Moderate intensity continuous training reverses the detrimental effects of ovariectomy on RyR1 phosphorylation in rat skeletal muscle.

High 17ß-Estradiol (E2) concentrations in isolated ventricular myocytes as well as a lack of ovarian hormones in cardiac muscle of ovariectomized (OVX) rodents has been shown to lead to arrhythmogenic effects by inducing post-translational modifications, including phosphorylation of the sarcoplasmic reticulum (SR) Ca2+ release channel ryanodine receptor-2 (RyR2). The effects of estrogens on the phosphorylation status of the RyR1 in skeletal muscle have not been investigated before. Furthermore, while high intensity exercise has been shown to increase RyR phosphorylation, there is no data on the effects of moderate intensity continuous training (MICT). The aims of the study were to investigate the effects of a 3-day treatment with low (1 nM, moderate (5 nM) and high (10 nM, 100 nM) E2 concentrations on RyR1 mRNA and protein expression and phosphorylation status (pRyRSer2844) in cultured C2C12 myotubes and to study the effects of OVX on RyR1 expression and phosphorylation in rat skeletal muscle in combination with 3 weeks of MICT. Treatment with low, physiological E2 concentrations reduced dihydropyridine receptor (DHPR) and RyR1 mRNA content in C2C12 myotubes compared to untreated control cells, whereas RyR1 protein phosphorylation (pRyRSer2844) was significantly increased after treatment with high, non-physiological E2 concentrations (p ≤ 0.05). RyR1 protein content (p ≤ 0.05) and pRyRSer2844 (p ≤ 0.05) were significantly elevated in skeletal muscle of OVX vs. sham-operated rats. Importantly, pRyRSer2844 levels were similar to sham-operated controls in OVX rats after MICT (OVX vs. OVX + MICT, p ≤ 0.05). Our results indicate, that one of the actions of estrogens is to alter skeletal muscle Ca2+ homeostasis by modulating the expression and phosphorylation of the RyR1 in skeletal muscle. Notably, regular MICT was able to counteract RyR1 phosphorylation in skeletal muscle of OVX rats.

Attenuated heart rate recovery predicts risk of incident diabetes: insights from a meta-analysis.

AIMS: To assess the association between attenuated heart rate recovery, a non-invasive measure of autonomic dysfunction, and risk of diabetes in the general population. METHODS: Databases were searched for cohort studies up to May 2017 that reported the association of heart rate recovery with the risk of diabetes. The overall hazard ratios for slowest vs fastest heart rate recovery (the referent) and for every 10-beats-per-min decrement in heart rate recovery were calculated using a random effects meta-analysis model. RESULTS: Four cohort studies with 430 incident cases of diabetes among a total of 9113 participants during a mean follow-up period of 8.1 years were included. Results showed that the slowest heart rate recovery was associated with a higher risk of diabetes (hazard ratio 1.66, 95% CI 1.16 to 2.38) vs the fastest heart rate recovery, and the hazard ratio of risk of diabetes for every 10-beats-per-min decrement in heart rate recovery was 1.29 (95% CI 1.13 to 1.48). No significant interaction effect was observed regarding the efficacy of 1-min and 2-min heart rate recovery in predicting risk of diabetes (both Pfor interaction >0.60); however, a linear dose-response relationship existed for overall studies and for studies using 1-min heart rate recovery as the exposure (both P >0.60 for non-linearity). CONCLUSIONS: Attenuated heart rate recovery is associated with an increased risk of diabetes in a dose-dependent manner, and measurement of heart rate recovery is worth recommending as part of diabetes risk assessment in clinical routines.

The role of sex, adiposity, and gonadectomy in the regulation of irisin secretion.

A sexual dimorphism has been reported for the adipo-myokine irisin at rest and in response to exercise. The effects of male and female sex, adiposity, and gonadectomy on irisin secretion have not been investigated before. The objective of this study was to elucidate the effects of sex, adiposity, and gonadectomy in the regulation of irisin secretion as well as PGC-1α/FNDC5 mRNA and protein expression. We hypothesized that a lack of female sex hormones by ovariectomy reduces irisin levels and inhibits skeletal muscle expression of PGC-1α and FNDC5. Circulating irisin was measured in vivo in serum samples of healthy and obese men and women at rest and in response to acute exercise. The effects of gonadectomy on serum irisin, PGC-1α and FNDC5 muscle mRNA, and protein expression were investigated in ovariectomized (OVX) and orchiectomized (ORX) Wistar rats. Serum irisin at rest was not significantly different between men and women (lean or obese). However, in response to acute aerobic exercise, irisin levels increased significantly more in lean women versus men (p ≤ 0.05). In obese individuals, resting irisin concentrations were significantly higher compared to lean subjects (p ≤ 0.001) and the irisin response to acute exercise was blunted. Only the lack of gonadal hormones in OVX but not ORX rats increased serum irisin levels (p ≤ 0.01) and resulted in significantly increased body weight (p ≤ 0.01), adipose tissue content (p ≤ 0.05), muscle FNDC5 mRNA (p ≤ 0.05), and protein (p ≤ 0.01) expression without altering PGC-1α expression. Testosterone treatment in ORX rats leads to increased PGC-1α mRNA content and reduced PGC-1α protein content without affecting FDNC5 expression or serum irisin levels. We show that a sexual dimorphism exists for the acute irisin response to exercise in normal-weight but not in obese subjects. OVX, which is associated with increased adiposity and insulin insensitivity, increases basal FNDC5 expression and serum irisin, without altering PGC-1α expression. This may be an early sign for metabolic disturbances associated with menopause, such as a developing irisin resistance or an attempt of the organism to improve glucose metabolism.

Pedometer intervention and weight loss in overweight and obese adults with Type 2 diabetes: a meta-analysis.

AIM: Although pedometer intervention is effective in increasing physical activity among adults with Type 2 diabetes, its impact on weight loss remains unclear. This meta-analysis was aimed to assess whether pedometer intervention promotes weight loss. METHODS: Three different databases were searched for randomized controlled trials (RCTs) published in English up to April 2015. Studies were included if they investigated the effects of pedometer intervention on weight loss, as measured by BMI or weight. Effect sizes were aggregated using a random-effects model. Subgroup and meta-regression analyses were used to identify potential moderators. Eleven RCTs with 1258 participants were included. All enrolled participants were overweight or obese. RESULTS: Pedometer intervention led to significantly decreased BMI [weighted mean difference (WMD) -0.15 kg/m(2) , 95% confidence interval (CI) -0.29 to -0.02 kg/m(2) ] and reduced weight (WMD -0.65 kg, 95% CI -1.12 to -0.17 kg). Dietary counselling seemed to be a key predictor of the observed changes. However, none of the following variables had a significant influence: step goal setting, baseline age, BMI, weight, sex distribution, disease duration, intervention duration, and baseline values or change scores for total or moderate-to-vigorous physical activity. After completion of the pedometer intervention, non-significant declines in BMI and weight were observed during the follow-up periods. CONCLUSIONS: Pedometer intervention promotes modest weight loss, but its association with physical activity requires further clarification. Future studies are also required to document dietary and sedentary behaviour changes to facilitate the use of pedometers for weight loss in overweight and obese adults with Type 2 diabetes.

In vitro inhibition of stable 1,3-beta-D-glucan synthase activity from Neurospora crassa.

Glucan synthase activity of Neurospora crassa was isolated by treatment of protoplast lysates with 0.1% 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate and 0.5% octylglucoside in 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, pH 7.4, containing 5 mM EDTA, 1 mM phenylmethylsulfonylfluoride, 200 mM inorganic phosphate, 10 microM GTP, 1 mM DTT, 10 mM sodium fluoride, and 600 mM glycerol. Resulting activity was partially purified by sucrose gradient density sedimentation. Approximately 70% of enzyme activity in the sucrose gradient peak fraction was soluble and enzyme activity was purified 7.3-fold. Partially purified enzyme activity had a half-life of several weeks at 4 degrees C, and a Km(app) of 1.66 +/- 0.28 mM. Inhibitors (Cilofungin, papulacandin B, aculeacin A, echinocandin B, sorbose and UDP) of 1,3-beta-D-glucan synthase activity were tested against crude particulate and detergent treated enzyme fractions and the Ki(app) of each inhibitor determined. It seems likely that this stable preparation of glucan synthase activity may be useful for in vitro enzyme screens for new glucan synthase inhibitors.

Chemotherapy of metastatic soft tissue sarcoma with a combination of adriamycin and DTIC or adriamycin and ifosfamide.

Between 1982 and 1986, 38 patients with soft tissue sarcomas were treated with a combination of ADM/DTIC (group A), another 45 (group B) received ADM/IFO between 1986 and 1990. Clinical characteristics were comparable in both groups. Remission rate was 34% in group A and 43% in group B. Duration of remission was 10 months and median survival 13 months in both groups. Toxicity, especially myelotoxicity, was severe without marked differences between both groups. We conclude that adriamycin/DTIC and adriamycin/ifosfamide are both active regimens in metastatic soft tissue sarcomas, nevertheless, overall prognosis remains poor.

The antigenic structure of dengue type 1 virus envelope and NS1 proteins expressed in Escherichia coli.

The antigenic structures of the envelope protein, E, and the non-structural protein, NS1, of dengue type 1 virus (DEN1) have been studied in the form of recombinant fusion proteins expressed in Escherichia coli. Deletion analysis was used to identify two distinct antigenic domains in E that reacted with subsets of antiviral monoclonal antibodies (MAbs). Domain I of E extends from amino acid residues (aa) 76 to 93 of E; domain II extends from aa 293 to 402 and contains an essential disulphide bridge. MAbs also reacted with several determinants clustered near the N terminus of the NS1 protein (aa 57 to 126). Recombinant fusion proteins containing E. coli trpE sequences and most of the sequences for either E or NS1 were immunogenic in mice. The antibodies elicited by the E fusion protein reacted with a portion of the protein containing domain II, whereas antibodies elicited by the NS1 fusion protein did not react with the antigenic determinants defined by our MAbs.