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A patient with megaloblastic anaemia due to nutritional folate deficiency is described. Partial villous atrophy and malabsorption of xylose showed progressive improvement to normal with folic acid therapy.
OBJECTIVE: Determination of the plasma vitamin and carotenoid concentrations of a number of elderly populations to describe their micronutrient status and examine geographical patterns and the cross-sectional and longitudinal relationships with sex, age, food and alcohol intake. DESIGN: Longitudinal study. SETTING: Twelve small towns in ten European countries and one in the USA. SUBJECTS: Randomized sample of 1175 subjects of both sexes born in the period 1913-1918, stratified according to age and sex. INTERVENTIONS: Blood plasma collection and determination of alpha-tocopherol, gamma-tocopherol, alpha-carotene, all-trans- and cis-beta-carotene, lycopene, lutein, zeaxanthin, beta-cryptoxanthin, vitamin B-12, folic acid and pyridoxal 5'-phosphate. From the original sample examined in 1988/1989, measurements were repeated in 938 subjects in 1993. RESULTS: There were very large within and between country differences in the micronutrient levels with no definite geographical pattern emerging. The retinol levels decreased significantly between 1988/1989 and 1993 (-0.2 mumol/l, P = 0.0001), unlike the total carotene levels (0.01, NS) while the alpha-tocopherol (0.7 mumol/l, P = 0.002), folic acid (1.1 nmol/l, P < 0.01) and pyridoxal 5'-phosphate (12 nmol/l, P = 0.0001) levels increased significantly. Vitamin B-12 levels increased nonsignificantly in men (17.2 pmol/l, P = 0.77) and decreased significantly in women (-37 pmol/l, P = 0.012). The prevalence of biochemical vitamin A deficiency was zero in both 1988/1989 and 1993, that of vitamin E deficiency decreased from 1.1% to 0.6% and for vitamin B-6 from 23.3% to 5.7%. Vitamin B-12 biochemical deficiency increased from 2.7% to 7.3% and for folic acid from zero to 0.3%. CONCLUSIONS: Changes in the median micronutrient plasma levels over a 4-y period varied, exceeding 30%-40% in some elderly populations. This was reflected in changes, mostly decreases, in the prevalences of vitamin deficiency.
QUESTION: I read last year that Canada has followed the United States in fortifying flour with folic acid to prevent neural tube defects. Do we know yet whether this strategy is working? ANSWER: In Canada, flour is fortified with folic acid to a level of 0.15 mg/100 g. Although a mandatory date was set for November 1, 1998, most if not all companies implemented the change on or before January 1, 1998. Recent figures from the United States, where the deadline for fortification was January 1998, show that by March 1999, mean folate levels in flour doubled, substantially decreasing the risk for neural tube defects.
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The increased incidence of invasive mycoses and the emerging problem of antifungal drug resistance have encouraged the search for new antifungal agents or effective combinations of existing drugs. Infections due to Candida albicans are usually treated with azole antifungals such as fluconazole, ketoconazole or itraconazole. Whilst azoles may have little or no toxicity, they generally offer rather poor fungicidal activity. Even in the absence of resistance, treatment failures or recurrent infections are not uncommon, especially in immunocompromised individuals. Here we demonstrate that the non-classical antifolate pyrimethamine shows synergy with azole antifungal compounds and interferes with the ergosterol biosynthesis pathway in C. albicans. By disturbing folate metabolism in this fungus, pyrimethamine can inhibit ergosterol production. The molecular connection between the folic acid cycle and the ergosterol biosynthesis pathway is discussed and we show that the filamentous form of this fungus is more susceptible to methotrexate than the yeast form because the drug is more effectively transported through the membrane of the filamentous form. When used to treat the hyphal form, methotrexate showed synergy with other antifungals such as azoles and terbinafine. This finding could have important clinical applications, as a combination of azoles with antifolates and/or inhibitors of folic acid synthesis could represent an attractive alternative for the treatment of C. albicans infections.
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The present report describes the first visualization of folic acid-immunoreactive fibers in the mammalian central nervous system using a highly specific antiserum directed against this vitamin. The distribution of folic acid-immunoreactive structures was studied in the brainstem and thalamus of the monkey using an indirect immunoperoxidase technique. We observed fibers containing folic acid, but no folic acid-immunoreactive cell bodies were found. In the brainstem, no immunoreactive structures were visualized in the medulla oblongata, pons, or in the medial-caudal mesencephalon, since at this location immunoreactive fibers containing folic acid were only found at the rostral level in the dorsolateral mesencephalon (in the mesencephalic-diencephalic junction). In the thalamus, the distribution of folic acid-immunoreactive structures was more widespread. Thus, we found immunoreactive fibers in the midline, in nuclei close to the midline (dorsomedial nucleus, centrum medianum/parafascicular complex), in the ventral region of the thalamus (ventral posteroinferior nucleus, ventral posteromedial nucleus), in the ventrolateral thalamus (medial geniculate nucleus, lateral geniculate nucleus, inferior pulvinar nucleus) and in the dorsolateral thalamus (lateral posterior nucleus, pulvinar nucleus). The highest density of fibers containing folic acid was observed in the dorsolateral mesencephalon and in the pulvinar nucleus. The distribution of folic acid-immunoreactive structures in the monkey brain suggests that this vitamin could be involved in several mechanisms, such as visual, auditory, motor and somatosensorial functions.
In a consecutive study of 228 patients with folate deficiency originating from various gastrointestinal and haematological disorders, the clinical value of the folic acid absorption (TRIFA) test is assessed. It is concluded that the test is a simple, rapid, and reliable index for folic acid malabsorption of importance as well as a research tool as in daily practice.
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We have developed an improved method, using 96-well microtiter plates, for the microbiological assay of folic acid. With this method, the tedium of conventional microbiological analysis is substantially decreased. Culture volumes have been reduced 33-fold, and pipetting procedures have been simplified. Assay time has been reduced to 14 h, and sensitivity has increased 10-fold (0.1 ng/mL). Analytical recoveries range from 98 to 104%. Intra-assay and interassay variabilities are less than 11%. The assay does not require extensive manipulation of inoculum. Day-to-day variability has been minimized by using saline aliquots of the bacterial suspension stored at 4 degrees C. The procedure is accurate, selective, and useful for direct measurement of folic acid in multivitamin formulations.
A simple procedure for preparing glycerol-cryoprotected Lactobacillus casei cultures has been developed. L. casei grown in medium supplemented with low concentrations of folic acid (0.3 micrograms/L) is diluted with an equal volume of glycerol (800 mL/L) and stored at -20 degrees C. Growth response of the glycerol-cryoprotected L. casei to low concentrations of folic acid exceeded that of cultures maintained by monthly agar stab transfer. Also, growth for the zero-folate blanks was considerably less for the cryoprotected cultures. Assay of folate in several rat tissues correlated well (r = 0.999) with the standard microbiological assay. The growth rate of the culture depends on the inoculum size, and a heavy inoculum of cryoprotected L. casei may be used to complete the assay after only an overnight incubation.
mtrA of Bacillus subtilis was shown to be the structural gene for GTP cyclohydrolase I, an enzyme essential for folic acid biosynthesis. mtrA is the first gene in a bicistronic operon that includes mtrB, a gene involved in transcriptional attenuation control of the trp genes. mtrA of B. subtilis encodes a 20-kDa polypeptide that is 50% identical to rat GTP cyclohydrolase I. Increased GTP cyclohydrolase I activity was readily detected in crude extracts of B. subtilis and Escherichia coli in which MtrA was overproduced. Biochemical evidence indicating that MtrA catalyzes dihydroneopterin triphosphate and formic acid formation from guanosine triphosphate is presented. It was also shown that mtrB of B. subtilis encodes a 6-kDa polypeptide. Expression of mtrB is sufficient for transcriptional attenuation control of the B. subtilis trp gene cluster in Escherichia coli. Known interrelationships between genes involved in folic acid and aromatic amino acid biosynthesis in B. subtilis are described.
Hyperhomocysteinaemia is a risk factor for premature atherosclerosis and venous thromboembolic disease. Supplementation with folic acid and vitamin B6 has been shown to decrease plasma homocysteine but data fail to assess an effect on the progression of vascular disease. We measured plasma homocysteine and two markers of endothelial injury (plasma soluble thrombomodulin and von Willebrand factor) at baseline and after 3 months of treatment with folic acid and vitamin B6. After this treatment there was a significant decrease in fasting soluble thrombomodulin (-15 ng/ml, 95%CI 5-22.2). Von Willebrand factor was significantly raised after methionine load at baseline but did not significantly rise after supplementation.
OBJECTIVE: A summary about the final results of the Hungarian double-blind placebo controlled randomised trial of periconceptional folic acid containing multivitamin and trace element supplementation. RESULTS: The major finding is a significant prevention of the first occurrence of neural-tube defect, urinary tract and cardiovascular defects, in addition a decrease in the rate of limb deficiencies and congenital hypertrophic pyloric stenosis. Fertility was slightly improved and the rate of twins increased significantly after periconceptional multivitamin supplementation. The effect of multivitamin supplementation for fetal death is controversial, but in general there is no clinically significant change. Periconceptional multivitamin supplementation can reduce the occurrence of nausea and vomiting. PRACTICAL IMPLEMENTATIONS: Consumption of foods which are rich in folate may not be the best way to prevent neural-tube defects and other congenital abnormalities. Periconceptional multivitamin supplementation is part of the periconceptional care in Hungary and it is an appropriate forum for the practical delivery for this primary prevention action. However, as a large proportion of pregnancies are unplanned, the widespread use of bread fortified with folic acid, vitamin B12 and B6 may decrease a considerable part of neural-tube defects and some other congenital abnormalities, in addition to vascular diseases due to hyperhomocysteinemia.
We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.
OBJECTIVE: To assess the efficacy of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) side effects of low dose methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: A systematic review was carried out using the methods recommended by the Cochrane Collaboration. We used MEDLINE and performed hand searches that included bibliographic references, Current Contents, abstracts of rheumatology meetings, and 4 rheumatology journals to select double blind randomized controlled trials (RCT) in which adult patients with RA were treated with low doses of MTX (< 20 mg/week), concurrently with folic or folinic acid. The quality of the RCT was assessed. The overall treatment effect across trials (reduction in toxicity) was estimated using a fixed effects model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Sensitivity analyses were conducted evaluating different doses and the quality of the trials. Costs per month in different countries were compared. RESULTS: Of 11 trials retrieved, 7 met inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 67 patients with folic, and 80 with folinic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but nonstatistically significant reduction of 42% was found [OR = 0.58 (95% CI 0.29 to 1.16)]. No major differences were observed between low and high doses of folic or folinic acid. Hematologic side effects could not be analyzed, since details by patients of each event were not provided. No consistent differences in disease activity variables were observed when comparing placebo and folic acid or folinic acid at low doses; patients receiving high dose folinic acid had increased tender and swollen joint counts. Substantial differences in costs across countries were found; folinic acid was more expensive. CONCLUSION: Our results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems.
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The combination of biochemical theory, case studies, and patient population surveys suggests that the water soluble vitamin, folic acid, is relevant to mental functions. Several studies demonstrate a clinical correlation between folate deficiency and psychiatric hospitalization. The role of dietary deficiency to these observations has needed further examination. After reviewing the serum folate values of 269 psychiatric hospital admissions, the incidence of serum folates below 5.9 ng./ml. was found to be greater than a control group. A dietary rating for all admissions revealed a high frequency of deficiency in all patients with no greater prevalence among the low folate group. These observations agree that psychiatric patients are more likely to have low serum folate values, and suggest that poor diet does not explain the increased likelihood.