Dietary Folic Acid Supplementation Research Articles

Effects of Intramuscular Injections of Vitamin B12 on Lactation Performance of Dairy Cows Fed Dietary Supplements of Folic Acid and Rumen-Protected Methionine

The experiment was undertaken to determine the effects of i.m. injections of vitamin B12 on lactational performance of primiparous dairy cows fed dietary supplements of folic acid and rumen-protected methionine from 4 to 18 wk of lactation. Fourteen primiparous Holstein cows were assigned to 7 blocks of 2 cows each, according to milk production during the third week of lactation. All cows were fed a basal diet supplemented daily with rumen-protected methionine (18g of supplement, to bring the estimated supply of methionine to 2.2% of metabolizable protein) plus folic acid (4mg per kg of BW). Within each block, the cows received a weekly i.m. injection (2mL) of saline or 10mg of vitamin B12. Milk production was recorded daily. Milk and blood were sampled every 2 wk. Supplementary vitamin B12 increased energy-corrected milk from 25.8 to 29.0 (SE 1.6) kg/d, as well as milk yields of solids [3.52 to 3.90 (SE 0.22) kg/d], fat [0.87 to 1.01 (SE 0.06) kg/d], and lactose [1.48 to 1.64 (SE 0.11) kg/d]. Supplementation also increased concentrations and amounts of vitamin B12 secreted in milk but had no significant effect on dry matter intake and concentrations and amounts of folates in milk. Packed cell volume, blood hemoglobin, and serum vitamin B12 were increased by supplementary vitamin B12, whereas serum methylmalonic acid was decreased. Serum concentrations of sulfur amino acids were unchanged by treatment. These findings support the hypothesis that, in early lactation, supply of vitamin B12 was not optimal and limited the lactation performance of the cows.

Effects of Dietary Supplements of Folic Acid and Rumen-Protected Methionine on Lactational Performance and Folate Metabolism of Dairy Cows

The present experiment was undertaken to determine the interactions between dietary supplements of folic acid and rumen-protected methionine on lactational performance and on indicators of folate metabolism during one lactation. Fifty-four multiparous Holstein cows were assigned to 9 blocks of 6 cows each according to their previous milk production. Within each block, 3 cows were fed a diet calculated to supply methionine as 1.75% metabolizable protein, equivalent to 70% of methionine requirement, whereas the 3 other cows were fed the same diet supplemented with 18g of a rumen-protected methionine supplement. Within each diet, the cows received 0, 3, or 6 mg/d of folic acid per kg of body weight. Rumen-protected methionine increased milk total solid concentration but not yield. Supplementary folic acid increased crude protein and casein concentrations in milk of cows fed no supplementary methionine and the effect increased as lactation progressed; it also decreased milk lactose concentration. Folic acid supplements had the opposite effects on milk crude protein, casein, and lactose concentrations in cows fed rumen-protected methionine. Milk and milk component yields and dry matter intake were unchanged. Folic acid supplementation increased serum folates and this response was greater at 8 wk of lactation. It decreased serum cysteine in cows fed rumen-protected methionine, whereas it had no effect in cows fed no supplementary methionine. The highest serum concentrations of cysteine but the lowest of vitamin B12 were observed at 8 wk of lactation. Serum clearance of folic acid following an i.v. injection of folic acid was slower at 8 wk of lactation. During this period, the high concentrations of serum folates and cysteine, the low serum concentrations of vitamin B12 and methionine, and the slow serum clearance of folates strongly suggest that the vitamin B12 supply was inadequate and interfered with folate use. It could explain the limited lactational response to supplementary folic acid observed in the present experiment.

Ineffectiveness of dietary folic acid supplementation on the incidence of lipomyelomeningocele: pathogenetic implications.

Periconceptual folic acid supplementation is effective in myelomeningocele prevention. The relationship between folic acid and lipomyelomeningocele (LMM) and the overall incidence of this occult form of spina bifida has never been studied. The objectives of this study were to determine the impact of dietary folic acid supplementation on the incidence of LMM and to measure its overall incidence. In a retrospective population-based study the authors calculated the incidence of LMM in Nova Scotia between 1985 and 2001. Because of changes in public policy during this period, there are three intervals defined in relation to the treatment of the food supply with folic acid: 1) prior to folic acid fortification (1985-1994); 2) postsupplementation but prefortification (1995-1998); and 3) postfortification. The overall incidence of LMM in Nova Scotia between 1985 and 2001 was 16 per 100,000 live births or one case per 6121 live births. Its incidence between 1985 and 1994 was 15 per 100,000 live births, and between 1995 and 1998 it was 12 per 100.000 live births (relative risk [RR] 0.82, 95% confidence interval [CI] 0.31-2.22; p = 0.7). Between 1999 and 2001, the incidence of LMM was 29 per 100,000 live births, which was not significantly different from that between 1995 and 1998 (RR 2.41. 95% CI 0.79-7.36; p = 0.11) or between 1985 and 1994 (RR 1.98, 95% CI 0.86-4.56; p = 0.1). The overall incidence of LMM between 1985 and 2001 in Nova Scotia was 16 per 100,000 live births and has not been reduced by dietary folic acid supplementation. This finding provides epidemiological evidence that the embryogenesis of LMM is fundamentally different from that of myelomeningocele.

Effects of dietary folic acid supplementation on cerebrovascular endothelial dysfunction in rats with induced hyperhomocysteinemia

This study shows, for the first time, that hyperhomocysteinemia induces endothelial dysfunction in a rat brain, and that this can be alleviated by dietary folic acid supplementation. Our experiments examined the effects of folic acid supplementation on the endothelial nitric oxide synthase (eNOS) expression in the hyperhomocysteinemic rat brain, and related the observed changes in eNOS expression to the expression of the cell adhesion molecule and the glucose transporter protein. The animals were raised on an experimental diet containing 0.3% homocystine for 2 weeks and then they were placed either on a 0.3% homocystine, 0.3% homocystine with 8 mg/kg folic acid, or folic acid (8 mg/kg) diet for 2 weeks. The cerebrovascular eNOS activity was examined immunohistochemically. Cerebral levels of eNOS, glucose transporter-1 (GLUT-1), and the vascular cell adhesion molecule-1 (VCAM-1) proteins were evaluated by Western blot analysis. At 4 weeks, the homocystine diet induced a fourfold increase in plasma homocysteine (control: 6.5±0.4 μmol/l, homocystine: 26.2±2.5 μmol/l), and a reduction in the cerebral eNOS and GLUT-1 expression levels with a concomitant increase in the level of VCAM-1 expression. Dietary folic acid supplementation caused a significant decrease in the plasma homocysteine levels, a concomitant increase in the hyperhomocysteinemia-induced reduction in the cerebral eNOS and GLUT-1 expression levels, and a decrease in the hyperhomocysteinemia-induced VCAM-1 expression levels.

Folic acid with or without vitamin B12 for cognition and dementia.

Folic acid with or without vitamin B12 for cognition and dementia.

Intimal hyperplasia following carotid endarterectomy in an insulin-resistant rat model

Hyperhomocysteinemia, a known risk factor for cardiovascular disease, results in an elevation of intimal hyperplasia (IH) following a carotid endarterectomy (CEA) in a rat model. An exaggerated IH response following CEA has been observed in rats with dietary induced hyperhomocysteinemia. Type 2 diabetics often present with hyperhomocysteinemia and are at higher risk for developing vascular blockage following surgical procedures. To determine if insulin resistance increases IH risks following endarterectomy, the 3 goals of this study were: (1) to establish plasma homocysteine concentrations in dietary induced insulin-resistant rats and their controls, (2) to investigate whether a positive correlation of IH and plasma homocysteine response occurs following CEA in the insulin-resistant rat model, and (3) if so, to attempt to decrease IH by supplementation with folic acid, a known enzymatic cofactor in the homocysteine metabolic pathway. To achieve these aims, male rats (275 to 300 g) were fed 1 of 4 diets for a 4-month period: (1) high-fat sucrose (HFS), (2) low-fat complex carbohydrate (LFCC), (3) HFS + 25 mg/kg folic acid (HFS+F), or (4) LFCC + 25 mg/kg folic acid (LFCC+F). At the end of the 4-month period the rats underwent an open (non-balloon) unilateral CEA. Two weeks post-endarterectomy, blood, liver and carotid tissue were removed to measure plasma insulin, folic acid, and homocysteine, 2 key enzymes of homocysteine metabolism—methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS)—and percent lumenal stenosis (IH%). Computer-assisted morphometric analysis was used to measure the percentage of IH in the carotid artery. Plasma homocysteine was significantly higher in the HFS group when compared with the LFCC group (11.3 ± 1.3 μmol/L v 7.4 ± 0.6 μmol/L, P = .008) as was post-endarterectomy IH producing lumenal stenosis (30.7% ± 4.2% v 14.0% ± 4.3%, P = .008). Plasma insulin in the HFS group was higher than the LFCC (control) group and was significant (36.3 ± 3.0 μU/mL v 21.1 ± 0.8 μU/mL, P = .0004). Folic acid supplementation in the HFS group resulted in reductions of plasma homocysteine (HFS v HFS+F, 11.3 ± 1.3 μmol/L v 7.95 ± 1.0 μmol/L, P = .02) and post-endarterectomy IH (HFS v HFS+F, 30.7% ± 4.2 % v 10.4% ± 1.6%, P = .0001). The control or LFCC group was not statistically different from the HFS+F group in homocysteine or IH. Folate supplementation did not decrease insulin concentrations in the HFS+F group compared to the LFCC group. We conclude that the HFS diet produced an insulin-resistant state with an elevated plasma homocysteine and an exaggerated IH response following carotid endarterectomy in this rat model. Dietary folate supplementation reduced plasma homocysteine concentrations in the HFS diet, which implicates hyperhomocysteinemia as an etiologic factor in the development of post-CEA IH in this insulin-resistant rat model.

Cold-induced elevation of homocysteine and lipid peroxidation can be alleviated by dietary folic acid supplementation

This study was conducted to determine the effects of folic acid supplementation at various levels on performance, carcass characteristics and serum concentrations of homocysteine, malondialdehyde (MDA), an indicator of lipid peroxidation, folic acid, vitamin B 12, and adrenocorticotropic hormone (ACTH) in broiler Japanese quails (Coturnix coturnix japanica) reared under a low ambient temperature (6°C). One hundred twenty Japanese quails (10-d-old) were divided into four groups, 30 birds per group; 3 replicates of 10 birds each. The quails were fed either a basal diet or the basal diet supplemented with either 0.5, 1 or 2 mg of folic acid/kg of diet. Increased supplemental folic acid resulted in an increase in body weight ( P = 0.04, linear), carcass characteristics ( P = 0.01, linear), and also improved feed efficiency ( P = 0.01, linear). Serum folate ( P = 0.02) and vitamin B 12 concentrations linearly increased ( P = 0.01), whereas homocysteine ( P = 0.01, linear), malondialdehyde (MDA) ( P = 0.01, linear) and ACTH concentrations linearly decreased ( P = 0.05) as dietary folic acid supplementation increased. Results of the present study suggest that the detrimental effects of low ambient temperature on performance and serum concentrations of homocysteine and lipid peroxidation can be alleviated by dietary supplementation with folic acid, and that the best results were obtained when 2 mg folic acid/kg of diet was included and folic acid supplementation at such a level can be considered as a protective management practice in a quail diet for alleviating negative effects of cold stress.

Potential prevention of neural tube defects by assessment of women of childbearing age through monitoring of folate.

Three quarters of neural tube defects (NTD) can be prevented by sufficient dietary folate supplementation. Despite this knowledge, most women do not supplement their diet effectively. Red cell folate concentrations correlate with the risk of NTD, and levels of less than 900 nM are associated with an increased risk of these serious congenital anomalies. Laboratory tests to assess anemia include testing for folate. This study was conducted to estimate the potential benefits of informing women of reproductive age who are unaware of their low folate levels, uncovered in their anemia tests. The number of Ontario women of reproductive age who undergo folate tests and are at an increased risk of NTD was calculated. In addition, the authors calculated the number of NTD cases that could have been prevented if these women were informed of the possible consequences of their low folate levels should they become pregnant. In 1998, red cell folate concentrations were measured in 23,109 women of childbearing age (15-45 y). Approximately half of the women [n = 11,392 (49.3%)] had folate levels below 900 nM and thus were at an increased risk of giving birth to a child with NTD should they have become pregnant. Their overall mean relative risk (RR) of NTD was 1.95, or 1:512 births. If they would have been informed of this risk and subsequently increased their consumption of folate before becoming pregnant, 22.3 cases of NTD per year could have possibly been prevented at no extra cost, since the folic acid results were a part of investigational blood tests performed for another reason (anemia). Women of reproductive age who are being evaluated for the cause of anemia and have low red cell folate results constitute a high-risk group for NTD in their children. These women should be informed of the increased risk and of methods of dietary folate supplementation.

The enrichment of eggs with folic acid through supplementation of the laying hen diet

In light of evidence supporting a need for humans to increase their dietary folate intakes, experiments were conducted to evaluate the extent to which egg folate levels could be increased. In Study 1, Hyline W36 hens (n = 6/diet) received a barley-based diet, containing 0 or 10 mg/kg of crystalline folic acid, to establish the potential for folate incorporation into table eggs. In Study 2, 70 hens were divided into seven treatment groups (n = 10 hens/diet) and received diets supplemented with 0, 1, 2, 4, 8, 16, or 32 mg folic acid/kg diet. In Study 3, 64 hens received the barley-based diet with or without 4 mg folic acid/kg diet. Eggs were collected and stored for 0, 7, 14, 21, or 28 d, prior to folate determinations. The folate content of eggs was determined by HPLC for 5-methyltetrahydrofolate (the sole form of folate in egg yolk). Results from Study 1 showed that a 10 mg/kg inclusion of folic acid increased folate incorporation into egg yolk (41.0 +/− 0.7 microg /egg) over that of an unsupplemented diet (17.5 +/− 0.7 microg /egg; P = 0.0001). In Study 2, the response of egg folate to dietary folic acid supplementation was saturable, with 90% of maximal egg folate levels established at approximately 4 mg folic acid/ kg diet. Results from Study 3 showed that folate levels are stable, in control and fortified eggs, during 28 d of storage at 4 C. In terms of its nutritional value, one large egg collected from a folic acid-supplemented hen provided approximately 12.5% of the recommended dietary allowance (RDA) for adult humans (RDA = 400 mg/d).

Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior.

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.

Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype

OBJECTIVESWe sought to study the effect of low-dose folic acid supplementation or optimization of dietary folate intake on plasma homocysteine and endothelial function in healthy adults.BACKGROUNDElevated homocysteine is associated with cardiovascular disease, but it is not known whether this relationship is causal. Individuals homozygous (TT) for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (∼12% of the population) have increased homocysteine levels, particularly in association with suboptimal folate intake.METHODSHealthy subjects (n = 126; 42 of each MTHFR genotype) were included in this cross-over study of three interventions of four months each: 1) placebo plus natural diet; 2) daily 400-μg folic acid supplement plus natural diet; and 3) increased dietary folate intake to 400 μg/day.RESULTSAt baseline, homocysteine was inversely related to plasma folate and was higher in TT homozygotes. For the whole group, plasma folate increased by 46% after dietary folate and by 79% after supplementation, with reductions of homocysteine of 14% and 16%, respectively. Within the genotype, TT homozygotes exhibited the most marked changes in these variables. Brachial artery endothelial function, as determined by a change in end-diastolic diameter in response to increased flow, was not changed by increased folate intake (98 ± 73 μm at baseline, 110 ± 69 μm after a high-folate diet, 114 ± 59 μm after supplementation and 118 ± 68 μm after placebo). Plasma von Willebrand factor antigen was unaltered.CONCLUSIONSOptimization of dietary folate or low-dose folic acid supplementation reduces plasma homocysteine but does not enhance endothelial function, irrespective of the MTHFR (C667T) genotype.

Coronary artery disease--free radical damage, antioxidant protection and the role of homocysteine.

Traditional risk factors for coronary artery disease (CAD) can only explain approximately two thirds of the observed clinical events. This has maintained interest in other nutritional and biochemical factors that might contribute to the underlying pathophysiology of vascular disease. Two such factors are dietary antioxidants and plasma homocysteine. Established risk factors such as hypertension, smoking and diabetes mellitus are all associated with increased oxidative stresses due to excess free radical activity in the vascular wall. This may facilitate the development of vascular disease because of (i) increased oxidation of low-density lipoprotein (LDL) particles which increases their propensity to deposition in the vascular wall, (ii) inactivation of endothelium-derived nitric oxide, and (iii) direct cytotoxicity to endothelial cells. Protective antioxidant molecules include vitamin C and vitamin E of which the latter is lipid soluble and is the primary antioxidant defence in circulating LDL particles. Epidemiological studies have suggested strongly that individuals who have high circulating concentrations or dietary intake of natural antioxidant vitamins are protected against vascular disease events (18). Furthermore, many studies have demonstrated a beneficial effect of natural and synthetic antioxidants on surrogate markers of vascular disease such as endothelial function and lipoprotein oxidation. However, large prospective randomized controlled intervention trials, mostly involving vitamin E (e.g. CHAOS, HOPE (22)), have failed to demonstrate any beneficial effect upon vascular mortality in high risk individuals. Possible reasons for these disappointing results include the pro-oxidant effects of high dose antioxidant supplements, particularly in patients with established vascular disease. Homocysteine is a sulphydryl-containing amino acid derived from the demethylation of dietary methionine. Epidemiological studies over 30 years have shown that increased concentrations of homocysteine are associated with vascular disease. This link is independent of other risk factors, is consistent across many studies and is strongly dose-related. Recently, evidence has accumulated to suggest that this link is also biologically plausible because homocysteine promotes oxidant injury to the vascular endothelium, impairs endothelium-dependent vasomotor regulation and may also alter the coagulant properties of the blood. Plasma homocysteine levels can be reduced by dietary supplements of folic acid and B vitamins. Studies are currently being undertaken to examine the impact of these vitamins in high risk patients and, thereby, establish a causative role for homocysteine in promoting vascular events.

Reproductive performance and uterine prostaglandin secretion in gilts conditioned with dead semen and receiving dietary supplements of folic acid

The effects of dietary supplements of folic acid at 0 (F−) or 15 ppm (F+) and of conditioning the uterus (C+) or not (C−) with an intrauterine infusion of dead semen on embryonic survival and prostaglandin E2 (PGE2) concentrations in the allantoic fluid on day 30 of gestation were studied. Sixty-four F1 crossbred gilts (Yorkshire × Landrace) were used in a 2 × 2 factorial design. The initiation of folate supplementation and the intrauterine infusion of dead semen were done at the estrus preceding the fertile mating. Folate status in serum was lower in F+ gilts than in F− gilts during the estrus cycle (folic acid × period interaction, P ≤ 0.007). Conditioning increased ovulation rate in F− gilts while it tended to decrease it in F+ gilts (interaction folic acid × conditioning, P ≤ 0.03). A similar interaction (P ≤ 0.02) was observed on the number of presumably live embryos at 30 d of gestation. Mean PGE2 concentration in the allantoic fluid was not affected by treatments (P ≥ 0.44), but the frequency of sows having elevated allantoic PGE2 (> 4 ng mL−1) tended to be higher (P ≤ 0.06) in F+ sows. Overall values of PGE2 were correlated with total litter weight (R2 = 0.54). In conclusion, there was no synergism between folic acid supplements and conditioning of the uterus with dead semen on the reproductive performance or on the secretion of allantoic PGE2 at 30 d of gestation. The secretion of allantoic PGE2 appears as an important factor involved in the control of litter size and weight. Key words: Folic acid, artificial insemination, semen, gilts, conditioning, embryo mortality

Response of red blood cell folate to intervention: implications for folate recommendations for the prevention of neural tube defects

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.

High-dose folic acid supplementation in rats: effects on gestation and the methionine cycle

There is new evidence that a good folate status may play a critical role in the prevention of neural-tube defects and in lowering elevated homocysteine concentrations. This adequate folate status may be achieved through folic acid dietary supplementation. Folate is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term high-dose folic acid supplementation are unknown, especially those related to the methionine cycle, where folate participates as a substrate. With the aim of evaluating such possible effects, four groups of Wistar rats were classified on the basis of physiological status (virgin v. pregnant) and the experimental diet administered (folic-acid-supplemented, 40 mg/kg diet v. control, 2 mg folic acid/kg diet). Animals were fed on the diets for 3 weeks. Results showed that gestation outcome was adequate in both groups regardless of the dietary supplementation. However, there were reductions (P < 0.001) in body weight and vertex-coccyx length in fetuses from supplemented dams v. control animals. Folic acid administration also induced a higher (P < 0.01) S-adenosylmethionine: S-adenosylhomocysteine value due to increased S-adenosylmethionine synthesis (P < 0.01). However, hepatic DNA methylation and serum methionine concentrations remained unchanged. Serum homocysteine levels were reduced in supplemented dams (P < 0.05). Finally, pregnancy caused lower serum folate, vitamin B6 and vitamin B12 levels (P < 0.05). Folic acid administration prevented the effect of pregnancy and raised folate levels in dams, but did not change levels of vitamins B12 and B6. These new findings are discussed on the basis of potential benefits and risks of dietary folic acid supplementation.

Response of serum concentrations of folates to dietary supplements of folic acid given to ewes during gestation

Serum folates were determined during the 24 h following the ingestion of 0, 130, 260 or 520 mg of folic acid at 12, 61 and 131 d of gestation in 38 ewes. The response of serum folates increased with the dose ingested (P &lt; 0.0001) but decreased as gestation progressed (P &lt; 0.005). Key words: Ewe, dietary supplements, folic acid, vitamin B12

High Dietary Folate Supplementation Affects Gestational Development and Dietary Protein Utilization in Rats

There is new evidence that good folate status may play a critical role in the prevention of neural tube defects and in the maintenance of adequate homocysteine levels, an amino acid recently identified as a risk factor for cardiovascular disease. This has led to different folate recommendations, all of them much higher than the present dietary recommendations. Folic acid is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term, high folate intakes are unknown. Therefore, the present study was undertaken to determine the effects of long-term, high dietary folate supplementation on gestational and nutritional markers in pregnant and virgin rats. Four groups of Wistar rats were classified on the basis of physiological status (virgin or pregnant) and the experimental diets administered (folic acid supplemented, 40 mg/kg diet; or control diet, 2 mg folic acid/kg diet). Rats were fed their respective diets for 3 wk. Two critical periods were used for metabolic balance studies (experimental d 1–5 and 17–21), which involved the determination of fat and protein digestibilities as well as metabolic protein utilization (MPU) and net protein utilization (NPU). Gestational development (number of live fetuses) was adequate in both diet groups regardless of folate supplementation. However, body weight and vertex-coccyx length in fetuses from supplemented dams were less than (P < 0.0001) in fetuses of control dams. Fat and nitrogen digestibilities were not affected by supplementation, but MPU and NPU coefficients were significantly lower (P < 0.05) in the folic acid-supplemented groups, irrespective of physiological status, compared to control rats. These new findings of macro-micronutrient interactions caused by high folate supplementation are discussed on the basis that the vitamin may act as a xenobiotic more than as a nutrient.

Changes in serum concentrations of folates, pyridoxal, pyridoxal-5-phosphate and vitamin B12 during lactation of dairy cows fed dietary supplements of folic acid

The present experiment was undertaken to determine the effects of dietary supplements of folic acid (FA) administered from 4 wk prepartum to 305 d of lactation on serum concentrations of folates, vitamin B12, pyridoxal-5-phosphate (P-5-P) and pyridoxal. In addition, concentrations of blood hemoglobin and packed cell volume (PCV) were determined. Sixty-three Holstein cows were assigned to 22 incomplete blocks according to lactation number, milk production and body weight (BW). Within each block, cows received 0, 2 and 4 mg FA d−1 kg−1 BW. Dietary supplements of FA increased serum concentrations of folates (time × FA, P = 0.0001); the highest concentrations were observed during the first two months of lactation in cows fed supplementary FA. The lowest serum concentrations of vitamin B12 were also observed during the first two months of lactation, and the concentrations were lower in primiparous than in multiparous cows (time × parity, P = 0.03). Serum concentrations of P-5-P and pyridoxal were not affected by the dietary supplements of FA (P &gt; 0.1). In multiparous cows, dietary supplements of FA had no effect on changes of hemoglobin and PCV during the lactation (time × FA, P &gt; 0.13). In primiparous cows, PCV and hemoglobin were lower in control cows at parturition whereas by 24 wk of lactation, they were higher in cows fed the highest amount of FA. The lowest values of hemoglobin and PCV were observed during the first two months of lactation. These results give an indication that supply of B-complex vitamins by ruminal microorganisms could be suboptimal for high-producing dairy cows, for example, in early lactation when fed a diet with a high proportion of concentrates. More research is needed to determine the metabolic consequences of these variations. Key words: Dairy cow, vitamin B6, vitamin B12, folic acid, lactation

Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese.

Hyperhomocyst(e)inemia has been identified as an independent risk factor for atherosclerotic and thromboembolic diseases such as coronary artery disease, cerebral artery disease, and venous thrombosis. Recently, the alanine/valine (A/V) gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes that catalyzes the remethylation of homocysteine, was reported. The VV genotype is correlated with increased plasma homocyst(e)ine levels as a result of the reduced activity and increased thermolability of this enzyme. In this study, we examined the association between the V allele of the MTHFR gene and ischemic stroke in an elderly Japanese population. The diagnosis of cerebral infarction of all study patients was confirmed by CT of the brain. The MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. In 256 stroke patients and 325 control subjects, the frequencies of the V allele were 0.45 and 0.32, respectively. The odds ratios and 95% confidence intervals adjusted for the other risk factors were, respectively, 1.51 (1.02 to 2.23) for the AV genotype and 3.35 (1.94 to 5.77) for the VV genotype compared with the AA genotype. Both of these effects were statistically significant (P=0.041 and P<0.001, respectively). In patients with multiple infarcts in particular, the allele frequency of the V mutation was 0.56, and the association between the V allele and stroke was highly significant. Plasma homocyst(e)ine levels were significantly higher in patients with the VV genotype than in patients with the AA or AV genotype, especially those with low plasma folate levels. The V allele of the MTHFR gene was significantly associated with cerebral infarction in an elderly Japanese population in a codominant manner. The VV genotype may contribute to risk for ischemic stroke through a predisposition to increased plasma homocyst(e)ine levels, and dietary folate supplementation may be of benefit, particularly to patients with this genotype.

Neurologic care of pregnant women with epilepsy.

Epilepsy is a common neurologic condition in women of reproductive age. Although their risks are greater than those for women in the general population, the majority of women with epilepsy have a good pregnancy outcome. An understanding of the risks and appropriate management of both the pregnancy and epilepsy in these patients is essential for their physicians. Health-care providers should discuss contraception and reproductive issues with all of their female patients with epilepsy as they enter reproductive age. Optimal care requires prepregnancy counseling, including information about contraception, dietary folate supplementation, and the risks related to pregnancy. Although antiepileptic drugs (AEDs) have been implicated as the major cause of teratogenesis in infants born to mothers with epilepsy, uncontrolled epilepsy is also associated with maternal and fetal risk. Therefore, optimal seizure control during pregnancy remains an important goal for women with epilepsy. Women with epilepsy should be counseled about breast-feeding their infants and supported in their decision. The recommendations in this article reflect those of a Practice Parameter developed by the American Academy of Neurology Quality Standards Subcommittee.