AIMS The principal aim of this study was to investigate the oxidative effects of chronic ethanol consumption on the functions of the heart and the kidney and the possible modification of this effect by folic acid supplementation. Moreover, in order to find whether this oxidative profile affects cardiovascular function, parameters such as heart rate and glomerular filtration rate were also assessed. METHODS Four experimental groups of rats were used: control, ethanol-exposed, control supplemented with folic acid and ethanol-exposed plus folic acid. Ethanol-exposed rats were subjected to a chronic ethanol treatment (2 months), in which the level of alcohol reaches 30% v/v. Diet and ethanol solution were provided ad libitum, and folic acid supplementation was 8 vs. 2 ppm. Energy intake, creatinine clearance and heart rate were determined. Antioxidant enzyme activity and lipid and protein peroxidation of the kidney and the heart were measured by the spectrophotometric method. RESULTS Ethanol increases heart size and catalase (CAT) activity and decreases lipid peroxidation in heart without changing heart rate. However, in the kidney, ethanol decreases CAT activity, increases lipid peroxidation and decreases glomerular filtration rate. Folic acid supplementation avoids these situations; it does not, however, improve glomerular function. CONCLUSION Chronic ethanol consumption has many effects on the antioxidant enzymatic activity of the heart and the kidney, leading to increased renal lipid peroxidation prevented by folic acid supplementation.

PURPOSE: In 1992, preoperative radiotherapy was considered in France as the standard treatment for T3-4 rectal cancers. The present randomized trial compares preoperative radiotherapy with chemoradiotherapy. PATIENTS AND METHODS: Patients were eligible if they presented a resectable T3-4, Nx, M0 rectal adenocarcinoma accessible to digital rectal examination. Preoperative radiotherapy with 45 Gy in 25 fractions during 5 weeks was delivered. Concurrent chemotherapy with fluorouracil 350 mg/m2/d during 5 days, together with leucovorin, was administered during the first and fifth week in the experimental arm. Surgery was planned 3 to 10 weeks after the end of radiotherapy. All patients should receive adjuvant chemotherapy with the same fluorouracil/leucovorin regimen. The primary end point of the trial was overall survival. RESULTS: A total of 733 patients were eligible. Grade 3 or 4 acute toxicity was more frequent with chemoradiotherapy (14.6% v 2.7%; P <.05). There was no difference in sphincter preservation. Complete sterilization of the operative specimen was more frequent with chemoradiotherapy (11.4% v 3.6%; P <.05). The 5-year incidence of local recurrence was lower with chemoradiotherapy (8.1% v 16.5%; P <.05). Overall 5-year survival in the two groups did not differ. CONCLUSION: Preoperative chemoradiotherapy despite a moderate increase in acute toxicity and no impact on overall survival significantly improves local control and is recommended for T3-4, N0-2, M0 adenocarcinoma of the middle and distal rectum.

BACKGROUND The results of observational studies suggest that plasma homocysteine concentrations are inversely related to cognitive function in older people. Our objective was to test the hypothesis that lowering the plasma homocysteine concentration improves cognitive function in healthy older people. METHODS We conducted a two-year, double-blind, placebo-controlled, randomized clinical trial involving 276 healthy participants, 65 years of age or older, with plasma homocysteine concentrations of at least 13 micromol per liter. Homocysteine-lowering treatment was a daily supplement containing folate (1000 microg) and vitamins B12 (500 microg) and B6 (10 mg). Tests of cognition were conducted at baseline and after one and two years of treatment. Treatment effects were adjusted for baseline values, sex, and education. RESULTS On average, during the course of the study, the plasma homocysteine concentration was 4.36 micromol per liter (95 percent confidence interval, 3.81 to 4.91 micromol per liter) lower in the vitamin group than in the placebo group (P<0.001). Overall, there were no significant differences between the vitamin and placebo groups in the scores on tests of cognition. CONCLUSIONS The results of this trial do not support the hypothesis that homocysteine lowering with B vitamins improves cognitive performance.(Australian Clinical Trials registry number, ACTR NO 12605000030673.).

Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet +/-5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (P<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (P<0.01), impaired acetylcholine-induced vasodilatation (P<0.01), and reduced levels of endothelial NO synthase mRNA (P<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function.

Here we have identified a sensorimotor transformation that is used by a mammalian nervous system to produce a multijoint motor behavior. Using a simple biomechanical model, a delayed-feedback rule based on an optimal tradeoff between postural error and neural effort explained patterns of muscle activation in response to a sudden loss of balance in cats. Following the loss of large sensory afferents, changes in these muscle-activation patterns reflected an optimal reweighting of sensory feedback gains to minimize postural instability. Specifically, a loss of center-of-mass-acceleration information, which allowed for a rapid initial rise in the muscle activity in intact animals, was absent after large-fiber sensory neuropathy. Our results demonstrate that a simple and flexible neural feedback control strategy coordinates multiple muscles over time via a small set of extrinsic, task-level variables during complex multijoint natural movements.

Evidence is growing that optimal dietary intake of folate and choline (both involved in one-carbon transfer or methylation) is important for successful completion of fetal development. Significant portions of the population are eating diets low in one or both of these nutrients. Folates are important for normal neural tube closure in early gestation, and the efficacy of diet fortification with folic acid in reducing the incidence of neural tube defects is a major success story for public health nutrition. Similarly, maternal dietary choline is important for normal neural tube closure in the fetus and, later in gestation, for neurogenesis in the fetal hippocampus, with effects on memory that persist in adult offspring; higher choline intake is associated with enhanced memory performance. Although both folates and choline have many potentially independent mechanisms whereby they could influence fetal development, these 2 nutrients also have a common mechanism for action: altered methylation and related epigenetic effects on gene expression.

Impaired function of the central nervous system (CNS) in aged animals is associated with increased susceptibility to the development of many neurodegenerative diseases. Age-related functional deterioration in brain is consistent with the free radical theory of aging that predicts, among other things, that free radical reactions with and damage to biomolecules, such as proteins and membrane lipid bilayers, leads to loss of neurons and subsequently diminished cognition. These oxidatively modified biomolecules are believed to contribute to the decreased antioxidant content, mitochondrial dysfunction, and impaired plasticity in aged brains. Treatment of rodents with L-acetylcarnitine (LAC; gamma-trimethyl-beta-acetylbutyrobetaine) can improve these functional losses. Although it is well established that administration of LAC can decrease protein oxidation in aged brains, it is not clear which proteins are decreased in their level of oxidation in the brains of aged rats treated with LAC. The current study used a parallel redox proteomics approach to identify the proteins that are oxidized in aged rat cortex and hippocampus of aged rats. Moreover, those proteins that are reduced in oxidation status were identified in aged brains from rats treated in vivo with LAC. The findings are discussed in reference to brain aging and age-related cognitive impairment.

Leptospirosis occurs as seasonal outbreaks, lasting for about 3 weeks during October-November in North Andaman. A randomized controlled trial was undertaken to assess the efficacy of doxycycline prophylaxis in the prevention of infection and clinical disease due to leptospires during the outbreak period. A sample population of 782 persons, randomized into two groups was given doxycycline 200 mg/week and a placebo. The microscopic agglutination test was done on blood samples collected on day zero, after 6 weeks and after 12 weeks. Infection rates and attack rates of clinical illness were calculated in the two groups based on the serological results. Statistically there was no difference in the infection rates among the two groups. However, a statistically significant difference was observed in the clinical disease attack rates (3.11 vs. 6.82%) between study group and control group. The results of the study indicate that doxycycline prophylaxis does not prevent leptospiral infection in an endemic area, but has a significant protective effect in reducing the morbidity and mortality during outbreaks.

BACKGROUND/AIMS Treatments of diabetic nephropathy (DN) delay the onset of end-stage renal disease. We report the results of safety/tolerability studies in patients with overt nephropathy and type 1/type 2 diabetes treated with pyridoxamine, a broad inhibitor of advanced glycation. METHODS The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care. In PYR-206, patients were randomized 1:1 and had baseline serum creatinine (bSCr)<or=2.0 mg/dl. In PYR-205/207, randomization was 2:1 and bSCr was <or=2.0 for PYR-205 and >or=2.0 but <or=3.5 mg/dl for PYR-207. Treated patients (122 active, 90 placebo) received 50 mg pyridoxamine twice daily in PYR-206; PYR-205/207 patients were escalated to 250 mg twice daily. RESULTS Adverse events were balanced between the groups (p = NS). Slight imbalances, mainly in the PYR-205/207 groups, were noted in deaths (from diverse causes, p = NS) and serious adverse events (p = 0.05) that were attributed to pre-existing conditions. In a merged data set, pyridoxamine significantly reduced the change from baseline in serum creatinine (p < 0.03). In patients similar to the RENAAL/IDNT studies (bSCr >or=1.3 mg/dl, type 2 diabetes), a treatment effect was observed on the rise in serum creatinine (p = 0.007). No differences in urinary albumin excretion were seen. Urinary TGF-beta1 also tended to decrease with pyridoxamine (p = 0.049) as did the CML and CEL AGEs. CONCLUSION These data provide a foundation for further evaluation of this AGE inhibitor in DN.

Pyridoxal phosphate is the cofactor for over 100 enzyme-catalysed reactions in the body, including many involved in the synthesis or catabolism of neurotransmitters. Inadequate levels of pyridoxal phosphate in the brain cause neurological dysfunction, particularly epilepsy. There are several different mechanisms that lead to an increased requirement for pyridoxine and/or pyridoxal phosphate. These include:(i) inborn errors affecting the pathways of B(6) vitamer metabolism;(ii) inborn errors that lead to accumulation of small molecules that react with pyridoxal phosphate and inactivate it;(iii) drugs that react with pyridoxal phosphate;(iv) coeliac disease, which is thought to lead to malabsorption of B(6) vitamers;(v) renal dialysis, which leads to increased losses of B(6) vitamers from the circulation;(vi) drugs that affect the metabolism of B(6) vitamers; and (vii) inborn errors affecting specific pyridoxal phosphate-dependent enzymes. The last show a very variable degree of pyridoxine responsiveness, from 90% in X-linked sideroblastic anaemia (delta-aminolevulinate synthase deficiency) through 50% in homocystinuria (cystathionine beta-synthase deficiency) to 5% in ornithinaemia with gyrate atrophy (ornithine delta-aminotransferase deficiency). The possible role of pyridoxal phosphate as a chaperone during folding of nascent enzymes is discussed. High-dose pyridoxine or pyridoxal phosphate may have deleterious side-effects (particularly peripheral neuropathy with pyridoxine) and this must be considered in treatment regimes. None the less, in some patients, particularly infants with intractable epilepsy, treatment with pyridoxine or pyridoxal phosphate can be life-saving, and in other infants with inborn errors of metabolism B(6) treatment can be extremely beneficial.