Protection of hippocampal CA1 neurons against ischemia/Reperfusion injury by exercise preconditioning via modulation of Bax/Bcl-2 ratio and prevention of Caspase-3 Activation

Introduction: Ischemia leads to loss of neurons by apoptosis in specific brain regions, especially in the hippocampus. The purpose of this study was investigating the effects of exercise preconditioning on expression of Bax, Bcl-2, and caspase-3 proteins in hippocampal CA1 neurons after induction of cerebral ischemia. Methods: Male rats weighing 260-300 g were randomly allocated into three groups (sham, exercise, and ischemia). The rats in exercise group were trained to run on atreadmill 5 days a week for 4 weeks. Ischemia was induced by the occlusion of both common carotid arteries (CCAs) for 20 min. Levels of expression of Bax, Bcl-2, and caspase-3 proteins in CA1 area of hippocampus were determined by immunohistochemical staining . Results: The number of active caspase-3-positive neurons in CA1 area were significantly increased in ischemia group, compared to sham-operated group (P<0.001), and exercise preconditioning significantly reduced the ischemia/reperfusion-induced caspase-3 activation, compared to the ischemia group (P<0.05). Also, results indicated a significant increase in Bax/Bcl-2 ratio in ischemia group, compared to sham-operated group (P<0.001). Discussion: This study indicated that exercise has a neuroprotective effects against cerebral ischemia when used as preconditioning stimuli

Tribocorrosion behavior of NiTi biomedical alloy processed by an additive manufacturing laser beam directed energy deposition technique

The purpose of the present study was to experimentally assess the synergistic effects of wear and corrosion on NiTi alloy in comparison with Ti-6Al-4V alloy, the most extensively used titanium alloy in biomedical applications. Both alloys were processed by an additive manufacturing laser beam directed energy deposition (LB-DED) technique, namely laser engineered net shaping (LENS), and analyzed via tribocorrosion tests by using the ball-on-plate configuration. The tests were carried out in phosphate buffered saline solution at 37 °C under open circuit potential (OCP) to simulate the body environment and temperature. The synergistic effect of wear and corrosion was found to result in an improved wear resistance in both materials. It was also observed that, for the process parameters used, the LB-DED NiTi alloy exhibits a lower tendency to corrosion as compared to the LB-DED Ti-6Al-4V alloy. It is expected that, during the service life as an implant, the NiTi alloy is less susceptible to the metallic ions release when compared with the Ti-6Al-4V alloy.This work was partially funded by FCT (Fundação para a Ciência e Tecnologia) through the grant SFRH/BD/112280/2015 and the reference projects UID/EEA/04436/2019, COMPETE 2020 with the code POCI-01-0145-FEDER-006941; NORTE-01-0145-FEDER-000018-HAMaBICo and POCI-01-0145-FEDER-031035_LaserMULTICER. Also, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil) and Alexander von Humboldt Foundation are acknowledged for the partial support of this work. This work was also partially supported by the Project “EXPERT”, Contract no. 14PFE/17.10.2018 and Auburn University’s Presidential Award for Interdisciplinary Research (PAIR)

Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells

Background: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks. Results: We report that gene expression and inhibition of triple negative breast cancer cell growth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2, either by siRNA knockdown or pharmacological inhibition, rather than either enzyme independently. Indeed, expression of certain genes is only induced upon dual inhibition. We sought to identify compounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-based assay, based on the substrate competitive EHMT2 inhibitor BIX01294, we have identified proof-of-concept compounds that induce re-expression of a subset of genes consistent with dual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marks and an increase in permissive marks at the promoter and transcription start site of re-expressed genes, while Western analysis showed reduction in global levels of H3K27me3 and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma cell lines with low to sub-micromolar IC50s. Biochemically, the compounds are substrate competitive inhibitors against both EZH2 and EHMT1/2. Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells

Barriers to Family Caregivers’ Coping With Patients With Severe Mental Illness in Iran

The broad spectrum of problems caused by caring for a patient with mental illness imposes a high burden on family caregivers. This can affect how they cope with their mentally ill family members. Identifying caregivers’ experiences of barriers to coping is necessary to develop a program to help them overcome these challenges. This qualitative content analysis study explored barriers impeding family caregivers’ ability to cope with their relatives diagnosed with severe mental illness (defined here as schizophrenia, schizoaffective disorders, and bipolar affective disorders). Sixteen family caregivers were recruited using purposive sampling and interviewed using a semi-structured in-depth interview method. Data were analyzed by a conventional content analytic approach. Findings consisted of four major categories: the patient’s isolation from everyday life, incomplete recovery, lack of support by the mental health care system, and stigmatization. Findings highlight the necessity of providing support for caregivers by the mental health care delivery service system.The study was supported by Grant TBZMED·REC.5825 from the deputy of research in Tabriz University of Medical Sciences

The Effects of Cognitive Therapy versus ‘No Intervention’ for Major Depressive Disorder

BACKGROUND: Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Cognitive therapy may be an effective treatment option for major depressive disorder, but the effects have only had limited assessment in systematic reviews. METHODS/PRINCIPAL FINDINGS: We used The Cochrane systematic review methodology with meta-analyses and trial sequential analyses of randomized trials comparing the effects of cognitive therapy versus 'no intervention' for major depressive disorder. Participants had to be older than 17 years with a primary diagnosis of major depressive disorder to be eligible. Altogether, we included 12 trials randomizing a total of 669 participants. All 12 trials had high risk of bias. Meta-analysis on the Hamilton Rating Scale for Depression showed that cognitive therapy significantly reduced depressive symptoms (four trials; mean difference -3.05 (95% confidence interval (Cl), -5.23 to -0.87; P<0.006)) compared with 'no intervention'. Trial sequential analysis could not confirm this result. Meta-analysis on the Beck Depression Inventory showed that cognitive therapy significantly reduced depressive symptoms (eight trials; mean difference on -4.86 (95% CI -6.44 to -3.28; P = 0.00001)). Trial sequential analysis on these data confirmed the result. Only a few trials reported on 'no remission', suicide inclination, suicide attempts, suicides, and adverse events without significant differences between the compared intervention groups. DISCUSSION: Cognitive therapy might be an effective treatment for depression measured on Hamilton Rating Scale for Depression and Beck Depression Inventory, but these outcomes may be overestimated due to risks of systematic errors (bias) and random errors (play of chance). Furthermore, the effects of cognitive therapy on no remission, suicidality, adverse events, and quality of life are unclear. There is a need for randomized trials with low risk of bias, low risk of random errors, and longer follow-up assessing both benefits and harms with clinically relevant outcome measures

The effects of cognitive therapy versus 'treatment as usual' in patients with major depressive disorder

BACKGROUND: Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Cognitive therapy may be an effective treatment option for major depressive disorder, but the effects have only had limited assessment in systematic reviews. METHODS/PRINCIPAL FINDINGS: Cochrane systematic review methodology, with meta-analyses and trial sequential analyses of randomized trials, are comparing the effects of cognitive therapy versus 'treatment as usual' for major depressive disorder. To be included the participants had to be older than 17 years with a primary diagnosis of major depressive disorder. Altogether, we included eight trials randomizing a total of 719 participants. All eight trials had high risk of bias. Four trials reported data on the 17-item Hamilton Rating Scale for Depression and four trials reported data on the Beck Depression Inventory. Meta-analysis on the data from the Hamilton Rating Scale for Depression showed that cognitive therapy compared with 'treatment as usual' significantly reduced depressive symptoms (mean difference -2.15 (95% confidence interval -3.70 to -0.60; P<0.007, no heterogeneity)). However, meta-analysis with both fixed-effect and random-effects model on the data from the Beck Depression Inventory (mean difference with both models -1.57 (95% CL -4.30 to 1.16; P = 0.26, I(2) = 0) could not confirm the Hamilton Rating Scale for Depression results. Furthermore, trial sequential analysis on both the data from Hamilton Rating Scale for Depression and Becks Depression Inventory showed that insufficient data have been obtained. DISCUSSION: Cognitive therapy might not be an effective treatment for major depressive disorder compared with 'treatment as usual'. The possible treatment effect measured on the Hamilton Rating Scale for Depression is relatively small. More randomized trials with low risk of bias, increased sample sizes, and broader more clinically relevant outcomes are needed

Multiaxial cyclic deformation and non-proportional hardening employing discriminating load paths

Some novel discriminating multiaxial cyclic strain paths with incremental and random sequences were used to investigate cyclic deformation behavior of materials with low and high sensitivity to non-proportional loadings. Tubular specimens made of 1050 QT steel with no non-proportional hardening and 304L stainless steel with significant non-proportional hardening were used. 1050 QT steel was found to exhibit very similar behavior under various multiaxial loading paths, whereas significant effects of loading sequence were observed for 304L stainless steel. In-phase cycles with a random sequence of axial-torsion cycles on an equivalent strain circle were found to cause cyclic hardening levels similar to 90° out-of-phase loading of 304L stainless steel. In contrast, straining with a small increment of axial-torsion on an equivalent strain circle results in higher stress than for in-phase loading of 304L stainless steel, but the level of hardening is lower than for 90° out-of-phase loading. Tanaka\u27s non-proportionality parameter coupled with a Armstrong-Fredrick incremental plasticity model, and Kanazawa et al.\u27s empirical formulation as a representative of such empirical models were used to predict the stabilized stress response of the two materials under variable amplitude axial-torsion strain paths. Consistent results between experimental observations and predictions were obtained by employing the Tanaka\u27s non-proportionality parameter. In contrast, the empirical model resulted in significant over-prediction of stresses for 304L stainless steel. © 2010 Elsevier Ltd. All rights reserved

Multiaxial fatigue evaluation using discriminating strain paths

Fatigue life and available cycle counting methodologies based on the critical plane approach are examined under discriminating axial-torsion strain paths with random and incremental changes in straining direction. Fatigue lives for quenched and tempered 1050 steel with no non-proportional hardening were found to be more sensitive to non-proportionality of loadings as compared to 304L stainless steel with significant non-proportional hardening. Proportional or in-phase axial-torsion cycles with different axial to shear strain ratios within an equivalent strain circle when applied in a random sequence resulted in significant additional hardening for 304L stainless steel, similar to the non-proportional cyclic hardening observed in 90° out-of-phase loading. In contrast, when such cycles are applied with a gradual increment of the axial to shear strain ratio, the stress response of 304L stainless steel is closer to that observed for in-phase loading. However, the sequence of loading did not significantly affect fatigue life for either material. Experimentally observed failure planes for all strain paths were in very good agreements with predicted failure planes based on the Fatemi-Socie critical plane parameter. Finally, fatigue lives for both materials under various strain paths were predicted satisfactorily employing Fatemi-Socie parameter, Palmgren-Miner linear damage rule, and either Bannantine-Socie or Wang-Brown cycle counting method. © 2010 Elsevier Ltd. All rights reserved

Immune response to hepatitis B vaccine in health-care workers.

This study was performed to study the immune response to hepatitis B virus (HBV) vaccine in health-care workers. Through a cross-sectional study, relevant information and blood samples from 151 healthcare workers at the Firuzgar hospital were studied. The age range of the study individuals was 20-59 years, with the mean and standard deviation being 35.11 and 10.06, respectively. There were 24 males (15.9) and 127 females (84.1). The mean and median of months after HBV vaccination was 63.42 and 49.00, respectively. The mean and median of anti-HBs titer in those who received HBV vaccination was 164.81 and 200 milli international units per milliliter (mIU/mL), respectively. Of the 129 HBV-vaccinated subjects, 103 (68.2) had anti-HBs titer >10 and 26 (17.2) had anti-HBs titer <10. There was no association between gender and anti-HBs titer, but vaccination and adequate completion of its courses were associated with higher anti-HBs titer (P < 0.05). Also, the logistic regression method showed that the association between duration after vaccination and age with anti-HBs titer was not statistically significant. Our study suggests that the HBV vaccine immunization program had obtained excellent efficacy. There is need for further investigation among subjects who are not vaccinated against HBV but are positive for anti-HBs as well as in HBV-vaccinated subjects with low anti-HBs titers, about possible low-level viremia and other causes of lower vaccine efficacy, particularly in health-care workers

Improvement of growth performance, digestive enzymes and body composition of Persian sturgeon ( Acipenser persicus ) following feeding on probiotics: Bacillus licheniformis , Bacillus subtilis and Saccharomyces cerevisiae

The individual and combinational effects of probiotics on Persian sturgeon (Acipenser persicus) were evaluated through assessing the growth performance, proximate body composition, digestive enzymes and intestinal morphology. On the basis of feeding with experimental diets, the fish were assigned into four groups denoted as follows: control (basal diet), D‐Pro (basal diet + Bacillus subtilis and Bacillus licheniformis), D‐Pro/Yeast (basal diet + B. subtilis and B. licheniformis + Saccharomyces cerevisiae), Yeast (basal diet + S. cerevisiae). Maximum mean weight and length were measured for the fish fed with D‐pro regime. weight gain (WG), body weight gain (BWI%), feed efficiency (FE%), protein efficiency rate (PER), lipid efficiency rate (LER), and condition factor (CF) demonstrated the highest values for the fish fed with the diets containing D‐Pro and/or D‐Pro/yeast. LER and food conversion ratio (FCR) showed the highest performance for the fish received the D‐Pro diet. The diets containing D‐Pro exhibited higher performance in enhancing the activity of protease and lipase than the one supplemented only with the yeast, whereas the regimes treated with the yeast exhibited higher amylase activity. The fish received D‐Pro exhibited the highest protein and fat contents, yet did the lowest contents of moisture and total ash. Taken together, the findings revealed that the dietary administration of the D‐Pro and D‐Pro/Yeast could improve the growth performance of A. persicus