In vitro modeling of the neurobiological effects of glucocorticoids: A review

Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the adrenal glands as a result of HPA-axis activation. The release of GCs is implicated with several neurobiological changes that are associated with negative consequences of chronic stress and the onset and course of psychiatric disorders. Investigating the underlying neurobiological effects of GCs may help to better understand the pathophysiology of stress-related psychiatric disorders. GCs impact a plethora of neuronal processes at the genetic, epigenetic, cellular, and molecular levels. Given the scarcity and difficulty in accessing human brain samples, 2D and 3D in vitro neuronal cultures are becoming increasingly useful in studying GC effects. In this review, we provide an overview of in vitro studies investigating the effects of GCs on key neuronal processes such as proliferation and survival of progenitor cells, neurogenesis, synaptic plasticity, neuronal activity, inflammation, genetic vulnerability, and epigenetic alterations. Finally, we discuss the challenges in the field and offer suggestions for improving the use of in vitro models to investigate GC effects

Effectiveness of behavioural graded activity compared with physiotherapy treatment in chronic neck pain: design of a randomised clinical trial [ISRCTN88733332]

BACKGROUND: Chronic neck pain is a common complaint in the Netherlands with a point prevalence of 14.3%. Patients with chronic neck pain are often referred to a physiotherapist and, although many treatments are available, it remains unclear which type of treatment is to be preferred. The objective of this article is to present the design of a randomised clinical trial, Ephysion, which examines the clinical and cost effectiveness of behavioural graded activity compared with a physiotherapy treatment for patients with chronic non-specific neck pain. METHODS: Eligible patients with non-specific neck pain persisting longer than 3 months will be randomly allocated to either the behavioural graded activity programme or to the physiotherapy treatment. The graded activity programme is based on an operant approach, which uses a time-contingent method to increase the patient's activity level. This treatment is compared with physiotherapy treatment using a pain-contingent method. Primary treatment outcome is the patient's global perceived effect concerning recovery from the complaint. Global perceived effect on daily functioning is also explored as primary outcome to establish the impact of treatment on daily activity. Direct and indirect costs will also be assessed. Secondary outcomes include the patient's main complaints, pain intensity, medical consumption, functional status, quality of life, and psychological variables. Recruitment of patients will take place up to the end of the year 2004 and follow-up measurement will continue until end 2005

A systematic review on the effectiveness of physical and rehabilitation interventions for chronic non-specific low back pain

Low back pain (LBP) is a common and disabling disorder in western society. The management of LBP comprises a range of different intervention strategies including surgery, drug therapy, and non-medical interventions. The objective of the present study is to determine the effectiveness of physical and rehabilitation interventions (i.e. exercise therapy, back school, transcutaneous electrical nerve stimulation (TENS), low level laser therapy, education, massage, behavioural treatment, traction, multidisciplinary treatment, lumbar supports, and heat/cold therapy) for chronic LBP. The primary search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to 22 December 2008. Existing Cochrane reviews for the individual interventions were screened for studies fulfilling the inclusion criteria. The search strategy outlined by the Cochrane Back Review Groups (CBRG) was followed. The following were included for selection criteria: (1) randomized controlled trials, (2) adult (≥18 years) population with chronic (≥12 weeks) non-specific LBP, and (3) evaluation of at least one of the main clinically relevant outcome measures (pain, functional status, perceived recovery, or return to work). Two reviewers independently selected studies and extracted data on study characteristics, risk of bias, and outcomes at short, intermediate, and long-term follow-up. The GRADE approach was used to determine the quality of evidence. In total 83 randomized controlled trials met the inclusion criteria: exercise therapy (n = 37), back school (n = 5), TENS (n = 6), low level laser therapy (n = 3), behavioural treatment (n = 21), patient education (n = 1), traction (n = 1), and multidisciplinary treatment (n = 6). Compared to usual care, exercise therapy improved post-treatment pain intensity and disability, and long-term function. Behavioural treatment was found to be effective in reducing pain intensity at short-term follow-up compared to no treatment/waiting list controls. Finally, multidisciplinary treatment was found to reduce pain intensity and disability at short-term follow-up compared to no treatment/waiting list controls. Overall, the level of evidence was low. Evidence from randomized controlled trials demonstrates that there is low quality evidence for the effectiveness of exercise therapy compared to usual care, there is low evidence for the effectiveness of behavioural therapy compared to no treatment and there is moderate evidence for the effectiveness of a multidisciplinary treatment compared to no treatment and other active treatments at reducing pain at short-term in the treatment of chronic low back pain. Based on the heterogeneity of the populations, interventions, and comparison groups, we conclude that there are insufficient data to draw firm conclusion on the clinical effect of back schools, low-level laser therapy, patient education, massage, traction, superficial heat/cold, and lumbar supports for chronic LBP

Skeletal muscle capillary density and microvascular function are compromised with aging and type 2 diabetes

Background: Adequate muscle perfusion is required for the maintenance of skeletal muscle mass. Impairments in microvascular structure and/or function with aging and type 2 diabetes have been associated with the progressive loss of skeletal muscle mass. Objective: To compare muscle fiber type specific capillary density and endothelial function between healthy young, older men and age-matched type 2 diabetes patients. Design: 15 healthy young men (24+/-1 y), 15 healthy older men (70+/-2 y), and 15 age-matched type 2 diabetes patients (70+/-1 y) were selected to participate in the present study. Whole-body insulin sensitivity, muscle fiber type specific capillary density, sublingual microvascular density and dimension of the erythrocyte perfused boundary region were assessed to evaluate the impact of aging and/or type 2 diabetes on microvascular structure and function. Results: Whole body insulin sensitivity was significantly lower at a more advanced age, with lowest values reported in the type 2 diabetic patients. In line, skeletal muscle capillary contacts were much lower in the older and older type 2 diabetic patients when compared with the young. Sidestream darkfield imaging showed a significantly greater thickness of the erythrocyte perfused boundary region in the type 2 diabetic patients compared with the young. Conclusions: Skeletal muscle capillary density is reduced with aging and type 2 diabetes and accompanied by impairments in endothelial glycocalyx function, which is indicative of compromised vascular function

Skeletal muscle fiber characteristics in patients with chronic heart failure: impact of disease severity and relation with muscle oxygenation during exercise

Skeletal muscle function in patients with heart failure and reduced ejection fraction (HFrEF) greatly determines exercise capacity. However, reports on skeletal muscle fiber dimensions, fiber capillarization, and their physiological importance are inconsistent. Twenty-five moderately impaired patients with HFrEF and 25 healthy control (HC) subjects underwent muscle biopsy sampling. Type I and type II muscle fiber characteristics were determined by immunohistochemistry. In patients with HFrEF, enzymatic oxidative capacity was assessed, and pulmonary oxygen uptake (VO2) and skeletal muscle oxygenation during maximal and moderateintensity exercise were measured using near-infrared spectroscopy. While muscle fiber cross-sectional area (CSA) was not different between patients with HFrEF and HC, the percentage of type I fibers was higher in HC (46 ± 15 vs. 37 ± 12%, respectively, P = 0.041). Fiber type distribution and CSA were not different between patients in New York Heart Association (NYHA) class II and III. Type I muscle fiber capillarization was higher in HFrE.compared with HC[capillary- to-fiber perimeter exchange (CFPE) index: 5.70 ± 0.92 vs. 5.05 ± 0.82, respectively, P = 0.027]. Patients in NYHA class III had slower VO2 and muscle deoxygenation kinetics during onset of exercise and lower muscle oxidative capacity than those in class II (P < 0.05). Also, fiber capillarization was lower but no.compared with HC. Higher CFPE index was related to faster deoxygenation (rspearman±±0.682, P±0.001), however, not to muscle oxidative capacity (r±±0.282, P± 0.216). Type I muscle fiber capillarization is higher in HFrE.compared with HC but not in patients with greater exercise impairment. Greater capillarization may positively affect VO2 kinetics by enhancing muscle oxygen diffusion. NEW & NOTEWORTHY The skeletal myopathy of chronic heart failure (HF) includes a greater percentage of fatigable type II fibers and, for less impaired patients, greater skeletal muscle fiber capillarization. Near-infrared spectroscopy measurements of skeletal muscle oxygenation indicate that greater capillarization ma.compensate for reduced blood flow in mild HF by enhancing the diffusive capacity of skeletal muscle. This thereby augments and speeds oxygen extraction during contractions, which is translated into faster pulmonary oxygen uptake kinetics

Skeletal muscle fiber characteristics in patients with chronic heart failure:Impact of disease severity and relation with muscle oxygenation during exercise

\u3cp\u3eSkeletal muscle function in patients with heart failure and reduced ejection fraction (HFrEF) greatly determines exercise capacity. However, reports on skeletal muscle fiber dimensions, fiber capillarization, and their physiological importance are inconsistent. Twenty-five moderately impaired patients with HFrEF and 25 healthy control (HC) subjects underwent muscle biopsy sampling. Type I and type II muscle fiber characteristics were determined by immunohistochemistry. In patients with HFrEF, enzymatic oxidative capacity was assessed, and pulmonary oxygen uptake (VO2) and skeletal muscle oxygenation during maximal and moderateintensity exercise were measured using near-infrared spectroscopy. While muscle fiber cross-sectional area (CSA) was not different between patients with HFrEF and HC, the percentage of type I fibers was higher in HC (46 ± 15 vs. 37 ± 12%, respectively, P = 0.041). Fiber type distribution and CSA were not different between patients in New York Heart Association (NYHA) class II and III. Type I muscle fiber capillarization was higher in HFrE.compared with HC[capillary- to-fiber perimeter exchange (CFPE) index: 5.70 ± 0.92 vs. 5.05 ± 0.82, respectively, P = 0.027]. Patients in NYHA class III had slower VO2 and muscle deoxygenation kinetics during onset of exercise and lower muscle oxidative capacity than those in class II (P &lt; 0.05). Also, fiber capillarization was lower but no.compared with HC. Higher CFPE index was related to faster deoxygenation (rspearman±±0.682, P±0.001), however, not to muscle oxidative capacity (r±±0.282, P± 0.216). Type I muscle fiber capillarization is higher in HFrE.compared with HC but not in patients with greater exercise impairment. Greater capillarization may positively affect VO2 kinetics by enhancing muscle oxygen diffusion. NEW &amp; NOTEWORTHY The skeletal myopathy of chronic heart failure (HF) includes a greater percentage of fatigable type II fibers and, for less impaired patients, greater skeletal muscle fiber capillarization. Near-infrared spectroscopy measurements of skeletal muscle oxygenation indicate that greater capillarization ma.compensate for reduced blood flow in mild HF by enhancing the diffusive capacity of skeletal muscle. This thereby augments and speeds oxygen extraction during contractions, which is translated into faster pulmonary oxygen uptake kinetics.\u3c/p\u3

Active beam spectroscopy for ITER

Since the first feasibility studies of active beam spectroscopy on ITER in 1995 the proposed diagnostic has developed into a well advanced and mature system. Substantial progress has been achieved on the physics side including comprehensive performance studies based on an advanced predictive code, which simulates active and passive features of the expected spectral ranges. The simulation has enabled detailed specifications for an optimized instrumentation and has helped to specify suitable diagnostic neutral beam parameters.Four ITER partners share presently the task of developing a suite of ITER active beam diagnostics. which make use of the two 0.5 MeV/amu 18 MW heating neutral beams and a dedicated 0.1 MeV/amu, 3.6 MW diagnostic neutral beam. The IN ITER team is responsible for the DNB development and also for beam physics related aspects of the diagnostic. The RF will be responsible for edge CXRS system covering the outer region of the plasma (1 > r/a > 0.4) using an equatorial observation port, and the EU will develop the core CXRS system for the very core (0 < r/a < 0.7) using a top observation port. Thus optimum radial resolution is ensured for each system with better than a/30 resolution. Finally, the US will develop a dedicated MSE system making use of the HNBs and two equatorial ports. With appropriate modification, these systems could also potentially provide information on alpha particle slowing-down features..On the engineering side, comprehensive preparations were made involving the development of an observation periscope, a neutron labyrinth optical system and design studies for remote maintenance including the exchange of the first mirror assembly, a critical issue for the operation of the CXRS diagnostic in the harsh ITER environment.Additionally, an essential change of the orientation of the DNB injection angle and specification of suitable blanket aperture has been made to avoid trapped particle damage to the first wall. (C) 2010 Elsevier B.V. All rights reserved

Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder

Background: Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis. Results: Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region. Conclusions: This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD