vitamin B_1, vitamin B_2, vitamin C, vitamin E and their sources were acquired by 24-hour dietary recalls for 3 days in different areas. RESULTS: The elderly people' intakes of VA(296. 85(174. 32, 500. 28) µg RAE/d), VB_1(0. 68(0. 47, 0. 96) mg/d), VB2(0. 65(0. 47, 0. 90) mg /d) and VC(54. 54(33. 65, 83. 82) mg/d) were generally low. Intakes of vitamin B_1, vitamin C and vitamin E were significantly different in different areas( χ~2=41. 201, 39. 262 and 19. 474, P<0. 001). The food sources of vitamins were slightly variant. CONCLUSION: The insufficient status of vitamins intakes among elderly people in Zhejiang was serious, and there were differences among elderly people from different areas in intakes and food sources of vitamins.

Plasma Riboflavin and Vitamin B-6, but Not Homocysteine, Folate, or Vitamin B-12, Are Inversely Associated with Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition-Varese Cohort.

BACKGROUND: One-carbon metabolism-important for DNA stability and integrity-may play a role in breast carcinogenesis. However, epidemiologic studies addressing this issue have yielded inconsistent results. OBJECTIVE: We prospectively investigated associations between breast cancer and plasma folate, riboflavin, vitamin B-6, vitamin B-12, and homocysteine in women recruited to the Varese (Italy) cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: We performed a nested case-control study on women aged 35-65 y at recruitment with a median body mass index of 25.3 kg/m(2) who gave blood samples in 1987-1992 and again in 1993-1998. Breast cancer cases identified by 31 December 2009 were individually matched to controls. RRs of breast cancer (and subtypes defined by hormone receptor status) with 95% CIs were estimated by unconditional logistic regression, controlling for matching factors and breast cancer risk factors. RESULTS: After a median of 14.9 y, 276 breast cancer cases were identified and matched to 276 controls. Increasing plasma vitamin B-6 was associated with decreased risk of overall (RR: 0.78; 95% CI: 0.63, 0.96 for 1-SD increase), premenopausal (RR: 0.66; 95% CI: 0.48, 0.92 for 1-SD increase), estrogen receptor-positive (RR: 0.79; 95% CI: 0.63, 1.00 for 1-SD increase), and progesterone receptor-positive (RR: 0.72; 95% CI: 0.55, 0.95 for 1-SD increase) breast cancers. Increased plasma vitamin B-6 was also associated with decreased breast cancer risk in alcohol consumers (≥7 g/d) compared with consumption of <7 g/d or nonconsumption (RR: 0.71; 95% CI: 0.51, 0.99). High plasma riboflavin was associated with significantly lower risk in premenopausal women (RR: 0.45; 95% CI: 0.21, 0.94; highest compared with the lowest quartile, P trend = 0.021). Plasma homocysteine, folate, and vitamin B-12 were not associated with breast cancer risk. CONCLUSIONS: High plasma vitamin B-6 and riboflavin may lower breast cancer risk, especially in premenopausal women. Additional research is necessary to further explore these associations.

Usual Vitamin Intakes by Mexican Populations.

BACKGROUND: In the past several years, the consumption of high-energy, nutrient-poor foods has increased globally. Dietary intake data collected by the National Health and Nutrition Survey (ENSANUT) 2012 provide information to assess the quality of the Mexican diet and to guide food and nutrition policy. OBJECTIVE: The aim was to describe the usual intake and the prevalence of inadequate intakes of vitamins for the overall Mexican population and by subgroups defined by sex, age, region, urban or rural areas, and socioeconomic status (SES). METHODS: ENSANUT 2012 is a cross-sectional probabilistic survey representative of the Mexican population. Dietary information was collected by using the 24-h recall automated multiple-pass method (n = 10,096) with a repeated measurement on a subsample (n = 889) to permit adjustment for intraindividual variability with the use of the Iowa State University method. Mean usual intakes and the prevalence of inadequate intakes of thiamin, riboflavin, niacin, folate, and vitamins A, D, E, C, B-6, and B-12 were calculated for children aged 1-4 y (CH1-4y), children aged 5-11 y (CH5-11y), adolescents aged 12-19 y, and adults aged ≥20 y. RESULTS: In all of the age groups, prevalences of inadequate intakes of vitamins D and E were the highest (77-99% of adults and adolescents and 53-95% of CH5-11y and CH1-4y) and those of folate and vitamin A were intermediate (47-70% of adults and adolescents, 15-23% of CH5-11y and 8-13% of CH1-4y), whereas those of thiamin, riboflavin, niacin, and vitamins B-6, B-12, and C were the lowest (0-37% of adults, 1-27% of adolescents, and 0-2.4% of CH5-11y and CH1-4y). With few exceptions, the highest prevalences of inadequate intakes for vitamins were observed in the poorest populations (rural South region and the lowest tertile of SES). CONCLUSIONS: The intake of vitamins among Mexicans is inadequate overall. Information collected by ENSANUT can help target food assistance programs and develop strategies to prevent vitamin deficiencies.

Evaluation of carotid intima-media thickness in children with migraine: a marker of subclinical atherosclerosis.

Migraine is a commonly seen neurovascular disorder during childhood. Inflammation induced by the activation of cytokines and neuropeptides is implied in its pathophysiology. There is an association between inflammation and atherosclerosis in patients with migraine. In addition, there is a strong correlation between early atherosclerotic wall lesions and carotid intima-media thickness (CIMT). The study population consisted of 57 migraine patients aged 5-17 years, as well as 47 healthy children who served as the control group. Those migraine patients who were not receiving any medications at the interictal period were compared to healthy controls in terms of their measured lipid levels, thyroid function, vitamin B12 levels, serum iron levels, iron binding capacity, complete blood count, C-reactive protein (CRP) levels, and carotid intima-media thickness (CIMT) scores, which may comprise risk factors for atherosclerosis. When children in the migraine and control groups were compared in terms of those risk factors that are known to be related to vascular changes, no significant differences were found. However, a significant difference was detected in CIMT values (P < 0.05). Atherosclerosis commences in childhood, and there is a long period of time before the onset of ischemic symptoms occurs. In children with migraine, an evaluation of CIMT can be used as a non-invasive imaging modality to detect atherosclerosis, which develops in the context of chronic inflammation. In this way, measures to reduce morbidity and mortality, which may result from cardiovascular diseases, can be implemented.

Poor thiamin and riboflavin status is common among women of childbearing age in rural and urban Cambodia.

BACKGROUND: Thiamin deficiency in infancy is the underlying cause of beriberi, which can be fatal without rapid treatment. Reports of thiamin deficiency are common in Cambodia; however, population representative data are unavailable. Because B-complex vitamin deficiencies commonly occur in combination, riboflavin was also investigated. OBJECTIVE: We determined the biomarker status of thiamin and riboflavin in women of childbearing age in rural and urban Cambodia. METHODS: We measured thiamin (erythrocyte thiamin diphosphate; TDP) and riboflavin (erythrocyte glutathione reductase activity coefficient; EGRac) status in a representative sample of Cambodian women (aged 20-45 y) in urban Phnom Penh (n = 146) and rural Prey Veng (n = 156), Cambodia, and, for comparison purposes, in a convenience sample of women in urban Vancouver, British Columbia, Canada (n = 49). RESULTS: Thiamin insufficiency (TDP ≤ 90 nmol/L) was common among both urban (39%) and rural (59%) Cambodian women (P < 0.001), whereas <20% of Vancouver women were thiamin insufficient (P < 0.001). The prevalence of suboptimal and deficient riboflavin status (EGRac ≥ 1.3) was 89%, 92%, and 70% among women in Phnom Penh, Prey Veng, and Vancouver, respectively (P < 0.001). CONCLUSIONS: Suboptimal status of both thiamin and riboflavin were common in Cambodian women, with substantially higher rates among women living in rural Prey Veng than in urban Phnom Penh. Strategies may be needed to improve the thiamin and riboflavin status of women in Cambodia. The unexpected finding of high riboflavin inadequacy status in Vancouver women warrants further investigation.

Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case-control study.

BACKGROUND: The essential amino acid tryptophan is catabolised mainly through the kynurenine pathway. Altered circulating levels of kynurenines have been reported in chronic inflammatory conditions and in several neuropsychiatric disorders, including depression and schizophrenia. Candidate gene studies suggest that genes related to the kynurenine catabolism may be associated with attention-deficit hyperactivity disorder (ADHD). Additionally, ADHD patients often report comorbid depression or anxiety. In this study we investigated serum levels of kynurenines in Norwegian adult ADHD patients and adult controls. METHODS: We compared serum levels of tryptophan and the seven tryptophan metabolites kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid in 133 adult patients with ADHD and 131 adult controls (18-40 years). Riboflavin (vitamin B2), total vitamin B6 and the nicotine metabolite cotinine were also measured. Serum samples were analysed using mass spectrometry. Patients and controls reported comorbid disorders and past (childhood) and current ADHD symptoms using the Wender Utah Rating Scale (WURS) and the Adult ADHD Self-report Scale (ASRS). Logistic regression was used to calculate odds ratios for having an ADHD diagnosis for different serum levels of each metabolite. In addition, we used Spearman's correlation analysis to investigate the correlation between serum levels of tryptophan and kynurenines and ADHD symptom scores. RESULTS: Lower serum concentrations of tryptophan [odds ratio 0.61 (95 % confidence interval 0.45-0.83)], kynurenic acid [0.73 (0.53-0.99)], xanthurenic acid [0.65 (0.48-0.89)] and 3-hydroxyanthranilic acid [0.63 (0.46-0.85)], and higher levels of cotinine [7.17 (4.37-12.58)], were significantly associated with ADHD. After adjusting for tryptophan levels, only 3-hydroxyanthranilic acid and cotinine remained significant. Lower levels of tryptophan and kynurenine were also found to be correlated with higher total ASRS score and higher total WURS score, when adjusting for smoking and age. CONCLUSIONS: Our results suggest that there may be differences in serum levels of tryptophan and kynurenines between adult ADHD patients and adult controls. Although our findings do not suggest a chronic immune activation in ADHD, the underlying mechanisms and possible clinical implications of the differences should be further explored.

Motor development related to duration of exclusive breastfeeding, B vitamin status and B12 supplementation in infants with a birth weight between 2000-3000 g, results from a randomized intervention trial.

BACKGROUND: Exclusive breastfeeding for 6 months is assumed to ensure adequate micronutrients for term infants. Our objective was to investigate the effects of prolonged breastfeeding on B vitamin status and neurodevelopment in 80 infants with subnormal birth weights (2000-3000 g) and examine if cobalamin supplementation may benefit motor function in infants who developed biochemical signs of impaired cobalamin function (total homocysteine (tHcy) > 6.5 µmol/L) at 6 months. METHODS: Levels of cobalamin, folate, riboflavin and pyridoxal 5´-phosphate, and the metabolic markers tHcy and methylmalonic acid (MMA), were determined at 6 weeks, 4 and 6 months (n = 80/68/66). Neurodevelopment was assessed with the Alberta Infants Motor Scale (AIMS) and the parental questionnaire Ages and Stages (ASQ) at 6 months. At 6 months, 32 of 36 infants with tHcy > 6.5 µmol/L were enrolled in a double blind randomized controlled trial to receive 400 µg hydroxycobalamin intramuscularly (n = 16) or sham injection (n = 16). Biochemical status and neurodevelopment were evaluated after one month. RESULTS: Except for folate, infants who were exclusively breastfed for >1 month had lower B vitamin levels at all assessments and higher tHcy and MMA levels at 4 and 6 months. At 6 months, these infants had lower AIMS scores (p = 0.03) and ASQ gross motor scores (p = 0.01). Compared to the placebo group, cobalamin treatment resulted in a decrease in plasma tHcy (p < 0.001) and MMA (p = 0.001) levels and a larger increase in AIMS (p = 0.02) and ASQ gross motor scores (p = 0.03). CONCLUSIONS: The findings suggest that prolonged exclusive breastfeeding may not provide sufficient B vitamins for small infants, and that this may have a negative effect on early gross motor development. In infants with mild cobalamin deficiency at 6 months, cobalamin treatment significantly improvement cobalamin status and motor function, suggesting that the observed impairment in motor function associated with long-term exclusive breastfeeding, may be due to cobalamin deficiency. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01201005.

Low serum vitamin B-12 and folate concentrations and low thiamin and riboflavin intakes are inversely associated with greater adiposity in Mexican American children.

BACKGROUND: Micronutrient status may be a contributing factor to the development of childhood obesity in many industrializing countries passing the nutritional transition. The few studies investigating associations between serum concentrations of vitamin B and intake of B vitamins with adiposity, however, have reported inconsistent findings. OBJECTIVE: The aim of the study was to examine associations between serum vitamin B-12 and folate concentrations and intakes of B vitamins with body fat by using data on 1131 Mexican American children 8-15 y of age included in NHANES 2001-2004. METHODS: Children's body mass index (BMI), trunk fat mass (TrFM), and total body fat mass (TBFM) were used as body adiposity (BA) measures. Serum concentrations of folate and vitamin B-12 were measured in blood samples collected from children. Intake of B vitamins was collected according to 24-h dietary recall. Associations of BA with serum concentrations of vitamin B-12 and folate and intake of B vitamins were determined by using linear and multinomial regression models. RESULTS: Serum concentrations of vitamin B-12 and folate were inversely associated with BMI (ß: -2.68, P < 0.01; ß = -1.33, P < 0.01), TrFM (ß:-3.32, P < 0.01; ß: -0.14, P < 0.05), and TBFM (ß:-1.93, P < 0.01; ß: -3.19; P < 0.01). Higher serum concentrations of vitamin B-12 were associated with a reduced risk of obesity (OR: 0.48; 95% CI: 0.31, 0.77; P < 0.001). Thiamin and riboflavin intakes were inversely associated with BMI (ß:-1.35, P < 0.05; ß: -1.11, P < 0.05) and TrFM (ß:-1.26, P < 0.05; ß: -1.37, P < 0.05). CONCLUSION: Similar inverse associations between BA and status of both vitamin B-12 and folate and intake of thiamin and riboflavin suggest that these micronutrients may play a role in adipogenesis and risk of childhood obesity.

Mutations in riboflavin transporter present with severe sensory loss and deafness in childhood.

INTRODUCTION: We have identified a large consanguineous Lebanese family with 5 individuals with severe childhood-onset recessive sensory loss associated with deafness and variable optic atrophy. METHODS: Autozygosity mapping was performed in all affected individuals, followed by whole-exome sequencing (WES) in 2 individuals. RESULTS: WES identified a homozygous missense mutation (c.916G>A, p.G306R) in the cerebral riboflavin transporter SLC52A2, recently shown to cause Brown-Vialetto-Van-Laere syndrome (BVVLS), which is considered primarily a motor neuronopathy. Our patients have a phenotype distinct from BVVLS, characterized by severe progressive sensory loss mainly affecting vibration and proprioception that evolves to include sensorineural hearing loss in childhood, variable degrees of optic atrophy, and marked upper extremity weakness and atrophy. Treatment of 3 patients with 400 mg/day riboflavin over 3 months produced definite clinical improvement. CONCLUSIONS: Mutations in SLC52A2 result in a recognizable phenotype distinct from BVVLS. Early recognition of this disorder is critical, given its potential treatability.