Search

The level of plasma total homocysteine (tHcy), long known to be B vitamin dependent, has recently been shown to be inversely associated with plasma selenium (Se) concentration in human subjects. We therefore, chose to investigate the interaction between Se, tHcy and B vitamins in a double-blind, placebo-controlled trial where 501 healthy UK elderly volunteers were randomly allocated to receive 100, 200, or 300 microg Se/day as high-Se-yeast, or placebo-yeast for 6 months. Plasma Se, tHcy, folate, vitamin B-12, pyridoxal-5'-phosphate (PLP) and its catabolite, 4-pyridoxic acid, were measured in all participants at baseline and in samples from the placebo, 100 and 300 microg Se/day groups, at follow-up. At baseline, Se was inversely correlated with tHcy but only in males (p < 0.001). Before supplementation, tHcy concentration was significantly lower in the highest compared to the lowest Se tertile in males (p < 0.05), and in females when folate concentrations were also in the top tertile (p < 0.05). The effect of folate, PLP and vitamin B-12 concentrations on plasma tHcy correlated with Se concentration at baseline. After 6 months of Se supplementation, only Se concentration had changed significantly. Supplementation with Se does not affect tHcy concentration in the UK elderly population.

Folate and the metabolically related B-vitamins, vitamin B12and riboflavin, have attracted much scientific and public health interest in recent years. Apart from a well established role in preventing neural tube defects (NTDs), evidence is emerging to support other potential roles for folate and/or related B-vitamins in protecting against cardiovascular disease (especially stroke), certain cancers, cognitive impairment and osteoporosis. However, typical folate intakes are sub-optimal, in that although adequate in preventing clinical folate deficiency (i.e. megaloblastic anaemia) in most people, they are generally insufficient to achieve a folate status associated with the lowest risk of NTDs. Natural food folates have a limited ability to enhance folate status as a result of their poor stability under typical cooking conditions and incomplete bioavailability when compared with the synthetic vitamin, folic acid (as found in supplements and fortified foods). Current folate recommendations to prevent NTDs (based primarily on folic acid supplementation) have been found to be ineffective in several European countries. In contrast, in North America and Chile, the policy of mandatory folic acid-fortification has proven itself in terms of lowering the prevalence of NTD, but remains controversial because of concerns regarding potential risks of chronic exposure to high-dose folic acid. In the case of vitamin B12, the achievement of an optimal status is particularly difficult for many older people because of the common problem of food-bound B12malabsorption. Finally, there is evidence that riboflavin status is generally low in the UK population, and particularly so in younger women; this warrants further investigation.

There are few good sources of natural food folates apart from green leafy vegetables and these may have a limited potential to increase folate status because of substantial losses that can occur during cooking. Fortified foods can overcome this but are controversial because of safety concerns regarding chronic exposure to high-dose folic acid (FA; the synthetic form). The aim of the present study was to develop eggs with an enriched natural folate content and minimal unmetabolised FA. Forty-eight, 30-week-old laying hens were randomised to receive the basal feed (formulated to provide 1 mg folate/kg feed) to which had been added one of the following FA levels (0, 2, 4, 8, 16, 32 mg/kg feed). Total folate was measured in eggs collected throughout the 12-week study period and the FA content estimated at 12 weeks. Results showed that the maximal egg folate content was achieved by adding 16 mg FA/kg feed. At this optimal dose, the total folate content per egg was 75 μg (compared with 32 μg in a regular egg) of which FA represented at most 10 %, a level which would probably be converted into natural folates by humans after ingestion. The results demonstrate that it is possible to use synthetic FA at high doses to produce novel animal foods enriched with natural folates in a cost-efficient process. Such foods may be particularly relevant to European populations without access to FA fortification and therefore dependent on natural food folate sources for the primary prevention of folate-related disease.

There is considerable interest in plasma homocysteine (tHcy) as a CVD risk factor. Although the secondary prevention trials published to date have been inconclusive in confirming a benefit of tHcy-lowering treatment with B-vitamins on CVD events generally, such studies are widely recognised to have been insufficiently powered to detect a significant effect for the predicted magnitude of association between tHcy and heart disease risk, and therefore cannot be interpreted as evidence that no relationship exists. In fact, a recent meta-analysis of clinical trials has confirmed that folic acid supplementation reduces the risk of stroke, particularly in individuals without a history of stroke. Evidence supporting a causal relationship between elevated tHcy and heart disease also comes from genetic studies. The most important genetic determinant of tHcy in the general population is the common C677T variant in methylenetetrahydrofolate reductase (MTHFR) that results in higher tHcy. Individuals with the homozygous mutant (TT) genotype have a significantly higher (14-21%) risk of heart disease. Plasma tHcy is very responsive to intervention with the B-vitamins required for its metabolism, in particular folic acid, and to a lesser extent vitamins B12 and B6. Thus, although primarily aimed at reducing neural-tube defects, folic acid fortification may have an important role in the primary prevention of CVD via tHcy lowering. Besides folate, riboflavin is required as a cofactor for MTHFR and enhanced riboflavin status results in a marked lowering in tHcy specifically in individuals with the TT genotype, presumably by neutralising the variant form of the enzyme. About 10% of the UK and Irish populations have the TT genotype. In the present paper the potential role of folate and related B-vitamins in the primary prevention of CVD and the implications for nutrition policy are explored.

A high homocysteine phenotype, often accompanied by low folate, is associated with several pathologies including cardiovascular disease and birth defects. This phenotype appears to be influenced by both genetic and environmental factors, which may act in a sex-dependent manner. The present analyses were undertaken to identify the determinants of homocysteine concentrations in young men and women, and are based on data from a cohort of young, reproductive age (20-26 years old) individuals in Northern Ireland. Multivariate modeling indicated that homocysteine concentrations are associated with red blood cell (RBC) folate, vitamin B(12), MTHFR 677C>T genotype and smoking status in both males and females. However, the inter-relationships between these variables appear to differ between the sexes. Specifically, homocysteine levels in males were significantly associated with interactions between MTHFR 677C>T genotype and both RBC folate and smoking status. In contrast, homocysteine levels in females were significantly associated with interactions between smoking status and RBC folate. These results suggest that the characteristics of individuals who are at the highest risk for a high homocysteine phenotype differ for males and females. Among males, those with the MTHFR 677TT genotype appear to be at the highest risk and to be the most vulnerable to factors (e.g. smoking, low RBC folate) that are associated with homocysteine raising effects. Among females, smokers (regardless of MTHFR genotype) appear to be at the highest risk, and to be the most vulnerable to a single factor (i.e. RBC folate) that is associated with homocysteine raising effects.

A low serum folate and high homocysteine phenotype is associated with an increased risk of neural tube defects (NTDs), cardiovascular diseases and other pathologies. Thus defining both genetic and non-genetic factors that may impact folate/homocysteine metabolism will enhance our understanding of the etiologic mechanisms underlying these conditions and facilitate risk assessment. Dihydrofolate reductase catalyzes the reduction of folic acid to dihydrofolate and thereafter to tetrahydrofolate. The impact of the dihydrofolate reductase (DHFR) c.86 + 60_78 insertion/deletion (ins/del) polymorphism on folate and homocysteine concentrations was analyzed using data from healthy young adults from Northern Ireland, collected as part of visit three of the Young Hearts Project. Among men the DHFR c.86 + 60_78 polymorphism was not significantly associated with serum or red blood cell folate concentrations, or with homocysteine concentrations. Among women the DHFR c.86 + 60_78 polymorphism explained 2% of the variation in RBC folate levels and 5% of the variation in serum folate levels, but did not appear to have an independent effect on homocysteine. Relative to women with the DHFR c.86 + 60_78 ins/ins and ins/del genotypes, del/del homozygotes had increased serum and red blood cell folate concentrations and may therefore be at decreased risk of having offspring affected by NTDs and of other adverse reproductive and health outcomes attributable to low folate.

There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 micromol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.

We thank Powers et al for their positive comments on our article.1 Their criticism is that our sample is not representative of the United Kingdom or European populations, and that our interpretation of the results in relation to food policy is therefore inappropriate. The statement that statistical inference is compromised is misleading because it is very clear in our article that the inference is not being made about the general population, but …

Background: Evidence is conflicting as to whether the bioavailability of food folates is influenced by the extent of their conjugation. Objective: The objective was to compare the bioavailability of 3 representative food folate sources with various degrees of glutamylation-ie. egg yolk, spinach, and yeast, whose polyglutamyl folate content measured 0%, 50%, and 100%, respectively. Design: In a randomized crossover trial, 13 male subjects, after a prestudy folate saturation procedure, received in random order either placebo or 500 mu g total folate, which was provided as concentrated freeze-dried extract removed from the normal food matrix of egg yolk, spinach. or yeast. Blood samples (n = 10) were collected before and up to 10 h after treatments, which were administered at weekly intervals. Results: A significant increase from baseline plasma folate concentrations was observed by 0.5 h after treatment with egg yolk folate or spinach folate and by 1 h after treatment with yeast folate, and the concentrations remained significantly elevated for 3-5 h; no plasma folate response was observed after placebo treatment. The overall responses. calculated as plasma folate area under the curve (AUC) for egg yolk, spinach, and yeast folate, were 122.6 +/- 23.6, 136.2 +/- 21.4. and 102.5 +/- 21.1 nmol . h/L, respectively. No significant differences in AUC were seen between monoglutamyl (egg yolk) folate and either of the polyglutamate-containing folates examined. Conclusion: These results suggest that the ratio of monoglutamate to polyglutamate in natural folates is not a factor that limits the extent of intestinal absorption of food folate.

Background— Meta-analyses predict that a 25% lowering of plasma homocysteine would reduce the risk of coronary heart disease by 11% to 16% and stroke by 19% to 24%. Individuals homozygous for the methylenetetrahydrofolate reductase ( MTHFR ) 677C→T polymorphism have reduced MTHFR enzyme activity resulting from the inappropriate loss of the riboflavin cofactor, but it is unknown whether their typically high homocysteine levels are responsive to improved riboflavin status. Methods and Results— From a register of 680 healthy adults 18 to 65 years of age of known MTHFR 677C→T genotype, we identified 35 with the homozygous (TT) genotype and age-matched individuals with heterozygous (CT, n=26) or wild-type (CC, n=28) genotypes to participate in an intervention in which participants were randomized by genotype group to receive 1.6 mg/d riboflavin or placebo for a 12-week period. Supplementation increased riboflavin status to the same extent in all genotype groups (8% to 12% response in erythrocyte glutathione reductase activation coefficient; P P =0.003; n=32) and markedly so (by 40%) in those with lower riboflavin status at baseline (from 22.0±2.9 and 13.2±1.0 μmol/L; P =0.010; n=16). No homocysteine response was observed in the CC or CT groups despite being preselected for suboptimal riboflavin status. Conclusions— Although previously overlooked, homocysteine is highly responsive to riboflavin, specifically in individuals with the MTHFR 677 TT genotype. Our findings might explain why this common polymorphism carries an increased risk of coronary heart disease in Europe but not in North America, where riboflavin fortification has existed for >50 years.

Dietary supplementation with B vitamins that lower blood homocysteine concentrations is expected to reduce cardiovascular disease risk, but there has been uncertainty about the optimum regimen to use for this purpose.The objectives were to ascertain the lowest dose of folic acid associated with the maximum reduction in homocysteine concentrations and to determine the additional relevance of vitamins B-12 and B-6.A meta-analysis of 25 randomized controlled trials involving individual data on 2596 subjects assessed the effect on plasma homocysteine concentrations of different doses of folic acid and of the addition of vitamins B-12 and B-6.The proportional reductions in plasma homocysteine concentrations produced by folic acid were greater at higher homocysteine (P0.001) and lower folate (P0.001) pretreatment concentrations; they were also greater in women than in men (P0.001). After standardization for sex and to pretreatment plasma concentrations of 12 micromol homocysteine/L and 12 nmol folate/L, daily doses of 0.2, 0.4, 0.8, 2.0, and 5.0 mg folic acid were associated with reductions in homocysteine of 13% (95% CI: 10%, 16%), 20% (17%, 22%), 23% (21%, 26%), 23% (20%, 26%), and 25% (22%, 28%), respectively. Vitamin B-12 (x: 0.4 mg/d) produced 7% (95% CI: 4%, 9%) further reduction in homocysteine concentrations, but vitamin B-6 had no significant effect.Daily doses ofor =0.8 mg folic acid are typically required to achieve the maximal reduction in plasma homocysteine concentrations produced by folic acid supplementation. Doses of 0.2 and 0.4 mg are associated with 60% and 90%, respectively, of this maximal effect.

Evidence suggests that low folate status may be detrimental to mood and associated with depleted cerebrospinal fluid levels of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT). A placebo-controlled trial was carried out to determine the effect of folic acid supplementation (100 μg for 6 weeks followed by 200 μg for a further 6 weeks) upon subjective mood (Positive and Negative Affect Schedule) and biochemical markers of mood (5-HT) in healthy males (n23). Blood samples were obtained at baseline (week 0) and during the intervention at week 6 and week 12. Subjective mood assessments were obtained at week 0 and week 12. The results showed an increase in serum and erythrocyte folate concentrations (P=0·02 andP=0·003, respectively) and a corresponding decrease in plasma homocysteine (P=0·015) in response to the folic acid intervention. Neither subjective mood nor 5-HT levels, however, were significantly altered in response to the change in folate status. Folic acid given at physiological doses did not appear to improve the mood of healthy folate-replete individuals over a 12-week period. Further research is needed to address the effect of folic acid supplementation or of longer duration or increased dose, particularly in the face of sub-optimal folate status.

The achievement of optimal folate status to prevent neural-tube defects, and possibly other diseases, is hindered by the well-recognised incomplete bioavailability of the natural folates found in foods compared with the synthetic vitamin, folic acid. Folate bioavailability from different foods is considered to be dependent on a number of factors, including the food matrix, the intestinal deconjugation of polyglutamyl folates, the instability of certain labile folates during digestion and the presence of certain dietary constituents that may enhance folate stability during digestion. There is conflicting evidence as to whether the extent of conjugation of polyglutamyl folate (in the absence of specific inhibitors of deconjugation in certain foods) is a limiting factor in folate bioavailability. Estimates of the extent of lower bioavailability of food folates compared with folic acid (relative bioavailability) show great variation, ranging anywhere between 10 and 98%, depending on the methodological approach used. The lack of accurate data on folate bioavailability from natural food sources is of particular concern in those countries in which there is no mandatory folic acid fortification, and therefore a greater reliance on natural food folates as a means to optimise status. Apart from the incomplete bioavailability of food folates, the poor stability of folates in foods (particularly green vegetables) under typical conditions of cooking can substantially reduce the amount of vitamin ingested and thereby be an additional factor limiting the ability of food folates to enhance folate status. A recent workshop convened by the Food Standards Agency concluded that gaining a better understanding of folate bioavailability in representative human diets is a high priority for future research.

PUBLISHED, Substantial evidence suggests that a low folate/high homocysteine phenotype is pathogenic. We analyzed the impact of the thymidylate synthase (TYMS) 3UTR ins/del polymorphism on folate and homocysteine levels and assessed the relationship between the TYMS 3UTR ins/del polymorphism and key genetic and lifestyle variables. Among non-smokers only, the TYMS 3UTR ins/del polymorphism was significantly associated with red blood cell folate (RBC folate; P=0.002) and homocysteine (P=0.03) concentrations. Median RBC folate concentration was much higher for TYMS 3UTR del/del subjects (434 g/l) compared with either ins/ins (282 g/l) or ins/del (298 g/l) subjects. The median homocysteine concentration for del/del homozygotes was considerably lower compared with either ins/ins homozygotes or ins/del heterozygotes. A possible additive effect for the impact of the TYMS 3UTR del/del and MTHFR 677CC genotypes on RBC folate concentration was also observed. Our findings suggest that the TYMS 3UTR del/del genotype is a significant determinant of elevated RBC folate concentration in a non-smoking population of northwestern European adults and that this genotype confers protection against diseases for which a low folate/high homocysteine phenotype appears to be an etiologic component., This work was supported by NIH grant AR47663 and in part by NIH grants HD39195 and HD39081. Support for the Young Hearts Project was provided by the British Heart Foundation and the Wellcome Trust.

Summary Background Recommendations by the UK Department of Health suggest that protection from neural tube defects (NTD) can be achieved through intakes of an extra 400 μg daily of folate/folic acid as natural food, foods fortified with folic acid, or supplements. The assumption is that all three routes of intervention would have equal effects on folate status. Methods We assessed the effectiveness of these suggested routes of intervention in optimising folate status. 62 women were recruited from the University staff and students to take part in a 3-month intervention study. Participants were randomly assigned to one of the following five groups: folic acid supplement (400 μg/day; I); folic-acid-fortified foods (an additional 400 μg/day; II); dietary folate (an additional 400 μg/day; III); dietary advice (IV), and control (V). Responses to intervention were assessed as changes in red-cell folate between preintervention and postintervention values. Findings 41 women completed the intervention study. Red-cell folate concentrations increased significantly over the 3 months in the groups taking folic acid supplements (group I) or food fortified with folic acid (group II) only (p Interpretation We have shown that compared with supplements and fortified food, consumption of extra folate as natural food folate is relatively ineffective at increasing folate status. We believe that advice to women to consume folate-rich foods as a means to optimise folate status is misleading.

Background: In many countries, current recommendations are that women take a daily 400-μg folic acid supplement from before conception until the end of the 12th week of gestation for the prevention of neural tube defects. Low folate status is associated with an increased concentration of plasma total homocysteine (tHcy), a risk factor associated with pregnancy complications such as preeclampsia. Methods: In a longitudinal study, we determined tHcy and corresponding folate status in 101 pregnant women at 12, 20, and 35 weeks of gestation, in 35 nonpregnant controls sampled concurrently, and in a subgroup (n = 21 pregnant women and 19 nonpregnant controls) at 3 days postpartum. Results: Plasma tHcy was significantly lower throughout pregnancy compared with nonpregnant controls, with values lowest in the second trimester before increasing toward nonpregnant values in the third trimester. Importantly, mean tHcy concentrations were lower in pregnant women taking folic acid supplements than in those not, an effect that reached significance in the third trimester (5.45 vs 7.40 μmol/L; P Conclusions: This is the first longitudinal study to show that homocysteine concentrations increase in late pregnancy toward nonpregnant values; an increase that can be limited by enhancing folate status through continued folic acid supplementation. These results indicate a potential role for continued folic acid supplementation in reducing pregnancy complications associated with hyperhomocysteinemia.

Hyperhomocysteinaemia has been associated with reduced pulse wave velocity (PWV) in patients with end-stage renal disease and in those with hypertension. The aim of this study was to examine the association between total homocysteine (tHcy) concentrations, the biochemical and genetic determinants of tHcy and PWV in healthy young adults.A total of 489 subjects aged 20-25 years participated. A fasting blood sample was taken and PWV measured using a non-invasive optical method. tHcy did not correlate with PWV, whether assessed at the aorto-iliac segment (P = 0.18), the aorto-radial segment (P = 0.39) or the aorto-dorsalis-pedis segment (P = 0.22). When tHcy was classified into normal (15) and high (or =15micromol/l), PWV did not differ between the two groups at any segment. PWV did not differ by MTHFR C677T or NOS3 G894T genotype, even when smoking and folate sub-groups were considered. Considering aortic PWV as a dependent variable, stepwise regression analysis showed that the only parameter entering the model for all segments was systolic blood pressure (aorto-iliac, P0.001; aorto-radial, P = 0.01; aorto-dorsalis-pedis, P = 0.001). Age, sex, COL1A1 genotype and triglycerides entered the model significantly for two of three segments.This study shows that arterial PWV is not associated with tHcy in a healthy young population.

Objective: To explore the feasibility of low-fat spreads as vehicles for folic acid (FA) fortification by determining the acute absorption of FA from a fortified spread. Design: Double blind, crossover study to test each of the following treatments administered at 1-weekly intervals: (A) 20 g low-fat (40%) spread fortified with 200 μg FA and a placebo tablet; (B) 20 g low-fat placebo spread and a 200 μg FA tablet; (C) 20 g low-fat placebo spread and a placebo tablet. Subjects: A total of 13 male volunteers, aged 31.8±13.2 y. Main outcome measures: Plasma total folate concentrations, measured before and up to 10 h after each treatment (n=10 samples per treatment). Results: Plasma folate concentrations were significantly increased compared with baseline values 1 h after administration of the FA tablet, and 1.5 h after the FA spread, and remained significantly higher than the baseline values for up to 7 h after both treatments. The maximum plasma folate response (Rmax), corrected for baseline values and ‘placebo response’, was established between 1 and 3 h postprandially in response to both FA spread and FA tablet, and no significant difference in Rmax was found between the two treatments (13.4 vs 14.4 nmol/l, P=0.9). The acute absorption of FA from fortified spread relative to that from the tablet, calculated on the basis of area under the plasma folate response curve, was 67% (P=0.04). Conclusion: The absorption of FA from fortified low-fat spread, although lower than from a tablet, is effective. These results suggest that low-fat spreads, typically associated with fat-soluble vitamin fortification, may also be considered feasible as vehicles for FA fortification. Sponsorship: Unilever, The Netherlands.

Contains fulltext : 58670.pdf (Publisher’s version ) (Closed access) Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR C677T polymorphism on homocysteine (tHcy) concentrations. We tested this hypothesis in a healthy young adult population for which MTHFR C677T genotypes and tHcy concentrations were previously reported. The MTHFR 677TT genotype was significantly associated with elevated tHcy concentrations in smokers (P = 0.001) but not in non-smokers (P = 0.36). Among smokers, the MTHFR 677TT genotype was significantly associated with high tHcy in heavy smokers (P = 0.003) but not light smokers (P = 0.09), in men (P = 0.003) but not women (P = 0.11), and in subjects from the lowest serum folate quartile (P = 0.49) but not from folate quartiles 2-4 (P = 0.49). After adjustment for nutritional variables, interactions between MTHFR C677T genotype and NOS3 G894T genotype, and between MTHFR genotype, smoking status and gender were statistically significant. We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low.

To provide a tool to study folate bioavailability under controlled conditions, a methodology was developed to produce extracts representative of natural food folates but removed from their matrix and sufficiently concentrated so as to elicit a response in biomarkers of folate status without distorting usual dietary intake patterns. Egg, spinach, and yeast were selected to represent the wide range in extent of folate conjugation found in foods (0, 60, and 100% polyglutamyl folate, respectively). The protocol, which was based on extracting food folates using only reagents safe for human consumption, was optimized in the laboratory (thermal extraction for 10 min in a 2% ascorbate solution at pH 5) and then adapted for industrial scale production in a food-processing facility. Results showed that the extracts were 2.3-12 times more concentrated in folate compared with their corresponding food sources. Neither the mono- to polyglutamate ratio nor the distribution of the main folate derivatives was altered during processing, making these extracts suitable for use in human bioavailability studies.

Patients on antiepileptic drugs (AEDs) frequently have low serum folate and high plasma total homocysteine (tHcy) (1)(2)(3)(4). This metabolic disturbance has been implicated in an increased rate of cardiovascular disease, fetal malformations, dementia, and neuropsychiatric symptoms among patients on AEDs (5)(6)(7). Homocysteine metabolism is dependent on four B vitamins as cofactors: The methylation of homocysteine to methionine requires folate and vitamin B12, and the irreversible transsulfuration to cysteine requires vitamin B6 (8). The recycling of folate cofactors is dependent on vitamin B6 and B2, and vitamin B2 is necessary for activating vitamin B6 to pyridoxal 5′-phosphate (PLP) (9). Vitamin B2 and B6 status thus may have an impact on tHcy concentrations in patients taking AEDs, but few studies have reported on this matter (3)(4)(10)(11). The methionine loading test detects individuals with impaired homocysteine metabolism not detected by fasting Hcy concentrations alone and is often considered primarily a test of the transsulfuration pathway (1)(8)(12). We therefore determined the fasting and 6 h post-methionine loading (postload) plasma concentrations of thiols and B vitamins in patients taking AEDs. We recruited 101 patients with symptomatic, cryptogenic, or primary generalized epilepsy from our outpatient clinic. None of them had epilepsy secondary to ischemic stroke or other conditions considered to be associated with high tHcy, and none were on prescribed vitamin supplements. We recruited 101 controls among blood donors and hospital employees. All participants gave written informed consent before entering the study, and The Regional Ethics Committee (University of Bergen, Norway) approved the study. The number of male patients and controls was identical (n = 53), as was the mean (SD) age [37.9 (15.0) and 37.3 …

The alkaline single-cell gel electrophoresis or comet assay is a relatively simple method of measuring DNA single-strand breaks and alkali-labile sites in individual cells. Previously, we have used a combination of this with bromodeoxyuridine labelling of DNA and immunolocalisation of the BrdUrd to show that DNA replicative integrity can be assessed in single cultured cells. This study demonstrates the application of the technique to single cells derived from small human colonic biopsies isolated at routine endoscopy. A high level of reproducibility within replicate comet slides and between comet slides prepared from various colonic sites within a single patient is shown. Preliminary results demonstrate that defects in replication can be detected in tumour and premalignant colonic tissue adjacent to the tumour, suggesting that alterations in replicative integrity are an early event in neoplasia, appearing in premalignant mucosal cells. This development deems the BrdUrd comet assay suitable as an ex vivo molecular end point that can be measured easily in tissue collected by biopsy at routine colonic endoscopy. Thus, the BrdUrd comet assay has the potential to facilitate trial investigations of diet- or environment-related factors that may affect replicative integrity in the colon and provides a novel biomarker for colon carcinogenesis.

Item does not contain fulltext A modestly elevated total plasma homocysteine concentration (tHcy) is generally accepted as an independent and graded risk factor for various pathologies, including vascular diseases, neural tube defects, Alzheimer disease, and pregnancy complications. We analyzed 5 common functional polymorphisms in enzymes involved in homocysteine metabolism (ie, methylenetetrahydrofolate reductase [MTHFR] 677C>T and 1298A>C, methionine synthase [MTR] 2756A>G, cystathionine beta-synthase [CBS] 844ins68, and methionine synthase reductase [MTRR] 66A>G) in 452 young adults, and quantified their independent and interactive effects on tHcy concentrations. Serum folate, red cell folate, vitamin B(12), and tHcy concentrations were significantly influenced by MTHFR 677C>T genotypes. A particularly strong interaction was observed between the MTHFR 677TT genotype and serum folate, which led to a high tHcy phenotype that was more pronounced in males. The genetic contribution to the variance in tHcy was estimated to be approximately 9%, compared with approximately 35% that could be attributed to low folate and vitamin B(12). Our study indicates that dietary factors are centrally important in the control of tHcy levels in young adults with additional, but somewhat weaker, genetic effects. These data underscore the potential benefits that may be gained by improving the dietary status of young adults, and provide support for the implementation of folate/B-vitamin food fortification programs.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR; EC 1.7.99.5) supplies the folate needed for the metabolism of homocysteine. A reduction in MTHFR activity, as occurs in the homozygous state for the 677C-->T (so-called thermolabile) enzyme variant (TT genotype), is associated with an increase in plasma total homocysteine (tHcy). OBJECTIVE: In vitro studies suggest that the reduced activity of thermolabile MTHFR is due to the inappropriate loss of its riboflavin cofactor. We investigated the hypothesis that MTHFR activity in the TT genotype group is particularly sensitive to riboflavin status. DESIGN: We studied tHcy and relevant B-vitamin status by MTHFR genotype in a cross-sectional study of 286 healthy subjects aged 19-63 y (median: 27 y). The effect of riboflavin status was examined by dividing the sample into tertiles of erythrocyte glutathionine reductase activation coefficient, a functional index of riboflavin status. RESULTS: Lower red blood cell folate (P = 0.0001) and higher tHcy (P = 0.0082) concentrations were found in the TT group than in the heterozygous (CT) or wild-type (CC) groups. However, these expected relations in the total sample were driven by the TT group with the lowest riboflavin status, whose mean tHcy concentration (18.09 micromol/L) was almost twice that of the CC or CT group. By contrast, adequate riboflavin status rendered the TT group neutral with respect to tHcy metabolism. CONCLUSIONS: The high tHcy concentration typically associated with homozygosity for the 677C-->T variant of MTHFR occurs only with poor riboflavin status. This may have important implications for governments considering new fortification policies aimed at the prevention of diseases for which this genotype is associated with increased risk.

The timing of folic acid supplement usage is critical to preventing pregnancies affected by neural tube defects (NTDs) because the neural tube closes by Day 28 post-conception. We investigated compliance of pregnant women with current folic acid recommendations (400 µg/day from preconception to 12 weeks) in relation to achieving a folate status associated with lowest risk of NTDs.

Background: Despite having dietary intakes that typically greatly exceed current recommendations, 10–40% elderly population are affected by low vitamin B12 biomarker status as a result of atrophic gastritis (Pfeiffer et al., 2007), leading to an age-related decline in gastric acid secretion necessary for B12 separation from food protein. Despite its mild, non-specific clinical manifestation, this condition may contribute to the development of several diseases of ageing such as cardiovascular disease, dementia and osteoporosis (Hoey et al., 2007). However, B12 dietary intake recommendations remain uniform across adult age groups and there is as yet no evidence to support a revision of the recommendations specifically for older adults who are at increased risk of developing atrophic gastritis. This study aimed to investigate the role of ageing in the relationship between dietary B12 intake and biomarker status, and to provide scientific evidence to support the development of age-specific B12 dietary intake recommendations. Methods: The present research comprised new statistical analysis of a previous cross-sectional study of n250 older (≥60 years) and n191 younger participants who provided a blood sample analysed for B12 biomarkers (holotranscobalamin (holoTC); methylmalonic acid; total homocysteine and serum total B12); and gastric function biomarkers Pepsingonen I:II (Hoey et al., 2007). B12 Dietary intake was assessed using a 4 day food diary completed in conjunction with a semi-quantitative food frequency questionnaire used to identify fortified food consumers. Data were statistically analysed using chi-square, Pearson's correlation and independent samples t-tests as appropriate. Results: Mean dietary B12 intakes were higher amongst elderly participants (4.1 μg day−1 (SD 3.3 μg) versus 3.6 μg day−1 (SD 2.0 μg) amongst those aged

Background: Dementia is a growing public health concern; there are currently 750 000 people living with the disease in the UK. By 2025 this number is expected to rise to over a million with costs estimated at over £20 billion per annum (Alzheimer's society, 2010). Diet is considered to play an important role in the development of cognitive impairment with recent research now identifying a role for B vitamins (Kado et al., 2005). The aim of this observational study was to investigate the association between B-vitamin status (in particular, vitamin B12 and folate) and cognitive function in older people. Methods: This study was conducted as part of a larger ongoing observational study of older Irish adults; Trinity Ulster Department of Agriculture (TUDA) study. Patients who were not born in the Republic of Ireland or Northern Ireland and those with severe dementia were excluded. A non-fasting blood sample (50 mL) was collected; routine clinical markers of health were measured as well as B vitamin status [serum folate, red cell folate (RCF), serum B12 and holotranscobalamin (holoTC)]. Cognitive function was measured using various cognitive performance tests including Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Depression and anxiety were measured using the Centre of Epidemiological Studies Depression (CES-D) scale and Hospital Anxiety and Depression (HAD) scale respectively to adjust for these possible confounders of cognitive performance. Data were analysed statistically using independent t tests, chi-squared tests and Pearsons correlations. Ethical approval was granted for the recruitment of patients over the age of 60 years from outpatient clinics and GP practices within two health trusts in Northern Ireland. Results: The cohort (n = 100) was split for analysis purposes into those aged 60–69 years (n = 70) and those aged ≥70 years (n = 30). There were no significant differences between the groups in terms of cognitive scores or B vitamin status (some of the results are shown in Table 1). No significant associations were found between B vitamin status and cognitive scores in the group as a whole or in the younger age group. However, in those aged 70 years or older, folate status (RCF concentrations) was found to be significantly associated with MMSE scores (r = 0.370, P = 0.048) while the association between RCF and RBANS was approaching significance (r = 0.358, P = 0.057) in those aged 70 or older. No associations were found between vitamin B12 and cognitive scores in either of the age sub-groups. Table 1. Differences between those aged 60–69 years and those aged ≥70 years in terms of cognitive scores & B vitamin status Aged 60–69 years Aged ≥70 years P value Mean (SD) Mean (SD) RBANS 86.4 (12.8) 82.5 (14.1) 0.169 MMSE 27.5 (2.7) 27.5 (3.2) 0.822 RCF (nM) 1092.2 (96.9) 1099.0 (96.0) 0.737 Discussion: The results are in line with the current literature (Tettamanti et al., 2006). Some observational data have also found associations between vitamin B12 and cognitive impairment; however, this was not the case with the present study. These findings may suggest a possible role for folate (but not B12) in certain types of dementia, such as Alzheimer's disease, as status was not associated with FAB which is used mainly in the diagnosis of frontotemporal dementia. Conclusion: Future research is warranted to confirm these associations in larger cohort trials involving two time points which will pave the way for randomised controlled trials to examine cause-and-effect relationships between B-vitamin status and cognitive performance. References: Alzeihmer's Society UK (2010) Statistics. Available at http://www.alzheimers.org.uk Kado, D.M., Karlamangla, A.S., Huang, M.H., Troen, A., Rowe, J.W., Selhub, J. & Seeman, T.E. (2005) Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am. J. Med.118, 161–7. Tettamanti, M., Garri, M.T., Nobili, A., Riva, E. & Lucca, U. (2006) Low folate and the risk of cognitive and functional deficits in the very old: the Monzino 80-plus study. J. Am. Coll. Nutr.25, 502–508.

Background: Adult under-nutrition is well recognised and extensively researched, leading to the development of guidelines, policies and nutrition screening tools to address the problem (Brotherton et al., 2010), however, there is a little recognition of childhood under-nutrition in the developed world. Current estimates suggest that 8–79% of hospitalised children are at risk of under-nutrition (Stratton et al., 2003). Under-nutrition is slowly gaining greater recognition by healthcare professionals which in turn may increase the demands on dietetic services. The aim of the present survey was to examine current nutrition care in paediatric centres across the UK and Ireland. Methods: The Children's Nutrition Survey was undertaken during January and February 2010. Participating centres were asked to complete a 2-page questionnaire regarding nutrition services and practices within their centres. This questionnaire was adapted, with permission, from the BAPEN Adult Nutrition Screening Week 2010 questionnaire. Centres were asked to describe nutrition services, weighing and measuring procedures, referral rates, staff training and nutrition auditing practices. Due to the small sample size descriptive statistics were used Ethical approval was sought through the University of Ulster Research Ethics Committee. Results: Seven specialist paediatric hospitals and 20 district general/single wards participated in the survey. Thirteen hospitals (48%) reported the presence of a nutrition support team or nutrition steering committee. Only eight centres could define their referral rates (the percentage of referrals to dietetic services from total number of in-patients), of which five defined their rate as falling within the lowest quartile of 0–25%. Screening tools were being used in only four centres. Nutrition related information was routinely included in the discharge plan of only 6 (22%) centres surveyed. Centres that reported having a nutrition support team or steering committee tended to be more likely to record height on admission; however, this was not found to be statistically significant due to the small sample size (Table 1). Table 1. Impact of nutrition support teams/steering committees on defined nutrition practices Weight taken on admission n (%) Height taken on admission n (%) Nutrition Practices Audited n (%) Staff trained on nutrition topics/referral criteria Nutrition Support team/Steering committee (n = 13) 11 (85) 4 (31) 8 (62) 12 (92) No Nutrition Support team/Steering committee (n = 14) 13 (93) 0 (0) 1 (7) 9 (64) Discussion: In centres with a nutrition support team/steering committee height was more likely to be taken on admission, nutrition practices more likely to be audited and staff trained on nutrition topics and referral criteria. Although current NICE guidelines (2006) recommend all hospitals have a nutrition steering committee, this did not seem to be met by many centres. Nutrition screening guidelines (Brotherton et al., 2010) were not being met in many centres as only four reported using nutrition screening tools. The current study will contribute to future research examining how paediatric dietetic services adapt and deal with increasing demands on their services to provide evidence-based practice and quality dietetic services Conclusion: This small survey shows the current lack of uniformity in the way nutrition care is conducted in paediatric centres across the UK and Ireland and the benefit nutrition support teams/steering committees may have. References: Brotherton, A., Simmonds, N. & Stroud, M. (2010) Malnutrition Matters, Meeting quality standards in nutritional care. A toolkit for commissioners and providers in England. Available at http://www.bapen.org.uk. [Accessed on 27 August 2010. NICE. Nutrition Support in Adults: oral nutrition support, enteral tube feeding and parenteral nutrition, CG32. London, National Institute for Health and Clinical Excellence, 2006. Available at http://guidence.nice.org.uk/CG32/niceguidence/pdf/English. [Accessed on 6 October 2010]. Stratton, R. J., Green, C. J. & Elia, M. (2003) Disease-Related Malnutrition: An Evidence Based Approach to Treatment. UK, CAB International.

Hypertension, defined as a systolic/diastolic blood pressure of 140/90 mmHg or greater, is estimated to carry a 3-fold increased risk of developing cardiovascular disease (CVD), while treating hypertension significantly reduces CVD events, and stroke in particular. Among the many risk factors involved, there is much recent interest in the role of genetic factors that might predispose to hypertension. Evidence from genome-wide association studies has identified an association between blood pressure and the gene encoding the folate-metabolising enzyme, methylenetetrahydrofolate reductase (MTHFR), while recent meta-analyses of observational studies show an increased risk of hypertension in people homozygous for the 677C→T polymorphism in MTHFR. Riboflavin (vitamin B2) in the form of FAD acts as a cofactor for MTHFR and we have been studying its modulating role in relation to this polymorphism. The variant enzyme is known from molecular studies to become inactive as a result of having an increased propensity to dissociate from FAD, but our earlier work suggested that supplementation with low-dose riboflavin could stabilise MTHFR activity in vivo in homozygous individuals. In recent years we showed that CVD patients with the relevant MTHFR 677TT genotype (compared to CC or CT genotypes) had significantly higher blood pressure, and that blood pressure was highly responsive to riboflavin intervention, specifically in the TT genotype group [1]. Further investigations confirmed this gene-nutrient interaction in hypertensive patients (with and without overt CVD), and furthermore showed that the blood pressure lowering effect of riboflavin in the TT genotype group was independent of the number and type of antihypertensive drugs that they were taking [2]. Although the precise mechanism linking this polymorphism to hypertension remains to be established, it would appear that the biological perturbation that leads to higher blood pressure in individuals with the MTHFR 677TT genotype is modifiable by correcting the variant MTHFR enzyme through enhancing riboflavin status. Thus riboflavin, targeted specifically at this genetically at-risk group, may offer a personalized non-drug approach to managing hypertension.

Objective: To investigate the effect of riboflavin supplementation on plasma homocysteine (tHcy) concentrations in healthy elderly people with sub-optimal riboflavin status. Design: A double-blind, randomized, placebo-controlled riboflavin supplementation trial. Setting: Community based study in Northern Ireland. Subjects: From a screening sample of 101 healthy elderly people, 52 had sub-optimal riboflavin status (erythrocyte glutathione reductase activation coefficient, EGRAC≥1.20) and were invited to participate in the study. Intervention: The intervention had two parts. Part 1 was a 12 week randomized double blind, placebo-controlled intervention with riboflavin (1.6 mg/day). Following completion of part 1, the placebo group went on to part 2 of the study which involved supplementation with folic acid (400 µg/day) for 6 weeks followed by folic acid and riboflavin (1.6 mg/day) for a further 12 weeks, with a 16 week washout period post-supplementation. The purpose of part 2 was: (a) to address the possibility that homocysteine-lowering in response to riboflavin may be obscured by a much greater effect of folate, and that, once folate status was optimized, a dependence of homocysteine on riboflavin might emerge; and (b) to demonstrate that these subjects had homocysteine concentrations which could be lowered by nutritional intervention. Results: Although riboflavin supplementation significantly improved riboflavin status in both parts 1 and 2 of the study (P

BACKGROUND Current data suggest that physiologic doses of vitamin B-6 have no significant homocysteine-lowering effect. It is possible that an effect of vitamin B-6 was missed in previous trials because of a much greater effect of folic acid, vitamin B-12, or both. OBJECTIVE The aim of this study was to investigate the effect of low-dose vitamin B-6 supplementation on fasting total homocysteine (tHcy) concentrations in healthy elderly persons who were made replete with folate and riboflavin. DESIGN Twenty-two healthy elderly persons aged 63-80 y were supplemented with a low dose of vitamin B-6 (1.6 mg/d) for 12 wk in a randomized, double-blind, placebo-controlled trial after repletion with folic acid (400 microg/d for 6 wk) and riboflavin (1.6 mg/d for 18 wk); none of the subjects had a vitamin B-12 deficiency. RESULTS Folic acid supplementation lowered fasting tHcy by 19.6% (P < 0.001). After folic acid supplementation, baseline tHcy concentrations ranged from 6.22 to 23.52 micromol/L and 10 subjects had suboptimal vitamin B-6 status (plasma pyridoxal-P < 20 nmol/L). Two-way analysis of variance showed that the significant improvement in vitamin B-6 status in response to vitamin B-6 supplementation (on the basis of both pyridoxal-P: and the erythrocyte aspartate aminotransferase activation coefficient) was reflected in a significant reduction in plasma tHcy of 7.5%. CONCLUSIONS Low-dose vitamin B-6 effectively lowers fasting plasma tHcy in healthy subjects who are both folate and riboflavin replete. This suggests that any program aimed at the treatment or prevention of hyperhomocysteinemia should include vitamin B-6 supplementation.

Previous studies have shown that glycated insulin is secreted from pancreatic beta-cells under conditions of hyperglycaemia. This study has investigated the effects of monoglycated insulin on plasma glucose homeostasis and in vitro cellular glucose transport and metabolism by isolated abdominal muscle of mice. Monoglycated insulin was prepared under hypeglycaemic reducing conditions, purified by RP-HPLC and identified by electrospray ionisation mass spectrometry (5971.1 Dal. When administered to mice at an intraperitoneal dose of 7 nmoles/kg body weight, insulin (non-glycated) decreased plasma glucose concentrations and substantially reduced the glycaemic excursion induced by conjoint intraperitoneal injection of 2 g glucose/kg body weight. In comparison, the same dose of monoglycated insulin decreased plasma glucose concentrations to a lesser extent (P < 0.05), corresponding to an approx. 20% reduction of glucose lowering potency. Using isolated abdominal muscle, insulin (10(-9)-10(-7) M) stimulated dose-dependent increases in cellular 2-deoxy-D-[1(-3)H]glucose uptake, D-[U-14C]glucose oxidation and glycogen production. Monoglycated insulin was approx. 20% less effective than native insulin in stimulating glucose uptake and both indices of metabolism, generally requiring 10-fold greater concentrations to achieve significant stimulatory effects. These data indicate that the impaired biological activity of glycated insulin may contribute to glucose intolerance of diabetes. (C) 2000 Elsevier Science B.V. All rights reserved.

BACKGROUND Mandatory fortification of grain products with folic acid was introduced recently in the United States, a policy expected to result in a mean additional intake of 100 microgram/d. One way of predicting the effectiveness of this measure is to determine the effect of removing a similar amount of folic acid as fortified food from the diets of young women who had been electively exposed to chronic fortification. OBJECTIVE The objective was to examine the effect on folate status of foods fortified with low amounts of folic acid. DESIGN We investigated the changes in dietary intakes and in red blood cell and serum concentrations of folate in response to removing folic acid-fortified foods for 12 wk from the diets of women who reportedly consumed such foods at least once weekly (consumers). RESULTS Consumers (n = 21) had higher total folate intakes (P = 0.002) and red blood cell folate concentrations (P = 0.023) than nonconsumers (women who consumed folic acid-fortified foods less than once weekly; n = 30). Of greater interest, a 12-wk intervention involving the exclusion of these foods resulted in a decrease in folate intake of 78 +/- 56 microgram/d (P < 0.001), which was reflected in a significant reduction in red blood cell folate concentrations (P < 0.05). CONCLUSIONS Cessation of eating folic acid-fortified foods resulted in removing 78 microgram folic acid/d from the diet. Over 12 wk this resulted in a lowering of red blood cell folate concentrations by 111 nmol/L (49 microgram/L). This magnitude of change in folate status in women can be anticipated as a result of the new US fortification legislation and is predicted to have a significant, although not optimal, effect in preventing neural tube defects.

Background: The importance of the early identification and management of nutritional risk is well established in adult and elderly hospital care. Numerous nutritional screening tools are available for adults, for example Malnutrition Universal Screening Tool (MUST), Mini Nutritional Assessment (MNA) and NRS-2002 (Kondrup et al., 2003). Currently there is no validated nutrition risk screening tool for use with children admitted to hospital in the UK. The aim of this study was to test the validity of a newly developed nutrition risk screening tool for children. Methods: All children (aged 2–17 years) admitted to the study wards (two medical, two surgical) over a 4 week period were screened using a newly developed, nurse administered paediatric nutrition screening tool (NST). The NST consisted of three elements – clinical diagnosis, nutritional intake and anthropometric measures. Each element was scored and children with an overall score of three or more were considered at nutritional risk. Of those screened, a sample (n = 89) were further assessed for full nutritional status by a registered dietitian. The full nutritional assessment consisted of a face-to-face interview obtaining dietary and social information, anthropometric measurements and retrieval of medical information from case notes. Data were analysed using chi-square tests to compare groups within the sample and k statistic to compare agreement between the full nutritional assessment and NST. Full ethical approval was obtained prior to undertaking this study. Results: The majority of 89 participants were surgical admissions (58%), male (56%) and the mean (SD) age was 9.0 (4.5) years. Nutritional risk was identified in 21% of the sample using the NST, and in 20% of the sample by full nutritional assessment. The prevalence of nutritional risk was not significantly different between methods or between males and females (by either method), but was statistically higher (by both methods) in medical compared with surgical admissions (χ2 = 18.426, P

Free-living elderly people aged > or = 65 y were recruited to assess riboflavin and vitamin B-6 intakes and status and the effect of riboflavin supplementation on biochemical indicators of these 2 vitamins. The status of riboflavin (erythrocyte glutathione reductase activation coefficient; EGRAC) and vitamin B-6 (plasma pyridoxal-5'-phosphate; PLP) were determined in a total sample of 92 subjects, from whom dietary intake data were obtained by using the diet history method (n = 83). Although dietary intakes of both vitamins were considered to be adequate according to current reference values, abnormal EGRAC and plasma PLP values were identified in 49% and 38% of subjects, respectively, with 21% having suboptimal status for both nutrients. A subgroup of subjects from the initial sample (n = 45) was assigned in a double-blind manner to receive either 1.6 or 25 mg riboflavin or placebo daily for 12 wk. In those subjects with a baseline EGRAC or plasma PLP value falling outside the currently accepted threshold value for adequacy, low-dose riboflavin supplementation improved status of the limiting nutrient significantly (P

OBJECTIVE: To report micronutrient intakes in Northern Ireland schoolchildren, and to establish the contribution of fortified breakfast cereal to overall nutrient intakes and achievement of current dietary recommendations. DESIGN: Analysis of dietary intakes and physical characteristics of participants in a randomly selected 2% population sample of 1015 schoolchildren aged 12 and 15 years in Northern Ireland during the 1990/1 school year. MAIN OUTCOME MEASURES: Dietary intakes, physical characteristics, and their association with consumption of fortified breakfast cereal. RESULTS: Mean micronutrient intakes were generally adequate with the exception of low intakes of folate (boys and girls) and iron (girls). Fortified breakfast cereals, consumed by a high proportion (94% boys; 83% girls) of the sample, were associated with higher daily intakes of most micronutrients and fibre and with a macronutrient profile consistent with current nutritional recommendations. Appreciable proportions of subjects who did not consume fortified breakfast cereals had daily intakes that fell below the lower reference nutrient intake for riboflavin, niacin, folate, vitamin B-12, and iron (girls). CONCLUSIONS: The results demonstrate the potential of fortification in contributing to micronutrient intakes of schoolchildren, particularly where requirements are high, or for those on marginal diets of low nutritional quality.

Fortification of food with folic acid to prevent neural-tube defects in babies also lowers plasma total homocysteine, which is a risk factor for vascular disease. We investigated the effect of folate and vitamin B12 on homocysteine concentrations. 30 men and 23 women received sequential supplementation with increasing doses of folic acid. After supplementation, the usual dependency of homocysteine on folate diminished, and vitamin B12 became the main determinant of plasma homocysteine concentration. This finding suggests that a fortification policy based on folic acid and vitamin B12, rather than folic acid alone, is likely to be much more effective at lowering of homocysteine concentrations, with potential benefits for reduction of risk of vascular disease.

Folate plays a crucial and indispensible role in cell division so it is not surprising that it is important in pregnancy. This importance was first highlighted by the historical observation made by Lucy Wills in India1 that the latter stages of pregnancy are frequently associated with a megaloblastic anaemia that is folate responsive, i.e. in pregnancy not only is extra folate needed but it is frequently lacking. Subsequent studies over the years have found that folate deficiency in the second and particularly the third trimester is common in some countries and quite rare in others. The determining feature was found to be adequate folate nutrition for the mother not only during pregnancy but before the pregnancy began2. The most often suggested mechanism for folate deficiency in pregnancy is increased requirement for the rapidly growing fetus and placenta. However the mechanism is unclear and certainly cannot be accounted for by transfer of the vitamin to the fetus. One possible explanation is that the events of fetal/placental growth cause an increase in the rate of catabolism of the vitamin. Early studies in our laboratory demonstrated that the mechanism of folate catabolism in the rat was cleavage of the C9-N10 bond with excretion of a mixture of pteridines and p-aminobenzoylglutamate (pABGlu) with the latter being largely acetylated to acetamidobenzoylglutamate (apABGlu)3. Subsequent studies by us in the rat4 and by Krumdieck5 in man confirmed this mechanism. These studies used radioactive tracers. They had the disadvantage that they assumed that the exogenous tracer would equilibrate with the endogenous pool given sufficient time. In addition while they could be used to compare rates of catabolism in specific circumstances between animals, say treated with convulsant drugs and controls6, they did not measure true endogenous rates of catabolism. Furthermore, since they used radioactive tracers they were unsuitable for routine studies on humans.

Hypertension is a key risk factor for stroke, cardiovascular disease and dementia. Although the link between weight, sodium and hypertension is established in younger people, little is known about their inter-relationship in people beyond 80 years of age. Associations between blood pressure, anthropometric indices and sodium were investigated in 495 apparently healthy, community-living participants (age 90, SD 4.8; range 80–106), from the cross-sectional Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) study. In age-sex-adjusted logistic regression models, blood pressure ≥140/90 mmHg significantly associated with body mass index (BMI) [odds ratio (OR) = 1.28/ kg/m2], with weight (OR = 1.22/kg) approaching significance (P = 0.07). In further age-sex-adjusted models, blood pressure above the 120/80 mmHg normotensive reference value significantly associated with BMI (OR = 1.44/kg/m2), weight (OR = 1.36/kg), skin-fold-thickness (OR = 1.33/mm) and serum sodium (OR = 1.37 mmol/l). In BELFAST participants over 80 years old, blood pressure ≥140/90 mmHg is associated with BMI, in apparently similar ways to younger groups.

The United Kingdom Drug Information Network has been developed in recent years to form an effective service. The structure of the health service is discussed and the organization of drug information services within this framework is outlined. A number of collaborative and work sharing exercises have been undertaken between regional services and thus are reviewed together with future trends for the service.

Committees worldwide have set almost identical folate recommendations for the prevention of the first occurrence of neural tube defects (NTDs). We evaluate these recommendations by reviewing the results of intervention studies that examined the response of red blood cell folate to altered folate intake. Three options are suggested to achieve the extra 400 microg folic acid/d being recommended by the official committees: increased intake of folate-rich foods, dietary folic acid supplementation, and folic acid fortification of food. A significant increase in foods naturally rich in folates was shown to be a relatively ineffective means of increasing red blood cell folate status in women compared with equivalent intakes of folic acid-fortified food, presumably because the synthetic form of the vitamin is more stable and more bioavailable. Although folic acid supplements are highly effective in optimizing folate status, supplementation is not an effective strategy for the primary prevention of NTDs because of poor compliance. Thus, food fortification is seen by many as the only option likely to succeed. Mandatory folic acid fortification of grain products was introduced recently in the United States at a level projected to provide an additional mean intake of 100 microg folic acid/d, but some feel that this policy does not go far enough. A recent clinical trial predicted that the additional intake of folic acid in the United States will reduce NTDs by >20%, whereas 200 microg/d would be highly protective and is the dose also shown to be optimal in lowering plasma homocysteine, with possible benefits in preventing cardiovascular disease. Thus, an amount lower than the current target of an extra 400 microg/d may be sufficient to increase red blood cell folate to concentrations associated with the lowest risk of NTDs, but further investigation is warranted to establish the optimal amount.

Background Mandatory folic acid fortification of food is effective in reducing neural tube defects and may even reduce stroke-related mortality, but it remains controversial because of concerns about potential adverse effects. Thus, it is virtually nonexistent in Europe, albeit many countries allow food fortification on a voluntary basis. Objective The objective of the study was to examine the effect of a voluntary but liberal food fortification policy on dietary intake and biomarker status of folate and other homocysteine-related B vitamins in a healthy population. Design The study was a cross-sectional study. From a convenience sample of 662 adults in Northern Ireland, those who provided a fasting blood sample and dietary intake data were examined (n = 441, aged 18-92 y). Intakes of both natural food folate and folic acid from fortified foods were estimated; we used the latter to categorize participants by fortified food intake. Results Fortified foods were associated with significantly higher dietary intakes and biomarker status of folate, vitamin B-12, vitamin B-6, and riboflavin than were unfortified foods. There was no difference in natural food folate intake (range: 179-197 microg/d) between the fortified food categories. Red blood cell folate concentrations were 387 nmol/L higher and plasma total homocysteine concentrations were 2 micromol/L lower in the group with the highest fortified food intake (median intake: 208 microg/d folic acid) than in the nonconsumers of fortified foods (0 microg/d folic acid). Conclusions These results show that voluntary food fortification is associated with a substantial increase in dietary intake and biomarker status of folate and metabolically related B vitamins with potential beneficial effects on health. However, those who do not consume fortified foods regularly may have insufficient B vitamin status to achieve the known and potential health benefits.