Stimulated Muscle Contractions Regulate Membrane-Bound and Soluble TLR4 to Prevent LPS-Induced Signaling and Myotube Atrophy in Skeletal Muscle Cells

Toll-like receptor 4 (TLR4) activation by lipopolysaccharides (LPS) contributes to chronic inflammation and causes upregulation of muscle atrophy signaling pathways. Exercise can suppress LPS/TLR4 axis activation by reducing the expression of TLR4 on immune cells. It is unknown how this regulation occurs, and it is not clear how exercise affects TLR4 on skeletal muscle. PURPOSE: To uncover the nature and mechanisms by which exercise affects TLR4 expression and intracellular signaling using cell culture models and human experiments. METHODS: C2C12 myotubes were subjected to electrical pulse stimulation (EPS) with and without subsequent treatment with 500 ng/mL lipopolysaccharide (LPS) along with corresponding control conditions. To investigate the effect of muscle contraction on the regulation of TLR4 in-vivo, we analyzed PBMC and serum samples from eight recreationally active men that completed 60-minutes of cycling at a moderate intensity (65% of VO2max). RESULTS: In-vitro, LPS decreased membrane-bound TLR4, increased TLR4 signaling (decreased inhibitor of κBα), and induced myotube atrophy. However, stimulated muscle contractions decreased membrane-bound TLR4, increased soluble TLR4 (sTLR4), and prevented LPS-induced signaling and myotube atrophy. In human participants, a single bout of moderate-intensity exercise decreased membrane-bound TLR4 on PBMCs and increased serum-borne sTLR4. CONCLUSION: These experiments support exercise may exert a novel anti-catabolic/ anti-inflammatory effect by increasing sTLR4 and decreasing TLR4 expressed on the muscle membrane. These results could help improve interventions for conditions associated with TLR4-mediated inflammation and muscle atrophy, such as diabetes, sarcopenia, and cancer cachexia

Functional Electrical Stimulation following nerve injury in a Large Animal Model.

INTRODUCTION: Controversy exists over the effects of functional electrical stimulation (FES) on reinnervation. We hypothesized that intramuscular FES would not delay reinnervation after recurrent laryngeal nerve (RLn) axonotmesis. METHODS: RLn cryo-injury and electrode implantation in ipsilateral posterior cricoarytenoid muscle (PCA) were performed in horses. PCA was stimulated for 20 weeks in eight animals; seven served as controls. Reinnervation was monitored through muscle response to hypercapnia, electrical stimulation and exercise. Ultimately, muscle fiber type proportions and minimum fiber diameters, and RLn axon number and degree of myelination were determined. RESULTS: Laryngeal function returned to normal in both groups within 22 weeks. FES improved muscle strength and geometry, and induced increased type I:II fiber proportion (p=0.038) in the stimulated PCA. FES showed no deleterious effects on reinnervation. DISCUSSION: Intramuscular electrical stimulation did not delay PCA reinnervation after axonotmesis. FES can represent a supportive treatment to promote laryngeal functional recovery after RLn injury. This article is protected by copyright. All rights reserved

The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders

Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs—valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine—in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective

Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort

STUDY FUNDING The data were collected by a Research into Ageing programme grant; research continues as part of the Age UK–funded Disconnected Mind project. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1), with funding from the BBSRC and Medical Research Council. Imaging and image analysis was performed at the Brain Research Imaging Centre (sbirc.ed.ac.uk/), Edinburgh, supported by the Scottish Funding Council SINAPSE Collaboration. Derivation of mean cortical thickness measures was funded by the Scottish Funding Council’s Postdoctoral and Early Career Researchers Exchange Fund awarded by SINAPSE to David Alexander Dickie. L.C.A.C. acknowledges funding from the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) division.Peer reviewedPublisher PD

Transforming teacher education, an activity theory analysis

This paper explores the work of teacher education in England and Scotland. It seeks to locate this work within conflicting socio-cultural views of professional practice and academic work. Drawing on an activity theory framework that integrates the analysis of these contradictory discourses with a study of teacher educators’ practical activities, including the material artefacts that mediate the work, the paper offers a critical perspective on the social organisation of university-based teacher education. Informed by Engeström’s activity theory concept of transformation, the paper extends the discussion of contradictions in teacher education to consider the wider socio-cultural relations of the work. The findings raise important questions about the way in which teacher education work within universities is organised and the division of labour between schools and universities

The Effect of Quercetin on Bone Turnover Markers, Inflammatory Markers, and Bone Mineral Density in Postmenopausal Women: A Double-Blind Placebo-Controlled Investigation

Maintaining optimal bone health prevents major bone disorders (e.g., osteoporosis) and prolongs longevity. Quercetin is a plant-based flavonoid that is suggested to have anti-inflammatory effects and may improve bone health. PURPOSE: To investigate the effects of quercetin supplementation over 90-days on prominent bone turnover markers (BTMs), inflammatory markers, bone mineral density (BMD), body composition, and physical functioning in postmenopausal women. METHODS: Thirty-three healthy, nonosteoporotic, postmenopausal women (59.2±7.0 years) participated in a double-blind, placebo-controlled investigation. Participants were randomized into one of two supplement groups: 1) 500 mg of quercetin (QUE) once daily or 2) 500 mg of methylcellulose (placebo; PLB) once daily. Pre- and post-testing visits included assessments of BTMs (i.e., osteocalcin [OC], procollagen type-I N-terminal propeptide [PINP], and type-I collagen cross-linked C-terminal telopeptide [CTX]), inflammatory markers (i.e., interleukin [IL]-6, tumor necrosis factor-alpha [TNF-a], and C-reactive protein [CRP]), BMD measurements, body composition measurements (i.e., body fat percentage), and physical function. RESULTS: The QUE group increased OC (p=0.016; d=0.89), PINP (p=0.030; d=0.64), and CTX (p=0.023; d=0.91) levels and decreased IL-6 (p=0.045; d=0.73) and TNF-a (p=0.021; d=0.90) levels compared to PLB. CRP (p=0.448; d=0.34), BMD, body composition, and physical function remained unchanged. CONCLUSION: The results indicate that QUE may maintain optimal bone health by mediating bone formation and decreasing pro-inflammatory cytokines

Determinants of Oral Corticosteroid Responsiveness in Wheezing Asthmatic Youth (DOORWAY): Protocol for a prospective multicentre cohort study of children with acute moderate-to-severe asthma exacerbations

Introduction: Oral corticosteroids are the cornerstone of acute asthma management in the emergency department. Recent evidence has raised doubts about the efficacy of this treatment in preschool-aged children with viral-induced wheezing and in smoking adults. The aims of the study were to: (1) document the magnitude of response to oral corticosteroids in children presenting to the emergency department with moderate or severe asthma; (2) quantify potential determinants of response to corticosteroids and (3) explore the role of gene polymorphisms associated with the responsiveness to corticosteroids. Methods and analysis: The design is a prospective cohort study of 1008 children aged 1-17 years meeting a strict definition of asthma and presenting with a clinical score of ≥4 on the validated Pediatric Respiratory Assessment Measure. All children will receive standardised severity-specific treatment with prednisone/prednisolone and cointerventions (salbutamol with/without ipratropium bromide). Determinants, namely viral aetiology, environmental tobacco smoke and single nucleotide polymorphism, will be objectively documented. The primary efficacy endpoint is the failure of emergency department (ED) management within 72 h of the ED visit. Secondary endpoints include other measures of asthma severity and time to recovery within 7 days of the index visit. The study has 80% power for detecting a risk difference of 7.5% associated with each determinant from a baseline risk of 21%, at an α of 0.05. Ethics and dissemination: Ethical approval has been obtained from all participating institutions. An impaired response to systemic steroids in certain subgroups will challenge the current standard of practice and call for the immediate search for better approaches. A potential host-environment interaction will broaden our understanding of corticosteroid responsiveness in children. Documentation of similar effectiveness of corticosteroids across determinants will provide the needed reassurance regarding current treatment recommendations. Results: Results will be disseminated at international conferences and manuscripts targeted at emergency physicians, paediatricians, geneticists and respirologists. Trial registration number: This study is registered at Clinicaltrials.gov (NCT02013076)

Leukotriene antagonists as first-line or add-on asthma controller therapy

Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score =6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score =1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group

Low-voltage operation of metal-ferroelectric-insulator-semiconductor diodes incorporating a ferroelectric polyvinylidene fluoride copolymer Langmuir-Blodgett film

We report the electrical characteristics of metal-ferroelectric-insulator-semiconductor structures, where the ferroelectric layer is a Langmuir-Blodgett film of a copolymer of 70% vinylidene fluoride and 30% trifluoroethylene. The 36-nm thick copolymer films were deposited on thermally oxidized (10 nm SiO2) p-type silicon and covered with a gold gate electrode. Polarization-field hysteresis loops indicate polarization switching in the polymer film. The device capacitance shows hysteresis when cycling the applied voltage between ±3 V, exhibiting a zero-bias on/off capacitance ratio of over 3:1 and a symmetric memory window 1 V wide, with little evidence of bias that can arise from traps in the oxide. Model calculations are in good agreement with the data and show that film polarization was not saturated. The capacitance hysteresis vanishes above the ferroelectric- paraelectric transition temperature, showing that it is due to polarization hysteresis. The retention time of both the on and off states was approximately 15 min at room temperature, possibly limited by leakage or by polarization instability in the unsaturated film. These devices provide a basis for nonvolatile data storage devices with fast nondestructive readout

A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study

Background A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD