Impaired insulin-mediated glucose partitioning is an intrinsic metabolic defect in skeletal muscle from severely obese humans (BMI ≥ 40 kg/m
). Roux-en-Y gastric bypass (RYGB) surgery has been shown ...to improve glucose metabolism in severely obese humans. The purpose of the study was to determine the effects of RYGB surgery on glucose partitioning, mitochondrial network morphology, and the markers of mitochondrial dynamics skeletal muscle from severely obese humans.
Human skeletal muscle cells were isolated from muscle biopsies obtained from RYGB patients (BMI = 48.0 ± 2.1, n = 7) prior to, 1 month and 7 months following surgery and lean control subjects (BMI = 22.4 ± 1.1, n = 7). Complete glucose oxidation, non-oxidized glycolysis rates, mitochondrial respiratory capacity, mitochondrial network morphology, and the regulatory proteins of mitochondrial dynamics were determined in differentiated human myotubes.
Myotubes derived from severely obese humans exhibited enhanced glucose oxidation (13.5%; 95% CI 7.6, 19.4, P = 0.043) and reduced non-oxidized glycolysis (-1.3%; 95% CI -11.1, 8.6) in response to insulin stimulation at 7 months after RYGB when compared with the presurgery state (-0.6%; 95% CI -5.2, 4.0 and 19.5%; 95% CI 4.0, 35.0, P = 0.006), and were not different from the lean controls (16.7%; 95% CI 11.8, 21.5 and 1.9%; 95% CI -1.6, 5.4, respectively). Further, the number of fragmented mitochondria and Drp1(Ser
) phosphorylation were trended to reduce/reduced (0.0104, 95% CI 0.0085, 0.0126, P = 0.091 and 0.0085, 95% CI 0.0068, 0.0102, P = 0.05) in myotubes derived from severely obese humans at 7 months after RYGB surgery in comparison with the presurgery state. Finally, Drp1(Ser
) phosphorylation was negatively correlated with insulin-stimulated glucose oxidation (r = -0.49, P = 0.037).
These data indicate that an intrinsic metabolic defect of glucose partitioning in skeletal muscle from severely obese humans is restored by RYGB surgery. The restoration of glucose partitioning may be regulated through reduced mitochondrial fission protein Drp1 phosphorylation.
To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy.
A ...multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. Following a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin 600 mg/day administered twice daily (BID) or three times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing > or =50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population.
Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID (p < or = 0.0001) and 44% for pregabalin BID (p < or = 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo (p < or = 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia.
Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results.
Pregabalin is an alpha(2)-delta ligand that has anxiolytic, analgesic, and anticonvulsant properties.
To establish the efficacy, safety, and tolerability of pregabalin administered twice-daily (BID) ...without dose titration as adjunctive treatment in patients with partial seizures and to confirm the dose-response relationship.
This 76-center, double-blind, randomized, placebo-controlled, parallel-group study consisted of an 8-week baseline and a 12-week double-blind phase. Patients with refractory partial seizures on one to three antiepileptic drugs were randomly assigned to one of five treatment groups (placebo or 50, 150, 300, and 600 mg/d pregabalin, all administered BID). Efficacy was assessed using seizure frequency reduction and responder rate (> or =50% seizure reduction from baseline). Pharmacokinetic parameters were estimated.
A total of 453 patients were included in the intent-to-treat analysis. The median baseline seizure rate was 10 per month. Seizure frequency reductions from baseline were 7% (placebo; n = 100), 12% (50 mg/d; n = 88), 34% (150 mg/d; n = 86), 44% (300 mg/d; n = 90), and 54% (600 mg/d; n = 89). Responder rates (> or =50% seizure reduction) were 14% (placebo), 15% (50 mg/d), 31% (150 mg/d), 40% (300 mg/d), and 51% (600 mg/d). Discontinuation rates due to adverse events were 5% (placebo), 7% (50 mg/d), 1% (150 mg/d), 14% (300 mg/d), and 24% (600 mg/d). The 150-, 300-, and 600-mg/d pregabalin groups were associated with greater reductions in seizures (p < or = 0.0001) and greater responder rates compared with the placebo group (p < or = 0.006). There was a favorable dose-response trend for both seizure reductions (p < or = 0.0001) and responder rate (p < or = 0.001).
Adjunctive therapy with pregabalin 150, 300, and 600 mg/d, given in twice-daily doses without titration, is significantly effective and well tolerated in the treatment of patients with partial seizures as demonstrated in patients with refractory partial seizures.
Forward hadron calorimeters with transverse and longitudinal segmentation are developed for upgraded NA61/SHINE BM@N and future CBM experiments at CERN, JINR and FAIR respectively. The main purpose ...of these calorimeters is to provide an event-by-event measurements of centrality and reaction plane orientation in ion collisions. Hadron calorimeters in all these experiments are composed of sampling lead/scintillator modules. The light collection from longitudinal sections in modules is provided by Wave-Length Shifting (WLS) fibers embedded in scintillator plates. Micropixel photodetectors MPPCs are used for light detection. The light yield measured at muons beam for these modules is about 8 - 10 ph.el./MeV. Performance of the supermodule composed of these modules has been studied at proton beam energies 1.5 - 150 GeV at CERN. Radiation conditions at high heavy ion beam rates are studied by FLUKA simulations for calorimeters geometry optimization aimed to get acceptable radiation doses and neutron fluence both for the scintillator plates and for photodetectors in these experiments.
Degradation of the extracellular matrix around tumour cells is an essential step in the process of tumour invasion and metastasis. The family of structurally related metalloproteinases (MMPs) and ...their inhibitors, the tissue inhibitors of metalloproteinases (TIMP), play an important role in matrix degradation by tumour cells. In this paper MMP and TIMP activity was analysed in renal cell carcinoma. On the transcriptional level, RT-PCR was used to evaluate the expression of membrane type (MT) 1-MMP, MMp-2, MMP-9 and the inhibitors TIMP-1 and TIMP-2 in tumour tissue and normal kidney tissue. Zymography and reverse zymorgaphy measured the activity of MMPs and TIMPs in the supernatant of primary cell cultures derived from these tumour tissues at the protein level. In addition, MMP and TIMP serum levels of these patients were analysed before and 7 days after tumour nephrectomy. MMP expression revealed to be five times higher in low graded tumour tissue compared to normal kidney tissue. In the supernatant of the cell cultures, both MMP-2 and TIMP protein level was higher in samples derived from advanced carcinoma compared to samples derived from organ confined tumours. Serum levels of TIMP-2 decreased significantly after tumour nephrectomy. In conclusion, MMPs are key enzymes for tumour progression in renal cell carcinoma. New functions especially concerning the TIMP proteins may provide further understanding of the tumour progression processes.
Dynamin-related protein 1 (Drp1) is the key regulator of mitochondrial fission. We and others have reported a strong correlation between enhanced Drp1 activity and impaired skeletal muscle insulin ...sensitivity. This study aimed to determine whether Drp1 directly regulates skeletal muscle insulin sensitivity and whole-body glucose homeostasis.
We employed tamoxifen-inducible skeletal muscle-specific heterozygous Drp1 knockout mice (mDrp1+/−). Male mDrp1+/− and wildtype (WT) mice were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, followed by tamoxifen injections for five consecutive days, and remained on their respective diet for another four weeks. In addition, we used primary human skeletal muscle cells (HSkMC) from lean, insulin-sensitive, and severely obese, insulin-resistant humans and transfected the cells with either a Drp1 shRNA (shDrp1) or scramble shRNA construct. Skeletal muscle and whole-body insulin sensitivity, skeletal muscle insulin signaling, mitochondrial network morphology, respiration, and H2O2 production were measured.
Partial deletion of the Drp1 gene in skeletal muscle led to improved whole-body glucose tolerance and insulin sensitivity (P < 0.05) in diet-induced obese, insulin-resistant mice but not in lean mice. Analyses of mitochondrial structure and function revealed that the partial deletion of the Drp1 gene restored mitochondrial dynamics, improved mitochondrial morphology, and reduced mitochondrial Complex I- and II-derived H2O2 (P < 0.05) under the condition of diet-induced obesity. In addition, partial deletion of Drp1 in skeletal muscle resulted in elevated circulating FGF21 (P < 0.05) and in a trend towards increase of FGF21 expression in skeletal muscle tissue (P = 0.095). In primary myotubes derived from severely obese, insulin-resistant humans, ShRNA-induced-knockdown of Drp1 resulted in enhanced insulin signaling, insulin-stimulated glucose uptake and reduced cellular reactive oxygen species (ROS) content compared to the shScramble-treated myotubes from the same donors (P < 0.05).
These data demonstrate that partial loss of skeletal muscle-specific Drp1 expression is sufficient to improve whole-body glucose homeostasis and insulin sensitivity under obese, insulin-resistant conditions, which may be, at least in part, due to reduced mitochondrial H2O2 production. In addition, our findings revealed divergent effects of Drp1 on whole-body metabolism under lean healthy or obese insulin-resistant conditions in mice.
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•Partial loss of skeletal muscle Drp1 enhances insulin sensitivity in obese mice.•Partial loss of skeletal muscle Drp1 reduces mitochondrial H2O2 production under obese conditions.•Skeletal muscle Drp1 has divergent impacts on insulin sensitivity under lean and obese conditions.
The article summarizes series of experiments devoted to studies of (n,xn) cross-sections by the activation method and states numerical values of measured cross-sections. The activation samples are ...used to measure neutron flux produced during accelerator driven system studies. The threshold (n,xn) reactions are used but experimental cross-section data of such reactions are mostly not available for neutron energies above 30MeV. We focused for this reason on activation materials (Al, Au, Bi, In Ta, and Y) commonly used for such purposes and we also measured other materials (Cu, Fe, I, Mg, Ni, and Zn). The cross-sections were studied using quasi mono-energetic neutron sources based on proton reactions in a 7Li target in the energy range from 17MeV up to 94MeV. We observed a good agreement of the obtained data with the experimental data in the EXFOR database and also with the calculations performed using the code TALYS 1.4. Many of presented measurements represent the first ever measurement for a given reaction at a given neutron energy.
•The cross-sections were studied in the energy range from 17MeV up to 94MeV.•Results are compared with TALYS code, EXFOR database and with the library IRDFF.•Many of presented measurements represent the first ever measurement.
Dynamin‐related protein‐1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1‐mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired ...insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1‐specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi‐1), is effective in alleviating skeletal muscle insulin resistance and improving whole‐body metabolic health under the obese and insulin‐resistant condition. We subjected C57BL/6J mice to a high‐fat diet (HFD) or low‐fat diet (LFD) for 5‐weeks. HFD‐fed mice received Mdivi‐1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin‐resistant humans were treated with Mdivi‐1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H2O2 content. We found that Mdivi‐1 attenuated impairments in skeletal muscle insulin signaling and blood glucose AUC from a GTT induced by HFD feeding (p < 0.05). H2O2 content was elevated in skeletal muscle from the HFD group (vs. LFD, p < 0.05), but was reduced with Mdivi‐1 treatment, which may partially explain the improvement in skeletal muscle insulin action. Similarly, Mdivi‐1 enhanced the mitochondrial network structure, reduced reactive oxygen species, and improved insulin action in myotubes from obese humans (vs. saline, p < 0.05). In conclusion, inhibiting Drp1 with short‐term Mdivi‐1 administration attenuates the impairment in skeletal muscle insulin signaling and improves whole‐body glucose tolerance in the setting of obesity‐induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity‐induced insulin resistance.
We found that inhibiting Drp1 attenuates the impairment in skeletal muscle insulin signaling and improves whole‐body glucose tolerance in the setting of obesity‐induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity‐induced insulin resistance.
Objectives The present investigation explored the ability of fosfomycin to penetrate lung tissue of septic patients by utilizing the microdialysis technique. Methods After microdialysis probe ...insertion into healthy and infected lung tissue, a single intravenous dose of 4 g of fosfomycin was administered. Results The mean Cmax, Tmax, AUC0–4 and AUC0–∞ for healthy lung were 131.6 ± 110.6 mg/L, 1.1 ± 0.4 h, 242.4 ± 101.6 mg·h/L and 367.6 ± 111.9 mg·h/L, respectively. The corresponding values for infected lung were 107.5 ± 60.2 mg/L, 1.4 ± 0.5 h, 203.5 ± 118.4 mg·h/L and 315.1 ± 151.2 mg·h/L. The half-life of fosfomycin ranged from 2.2 to 2.7 h between compartments. The magnitude of lung tissue penetration, as determined by the ratios of the AUC0–∞ for lung to the AUC0–∞ for plasma, was 0.63 ± 0.31 and 0.53 ± 0.31 for healthy and infected lung, respectively. Conclusions We conclude that fosfomycin achieves antimicrobially effective concentrations in infected lung tissue.
Small molecules and metabolites often act as intra‐ or extracellular messengers in signal transduction pathways. Ligand‐gated ion channels provide a mean to transduce those biochemical signals at the ...membrane into electrical events and ion fluxes. In plants, cyclic nucleotides and glutamate represent intra‐ and extracellular signalling ligands, respectively. While the former have been shown to regulate voltage‐dependent ion channels and are supposed to activate cyclic nucleotide gated (CNG) channels, the latter are perceived by ionotropic glutamate receptors (GLRs). This review summarises our current knowledge about CNG channels and glutamate receptors in plants and their proposed roles in plant development and adaptation to biotic and abiotic stresses.
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