Коммутационные перенапряжения в сетях высокого напряжения

Исследование коммутационных перенапряжений в высоковольтных сетях. В работе проводилось моделирование коммутационных перенапряжений в двух расчётных программах. Был произведён подбор защитного оборудования.Research of surge overvoltages in high-voltage grids. The simulation of surge overvoltages in two computational programs was carried out. A selection of protective equipment was made

Peroxisomal alterations in Alzheimer’s disease

In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I–II, III–IV, and V–VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V–VI pathology compared with those modestly affected (stages I–II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology

Method for the quantitative assay of fatty acid-bile acid conjugates by tandem mass spectrometry

Fatty acid-bile acid conjugates and especially arachidyl amido cholic acid are synthetic molecules that were shown to prevent cholesterol gallstone formation in mice and hamsters as well as to dissolve pre-existing gallstones in mice. To measure these novel compounds we developed a liquid chromatography electrospray tandem mass spectrometry method based on the analysis of 100 mul of plasma with stearyl amido cholic acid (stamchol, 1.5 mumol/l) added as internal standard. Repeatable calibrations between 0 and 50 mumol/l exhibited consistent linearity and reproducibility. Inter- and intraassay C.V.s were 5.3-11.4% and 2.6-6.4%, respectively, at targeted concentrations of 0.1, 2.3 and 50 mumol/l. (C) 2003 Elsevier B.V. All rights reserve

Inhibition of the isoprenoid biosynthesis pathway; detection of intermediates by UPLC-MS/MS

The isoprenoid biosynthesis pathway provides the cell with a variety of compounds which are involved in multiple cellular processes. Inhibition of this pathway with statins and bisphosphonates is widely applied in the treatment of hypercholesterolemia and metabolic bone disease, respectively. In addition, since isoprenylation of proteins is an important therapeutic target in cancer research there is interest in interfering with isoprenoid biosynthesis, for which new inhibitors to block farnesylation and geranylgeranylation of small GTPases are being developed. We recently developed a sensitive method using UPLC-MS/MS that allows the direct detection and quantification of all intermediates of the mevalonate pathway from MVA to GGPP which can be used to verify the specificity of inhibitors of the isoprenoid biosynthesis pathway. We here investigated the specificity of several inhibitors of the isoprenoid biosynthesis pathway in HepG2 cells, fibroblasts and lymphoblasts. The nitrogen-containing bisphosphonates pamidronate and zoledronate specifically inhibit farnesyl pyrophosphate synthase indicated by the accumulation of IPP/DMAPP. However, zaragozic acid A. a squalene synthase inhibitor, causes an increase of MVA in addition to the expected increase of FPP. Analysis of isoprenoid intermediate profiles after incubation with 6-fluoromevalonate showed a very nonspecific result with an increase in MVA, MVAP, MVAPP and IPP/DMAPP. These results show that inhibitors of a particular enzyme of the isoprenoid biosynthesis pathway can have additional effects another enzymes of the pathway either direct or indirect through accumulation of isoprenoid intermediates. Our method can be used to test new inhibitors and their effect on overall isoprenoid biosynthesis. (C) 2011 Elsevier B.V. All rights reserve

The regulation of catalase activity by PPAR gamma is affected by alpha-synuclein

Objective: While evidence for oxidative injury is frequently detected in brains of humans affected by Parkinson's disease (PD) and in relevant animal models, there is uncertainty regarding its cause. We tested the potential role of catalase in the oxidative injury that characterizes PD. Methods: Utilizing brains of A53T alpha-Syn and ntg mice, and cultured cells, we analyzed catalase activity and expression, and performed biochemical analyses of peroxisomal metabolites. Results: Lower catalase expression and lower activity levels were detected in A53T alpha-Syn brains and alpha-Syn-expressing cells. The effect on catalase activity was independent of disease progression, represented by mouse age and alpha-Syn mutation, suggesting a potential physiological function for alpha-Syn. Notably, catalase activity and expression were unaffected in brains of mice modeling Alzheimer's disease. Moreover, we found that alpha-Syn expression downregulate the peroxisome proliferator-activated receptor (PPAR)gamma, which controls catalase transcription. Importantly, activation of either PPAR gamma 2, PPAR alpha or retinoic X receptor eliminated the inhibiting effect of alpha-Syn on catalase activity. In addition, activation of these nuclear receptors enhanced the accumulation of soluble alpha-Syn oligomers, resulting in a positive association between the degree of soluble alpha-Syn oligomers and catalase activity. Of note, a comprehensive biochemical analysis of specific peroxisomal metabolites indicated no signs of dysfunction in specific peroxisomal activities in brains of A53T alpha-Syn mice. Interpretation: Our results suggest that alpha-Syn expression may interfere with the complex and overlapping network of nuclear receptors transcription activation. In result, catalase activity is affected through mechanisms involved in the regulation of soluble alpha-Syn oligomer

Minimal sampling protocol for accurate estimation of urea production: a study with oral [13C]urea in fed and fasted piglets

Background & aims: An oral [13C]urea protocol may provide a simple method for measurement of urea production. The validity of single pool calculations in relation to a reduced sampling protocol was assessed. Methods: In eight fed and five fasted piglets, plasma urea enrichments from a 10 h sampling protocol were measured following an intragastric [13C]urea bolus. Blood [13C]bicarbonate was measured to trace gut [13C]urea oxidation. Two-compartment and regression (single pool) computations were performed. Pool sizes were compared to urea distribution over total body water (TBW). Shorter protocol duration was tested in regression simulations. Results: Differences in urea kinetics between fed and fasted piglets did not reach statistical significance. Mean (±SE) urea pool from TBW times plasma urea concentration was 2.2±0.16 mmol kg−1. Two-compartment modelling yielded similar results for pool size (despite the oxidation of a small amount of urea tracer). Urea appearance rate was 306±18 μmol kg−1 h−1. Regression calculations overestimated urea appearance rate vs. compartmental model (). When samples <2 h were discarded, results were comparable to compartmental calculations even if protocol length was 6 h (325±24 μmol kg−1 h−1, NS). Conclusions: Regression calculations using plasma enrichments sampled between 2 and 6 h after oral [13C]urea administration provide accurate rates of urea production, and are not affected by tracer oxidation

Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism. To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital, Hellerup, Denmark. Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. Bile acid and FGF-19 concentrations. Postprandial total bile acid concentrations increased with increasing meal fat content (P < .05), peaked after 1-2 hours, and were higher in T2D patients vs controls (oral glucose tolerance test, low and medium fat meals, P < .05; high fat meal, P = .30). Differences reflected mainly unconjugated and glycine-conjugated forms of deoxycholic acid (DCA) and to a lesser extent cholic acid (CA) and ursodeoxycholic acid (UDCA), whereas chenodeoxycholic acid (CDCA) concentrations were comparable in the two groups. FGF-19 concentrations tended to be lower in T2D patients vs controls, but differences were not statistically significant due to considerable variation. Postprandial plasma patterns of bile acids with FXR agonistic properties (CDCA, DCA, and CA) and FXR antagonistic properties (UDCA) in T2D patients support the notion of a "T2D-bile acid-FGF-19" phenotype with possible pathophysiological implication

Cerebrospinal fluid in tuberculous meningitis exhibits only the L-enantiomer of lactic acid

The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study. In this follow-up study, we used targeted ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples. Here we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities. These results provide experimental evidence to support our conceptual astrocyte-microglia lactate shuttle model formulated from our previous NMR-based metabolomics study - highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease marker