The immunogenicity of midbrain dopaminergic neurons and the implications for neural grafting trials in Parkinson's disease.

Dopaminergic (DA) cell replacement therapies are a promising experimental treatment for Parkinson's disease (PD) and a number of different types of DA cell-based therapies have already been trialled in patients. To date, the most successful have been allotransplants of foetal ventral midbrain but even then, the results have been inconsistent. This coupled to the ethical and logistical problems with using this tissue has meant that an alternative cell source has been sought of which human pluripotent stem cells (hPSCs) sources have proven very attractive. Robust protocols for making mesencephalic DA (mesDA) progenitor cells from hPSCs now exist and the first in-human clinical trials have or are about to start. However, while their safety and efficacy are well understood, relatively little is known about their immunogenicity and in this review, we briefly summarise this with reference mainly to the limited literature on human foetal DA cells

Chromium Tolerant Microbial Communities from the Chesapeake Bay Watershed

Chromium tolerant bacteria were enumerated from portions of the Chesapeake Bay watershed and examined for their potential to reduce Cr(VI). Water and sediment samples were collected from various locations in Baltimore Harbor and Bear Creek, as well as Sandy Point State Park in Maryland and the Anacostia River in Washington, DC. Samples were spread onto agar plates with CrO42- (5 ppm) as the sole terminal electron acceptor. Plates were incubated anaerobically and colony forming units (CFU) enumerated. CFU arising on minimal-CrO42- medium ranged from 103-104 mL-1 or g-1 and community estimates from sites in proximity to Baltimore City were approximately 6-30X higher than distal sites. Bacterial identification by BIOLOG™ or 16S rRNA sequencing indicated the presence of bacteria of the genera Klebsiella, Pseudomonas, Burkholderia, Kluyvera and others. Typical Cr(VI) reduction rates by these isolates were significantly lower than Shewanella oneidensis, a known metal-reducing bacterium. Results suggested that microbial communities in the Chesapeake Bay watershed, particularly in Baltimore Harbor and Bear Creek, had a high tolerance for Cr(VI) and/or could grow slowly with Cr(VI) as a terminal electron acceptor. However, the isolates did not rapidly degrade Cr(VI) in the laboratory

A high-density immunoblotting methodology for quantification of total protein levels and phosphorylation modifications

The components of many signaling pathways have been identified and there is now a need to conduct quantitative data-rich temporal experiments for systems biology and modeling approaches to better understand pathway dynamics and regulation. Here we present a modified Western blotting method that allows the rapid and reproducible quantification and analysis of hundreds of data points per day on proteins and their phosphorylation state at individual sites. The approach is of particular use where samples show a high degree of sample-to-sample variability such as primary cells from multiple donors. We present a case study on the analysis of >800 phosphorylation data points from three phosphorylation sites in three signaling proteins over multiple time points from platelets isolated from ten donors, demonstrating the technique's potential to determine kinetic and regulatory information from limited cell numbers and to investigate signaling variation within a population. We envisage the approach being of use in the analysis of many cellular processes such as signaling pathway dynamics to identify regulatory feedback loops and the investigation of potential drug/inhibitor responses, using primary cells and tissues, to generate information about how a cell's physiological state changes over time

Prognostic factors and models for predicting work absence in adults with musculoskeletal conditions consulting a healthcare practitioner : A systematic review

Peer reviewe

A burst chasing x-ray polarimeter

Gamma-ray bursts are one of the most powerful explosions in the universe and have been detected out to distances of almost 13 billion light years. The exact origin of these energetic explosions is still unknown but the resulting huge release of energy is thought to create a highly relativistic jet of material and a power-law distribution of electrons. There are several theories describing the origin of the prompt GRB emission that currently cannot be distinguished. Measurements of the linear polarization would provide unique and important constraints on the mechanisms thought to drive these powerful explosions. We present the design of a sensitive, and extremely versatile gamma-ray burst polarimeter. The instrument is a photoelectric polarimeter based on a time-projection chamber. The photoelectric time-projection technique combines high sensitivity with broad band-pass and is potentially the most powerful method between 2 and 100 keV where the photoelectric effect is the dominant interaction process. We present measurements of polarized and unpolarized X-rays obtained with a prototype detector and describe the two mission concepts; the Gamma-Ray Burst Polarimeter (GRBP) for the U.S. Naval Academy satellite MidSTAR-2, and the Low Energy Polarimeter (LEP) onboard POET, a broadband polarimetry concept for a small explorer mission

Gaining approvals for mental health research in the NHS

When embarking on mental health research it is often necessary to apply for approvals from one or more review bodies to ensure that the research is ethical and that the safety and well-being of participants are safeguarded. This can be complicated and time consuming, particularly to those unfamiliar with the process. In this article we describe the approvals commonly required for National Health Service-based research involving patients and endeavour to clearly explain what is involved at each stage. We then highlight some of the main considerations, including ethical aspects, which are particularly pertinent to conducting research in the field of mental health, and finish with general advice and considerations for future developments in the area

Damned if they do, damned if they don't: negotiating the tricky context of anti-social behaviour and keeping safe in disadvantaged urban neighbourhoods

Young people's relationship with anti-social behaviour (ASB) is complicated. While their behaviours are often stereotyped as anti-social (e.g. ‘hanging about’), they also experience ASB in their neighbourhood. In this study, we explore young people's own perspectives on ASB, comparing results from ‘go-along’ interviews and focus groups conducted in disadvantaged neighbourhoods in Glasgow, Scotland. This article discusses how young people's everyday experience of ASB was contextualised by social factors such as cultural stereotyping of marginalised groups, poor social connectivity and spatial marginalisation within their neighbourhood. Furthermore, we found that these social factors were mutually reinforcing and interacted in a way that appeared to leave young people in a ‘no-win’ situation regarding their association with ASB. Participation in ASB and attempts to avoid such involvement were seen to involve negative consequences: participation could entail violence and spatial restrictions linked to territoriality, but avoidance could lead to being ostracised from their peer group. Regardless of involvement, young people felt that adults stereotyped them as anti-social. Our findings therefore provide support for policies and interventions aimed at reducing ASB (perpetrated by residents of all ages); in part by better ensuring that young people have a clear incentive for avoiding such behaviours

Comparative effectiveness of treatment options for subacromial shoulder conditions:a systematic review and network meta-analysis

Background: There are currently many treatment options for patients with subacromial shoulder conditions (SSCs). Clinical decision-making regarding the best treatment option is often difficult. This study aims to evaluate the comparative effectiveness of treatment options for relieving pain and improving function in patients with SSCs. Methods: Eight databases [including MEDLINE, Embase, CINAHL, AMED, PEDro, Cochrane Database of Systematic Reviews and World Health Organization (WHO) International Clinical Trials Registry] were searched from inception until April 2020. Randomised clinical/controlled trials of adult patients investigating the effects of nonsurgical (e.g. corticosteroid injections, therapeutic exercise, shockwave therapy) and surgical treatment for SSCs, compared with each other, placebo, usual care or no treatment, were retrieved. Pairs of reviewers screened studies independently, quality appraised eligible studies using the Cochrane risk of bias tool, extracted and checked data for accuracy. Primary outcomes were pain and disability in the short term (⩽3 months) and long term (⩾6 months). Direct and indirect evidence of treatment effectiveness was synthesised using random-effects network meta-analysis. Results: The review identified 177 eligible trials. Summary estimates (based on 99 trials providing suitable data, 6764 patients, 20 treatment options) showed small to moderate effects for several treatments, but no significant differences on pain or function between many active treatment comparisons. The primary analysis indicated that exercise and laser therapy may provide comparative benefit in terms of both pain and function at different follow-up time-points, with larger effects found for laser in the short term at 2–6 weeks, although direct evidence was provided by one trial only, and for exercise in the longer term [standardised mean difference (SMD) 0.39, 95% confidence interval (CI) 0.18, 0.59 at 3–6 months] compared with control. Sensitivity analyses excluding studies at increased risk of bias confirmed only the comparative effects of exercise as being robust for both pain and function up until 3-month follow-up. Conclusion: Current evidence shows small to moderate effect sizes for most treatment options for SSCs. Six treatments had a high probability of being most effective, in the short term, for pain and function [acupuncture, manual therapy, exercise, exercise plus manual therapy, laser therapy and Microcurrent (MENS) (TENS)], but with low certainty for most treatment options. After accounting for risk of bias, there is evidence of moderate certainty for the comparative effects of exercise on function in patients with SSCs. Future large, high-quality pragmatic randomised trials or meta-analyses are needed to better understand whether specific subgroups of patients respond better to some treatments than others

Extracellular Lactate: A Novel Measure of T Cell Proliferation.

Following activation, T cells rapidly divide and acquire effector functions. This energetically demanding process depends upon the ability of T cells to undergo metabolic remodeling from oxidative phosphorylation to aerobic glycolysis, during which glucose is converted into lactate and released extracellularly. In this article, we demonstrate that extracellular lactate can be used to dynamically assess human T cell responses in vitro. Extracellular lactate levels strongly correlated with T cell proliferation, and measuring lactate compared favorably with traditional methods for determining T cell responses (i.e., [3H]thymidine incorporation and the use of cell proliferation dyes). Furthermore, we demonstrate the usefulness of measuring lactate as a read-out in conventional suppression assays and high-throughput peptide-screening assays. Extracellular lactate was stably produced over 7 d, and results were reproducibly performed over several freeze-thaw cycles. We conclude that the use of extracellular lactate measurements can be a sensitive, safe, stable, and easy-to-implement research tool for measuring T cell responses and cellular metabolic changes in vitro

Association of CREBRF variants with obesity and diabetes in Pacific Islanders from Guam and Saipan

Aims hypothesis Variants in CREBRF (rs12513649 and rs373863828) have been strongly associated with increased BMI and decreased risk of type 2 diabetes in Polynesian populations; the A allele at rs373863828 is common in Polynesians but rare in most other global populations. The aim of the present study was to assess the association of CREBRF variants with obesity and diabetes in Pacific Islander (largely Marianas and Micronesian) populations from Guam and Saipan. Methods CREBRF rs12513649 and rs373863828 were genotyped in 2022 participants in a community-based cross-sectional study designed to identify determinants of diabetes and end-stage renal disease (ESRD). Associations were analysed with adjustment for age, sex, ESRD and the first four genetic principal components from a genome-wide association study (to account for population stratification); a genomic control procedure was used to account for residual stratification. Results The G allele at rs12513649 had an overall frequency of 7.7%, which varied from 2.2% to 20.7% across different Marianas and Micronesian populations; overall frequency of the A allele at rs373863828 was 4.2% (range: 1.1–5.4%). The G allele at rs12513649 was associated with higher BMI (β=1.55 kg/m2 per copy; p=0.0026) as was the A allele at rs373863828 (β=1.48 kg/m2, p=0.033). The same alleles were associated with lower risk of diabetes (OR per copy: 0.63 [p=0.0063] and 0.49 [p=0.0022], respectively). Meta-analyses combining the current results with previous results in Polynesians showed a strong association between the A allele at rs373863828 and BMI (β=1.38 kg/m2;p=2.5×l0−29) and diabetes (OR=0.65, p=1.5×l0−13). Conclusions interpretation These results confirm the associations of CREBRF variants with higher BMI and lower risk of diabetes and, importantly, they suggest that these variants contribute to the risk of obesity and diabetes in Oceanic populations