Plasma Methylmalonic Acid Concentration in Folic Acid-Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial.

BACKGROUND: Individuals with low serum vitamin B-12 and high serum folate have higher plasma concentrations of methylmalonic acid (MMA). Whether folic acid (FA) causes an increase in MMA is not known. OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12. METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/d for 12 wk) in middle-aged patients treated with antidepressant medication participating in the FoLATED (Folate Augmentation of Treatment-Evaluation for Depression) trial. Participants defined as having "low" serum vitamin B-12 (vitamin B-12 ≥150 and <220 ng/L) or "marginal" serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/L) were included. The primary outcome of this substudy was MMA at week 12. A mixed-effects linear regression was fitted and reported using the adjusted mean difference (aMD). RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 y, and 112 (63.3%) were female. The MMA analysis included 135 participants and the aMD was -0.01 (95% CI: -0.06, 0.04; P = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 µg/L (95% CI: 8.13, 25.02 µg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 µg/L (95% CI: 387, 535 µg/L; P < 0.001). CONCLUSIONS: Supplementation of FA leads to an increase of serum and RBC folate, but does not change plasma MMA concentration in individuals with serum vitamin B-12 between 150 and 280 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/L. Previously reported associations may arise from effects of impaired vitamin B-12 status on folate metabolism.This trial was registered at www.isrctn.com as ISRCTN37558856.

Antipsychotic medication and oxidative cell stress: a systematic review.

OBJECTIVE: To look at (1) the association between antipsychotics and cell stress, (2) whether first-generation antipsychotics may show different effects than second-generation antipsychotics, and (3) whether recommendations can be made regarding medication. DATA SOURCES: We conducted a systematic review of 5 databases for all articles published until December 31, 2007: PubMed, Ovid MEDLINE, EMBASE, PsycINFO, and EBM Reviews. Under specific headings (eg, "heat shock proteins" and "oxidative stress"), a systematic search of these databases included such terms as HSP70 and homocysteine, and specific search strings were constructed. No limits were placed on the year or language of publication. References from pertinent articles or books were retrieved. STUDY SELECTION: We included 42 articles of human studies from 2,387 references originally retrieved. We included only articles that (1) were quantitative; (2) referred only to human tissue, in vivo, or in vitro; (3) stated what tissue was examined; (4) identified what metabolites were measured; and (5) had references. DATA EXTRACTION: All articles were assessed by 2 authors, which ensured that the inclusion criteria were met. The selected studies were too heterogeneous to be combined for any useful meta-analysis. Three authors, therefore, independently interpreted the data, using specified criteria to judge whether each study showed a beneficial, detrimental, or no effect on the markers measured. DATA SYNTHESIS: The analysis revealed no conclusive association with direct or indirect markers of oxidative cell stress and antipsychotics. For every reviewed antipsychotic, we revealed differing research results showing a beneficial, detrimental, or no effect. This was true for in vivo as well as in vitro studies. CONCLUSIONS: It remains unclear whether antipsychotics increase or reduce cell stress. Claims of neuroprotective properties of antipsychotics seem premature.

L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline.

Neuroinflammatory oxidative stress occurs early in AD pathology. Elevated blood Hcy is a useful marker for such neuroinflammation. Hcy contributes to pathological cascades involving AP and NFTs. In AD, Hcy should be lowered by B-vitamin supplements and NAC.

Problems in the metabolic evaluation of renal stone disease: audit of intra-individual variation in urine metabolites.

Preliminary metabolic assessment of patients with renal stones includes measurement of urine metabolites. This paper reports on the degree of intra-individual variation in some key urine metabolites. Over 80 medically untreated patients under initial metabolic investigation were audited from whom 24-h urine results were available as three separate urine pairs collected at intervals not less than 1 month apart. Ranking patients by intra-individual variation, above the 75th centile, the highest calcium was at least 216% of the lowest calcium, the respective figures for phosphate, urate, oxalate, citrate, creatinine and sodium were 207, 190, 271, 412, 175 and 233%. In order to estimate pre-treatment excretion within 30% of a true mean at the 95% confidence limit, for calcium and oxalate, the number of 24-h samples required were 3 and 4 respectively with 6 and 9 required to be within 20%. These observations illustrate significant practical clinical problems in assessing patients with renal stones when assessing these basic parameters. Regimens based on small numbers of urine collections are flawed, hence evidence based protocols should be devised. A minimum of three pairs of 24-h urine samples based upon predicting metabolite output within 20-30% or less of the true mean is recommended.

Birth defects and anti-heat shock protein 70 antibodies in early pregnancy.

Abstract It has been suggested that induction of the heat shock response in the mammalian embryo during the critical period of organogenesis can result in anatomical malformation. We measured serum heat shock protein 70 (Hsp70), anti-Hsp70, and anti-Hsp60 in samples taken from expectant mothers at 16 weeks gestation. Samples from women whose babies were born with a birth defect (n = 30) were compared with controls who gave birth to healthy babies (n = 46). Anti-Hsp70 levels were significantly elevated in patients who later gave birth to babies with cleft lip or palate or neurological abnormalities (n = 10): 260 (223-406) microg/mL compared to 150 (88-207) microg/mL in controls (P < 0.001). No significant differences were found in serum Hsp70 and anti-Hsp60 levels between cases and controls. This finding of increased maternal anti-Hsp70 in patients who later gave birth to babies with these abnormalities suggests a previous stressful event may have contributed to the pathogenesis. Further work is required to determine whether Hsp70 has a direct or indirect role in this pathogenesis or whether anti-Hsp70 is simply a marker of a prior increase in Hsp70 due to a physiological stress that itself resulted in the damage. This work is consistent with previous studies showing a buffering role for Hsps in evolution.

Folate supplementation reduces serum hsp70 levels in patients with type 2 diabetes.

Type 2 diabetes patients are subject to oxidative stress as a result of hyperglycemia. The aim of this study was to determine whether administration of the antioxidant folic acid, previously shown to reduce homocysteine levels, would reduce circulating levels of Hsp70 while improving the condition of type 2 diabetes patients with microalbuminuria. Plasma homocysteine fell from pretreatment values of 12.9 to 10.3 microM (P < 0.0001). The urine albumin-creatinine ratio fell from 12.4 to 10.4 mg/mM (P = 0.38). Pretreatment Hsp70 levels were higher in patients not taking insulin (5.32 ng/mL) compared with those on insulin (2.44 ng/mL) (P = 0.012). Folic acid supplementation resulted in a significant fall in Hsp70 (5.32 to 2.05 ng/mL) (P = 0.004). There was no change in Hsp70 in those receiving insulin. Folic acid supplementation in non-insulin-treated type 2 diabetes patients, therefore, resulted in a fall in Hsp70, reflecting an improvement in oxidative stress. The data shows that improvement in homocysteine status can lead to a reduction in Hsp70, indicating the possibility of its use as a marker for severity of disease.