Incidence, time course and predictors of impairments relating to caring for the profoundly affected arm after stroke: A systematic review

Background and purpose - A significant number of stroke survivors will not recover the use of their affected arm. A proportion will experience pain, stiffness and difficulty with basic care activities. The purpose of the review was to identify predictors of difficulty caring for the profoundly affected arm and establish the incidence and time-course of the related impairments of pain, spasticity and contracture. Method - Data sources: Databases (PubMED, MEDLINE, AMED, EMBASE, CINAHL and the Cochrane Controlled Trials Register) were searched from inception to December 2013. Additional studies were identified from citation tracking. Review methods: Independent reviewers used pre-defined criteria to identify eligible studies. Quality assessment and risk of bias were assessed using the McMasters Assessment Tool. A narrative evidence synthesis was performed. Results - Thirty-nine articles reporting 34 studies were included. No studies formally measured difficulty caring for the arm, but related impairments were common. Incidence of spasticity in those with weakness ranged from 33% to 78%, shoulder pain affected 22% to 90% and contracture was present in at least 50%. Spasticity and pain appear within 1 week of stroke, and contracture within two weeks. Impairments continued to develop over at least 3–6 months. The most frequent predictors of spasticity and contracture were weakness and reduced motor control, and the risk of pain is most commonly predicted by reduced sensation, shoulder subluxation, weakness and stroke severity. Discussion - There is no published evidence on predicting the likelihood of difficulty caring for the arm following stroke. However, the related impairments of spasticity, pain and contracture are common. Given the time-course of development, clinicians may need not only to intervene early but also be prepared to act over a longer time period. Further research is needed to examine difficulty caring for the arm and the relationship with associated impairments to enable researchers and clinicians to develop targeted interventions

Assay validation and interspecific comparison of salivary glucocorticoids in three amphibian species

Amphibians are one of the most threatened groups of species, facing stressors ranging from habitat degradation and pollution to disease and overexploitation. Stress hormones (glucocorticoids, GCs) provide one quantitative metric of stress,and developing non-invasive methods for measuring GCs in amphibians would clarify how diverse environmental stressors impact individual health in this taxonomic group. Saliva is an advantageous matrix for quantifying GCs, as it is sampled less invasively than plasma while still detecting both baseline and acute elevation of GCs within a short timeframe. Little work has employed this method in amphibian species, and it has never been pharmacologically and biologically validated. Here, we conduct analytical, pharmacological and biological validation experiments for measuring salivary corticosterone in three amphibian species: the American bullfrog (Rana catesbeiana), the green frog (Rana clamitans) and the northern leopard frog (Rana pipiens). These species are faced with a broad range of environmental challenges, and in part of its range R. pipiens populations are currently in decline. In addition to demonstrating that this method can be reliably used in multiple amphibian species, we present an examination of intrinsic biological factors (sex, body condition) that may contribute to GC secretion, and a demonstration that saliva can be collected from free-living animals in the field to quantify corticosterone. Our findings suggest that saliva may be useful for less invasively quantifying GCs in many amphibian species

Genetic and Transcriptional Analysis of Human Host Response to Healthy Gut Microbiota

Many studies have demonstrated the importance of the gut microbiota in healthy and disease states. However, establishing the causality of host-microbiota interactions in humans is still challenging. Here, we describe a novel experimental system to define the transcriptional response induced by the microbiota for human cells and to shed light on the molecular mechanisms underlying host-gut microbiota interactions. In primary human colonic epithelial cells, we identified over 6,000 genes whose expression changed at various time points following coculturing with the gut microbiota of a healthy individual. Among the differentially expressed genes we found a 1.8-fold enrichment of genes associated with diseases that have been previously linked to the microbiome, such as obesity and colorectal cancer. In addition, our experimental system allowed us to identify 87 host single nucleotide polymorphisms (SNPs) that show allele-specific expression in 69 genes. Furthermore, for 12 SNPs in 12 different genes, allele-specific expression is conditional on the exposure to the microbiota. Of these 12 genes, 8 have been associated with diseases linked to the gut microbiota, specifically colorectal cancer, obesity, and type 2 diabetes. Our study demonstrates a scalable approach to study host-gut microbiota interactions and can be used to identify putative mechanisms for the interplay between host genetics and the microbiota in health and disease

Minimum message length inference of secondary structure from protein coordinate data

Motivation: Secondary structure underpins the folding pattern and architecture of most proteins. Accurate assignment of the secondary structure elements is therefore an important problem. Although many approximate solutions of the secondary structure assignment problem exist, the statement of the problem has resisted a consistent and mathematically rigorous definition. A variety of comparative studies have highlighted major disagreements in the way the available methods define and assign secondary structure to coordinate data

Interspecies variation in hominid gut microbiota controls host gene regulation

The gut microbiome exhibits extreme compositional variation between hominid hosts. However, it is unclear how this variation impacts host physiology across species and whether this effect can be mediated through microbial regulation of host gene expression in interacting epithelial cells. Here, we characterize the transcriptional response of human colonic epithelial cells in vitro to live microbial communities extracted from humans, chimpanzees, gorillas, and orangutans. We find that most host genes exhibit a conserved response, whereby they respond similarly to the four hominid microbiomes. However, hundreds of host genes exhibit a divergent response, whereby they respond only to microbiomes from specific host species. Such genes are associated with intestinal diseases in humans, including inflammatory bowel disease and Crohn’s disease. Last, we find that inflammation-associated microbial species regulate the expression of host genes previously associated with inflammatory bowel disease, suggesting health-related consequences for species-specific host-microbiome interactions across hominids

A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma

Bendamustine in combination with rituximab (BR) has been associated with high response rates and acceptable toxicity in older patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Evaluation of BR is warranted in the front-line setting for DLBCL patients not eligible for anthracyclines or for the elderly. In this phase II study, we enrolled DLBCL patients aged ≥65 years who were poor candidates for R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to determine the efficacy and safety of BR in previously untreated stage II–IV DLBCL. Twenty-three patients were enrolled with a median age of 80 years. 52% of patients presented with poor functional status (Eastern Cooperative Oncology Group performance score of ≥2). The overall response rate was 78% with 12 complete responses (52%). At a median follow up of 29 months, the median overall survival was 10.2 months and the median progression-free survival was 5.4 months. The most common grade 3/4 adverse events were haematological. Combination therapy with BR demonstrates high response rates as front-line therapy in frail older patients with DLBCL, but survival rates were low. BR should be used with caution in future clinical trials involving older DLBCL patients with poor functional status

High-throughput allele-specific expression across 250 environmental conditions

Gene-by-environment (GxE) interactions determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions in response to drug treatment and pathogen exposure. However, eQTL mapping approaches are infeasible for large-scale analysis of multiple cellular environments. Recently, allele-specific expression (ASE) analysis emerged as a powerful tool to identify GxE interactions in gene expression patterns by exploiting naturally occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in five cell types. We discovered 1455 genes with ASE (FDR \u3c 10%) and 215 genes with GxE interactions. We demonstrated a major role for GxE interactions in complex traits. Genes with a transcriptional response to environmental perturbations showed sevenfold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE interactions (49%) were identified by GWAS as associated with complex traits. Examples include GIPR–caffeine interaction and obesity and include LAMP3–selenium interaction and Parkinson disease. Our results demonstrate that comprehensive catalogs of GxE interactions are indispensable to thoroughly annotate genes and bridge epidemiological and genome-wide association studies

Thermal Performance Curves of Multiple Isolates of Batrachochytrium dendrobatidis, a Lethal Pathogen of Amphibians

Emerging infectious disease is a key factor in the loss of amphibian diversity. In particular, the disease chytridiomycosis has caused severe declines around the world. The lethal fungal pathogen that causes chytridiomycosis, Batrachochytrium dendrobatidis (Bd), has affected amphibians in many different environments. One primary question for researchers grappling with disease-induced losses of amphibian biodiversity is what abiotic factors drive Bd pathogenicity in different environments. To study environmental influences on Bd pathogenicity, we quantified responses of Bd phenotypic traits (e.g., viability, zoospore densities, growth rates, and carrying capacities) over a range of environmental temperatures to generate thermal performance curves. We selected multiple Bd isolates that belong to a single genetic lineage but that were collected across a latitudinal gradient. For the population viability, we found that the isolates had similar thermal optima at 21°C, but there was considerable variation among the isolates in maximum viability at that temperature. Additionally, we found the densities of infectious zoospores varied among isolates across all temperatures. Our results suggest that temperatures across geographic point of origin (latitude) may explain some of the variation in Bd viability through vertical shifts in maximal performance. However, the same pattern was not evident for other reproductive parameters (zoospore densities, growth rates, fecundity), underscoring the importance of measuring multiple traits to understand variation in pathogen responses to environmental conditions. We suggest that variation among Bd genetic variants due to environmental factors may be an important determinant of disease dynamics for amphibians across a range of diverse environments

Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease

An Anglo-Saxon execution cemetery at Walkington Wold, Yorkshire

This paper presents a re-evaluation of a cemetery excavated over 30 years ago at Walkington Wold in east Yorkshire. The cemetery is characterized by careless burial on diverse alignments, and by the fact that most of the skeletons did not have associated crania. The cemetery has been variously described as being the result of an early post-Roman massacre, as providing evidence for a ‘Celtic’ head cult or as an Anglo-Saxon execution cemetery. In order to resolve the matter, radiocarbon dates were acquired and a re-examination of the skeletal remains was undertaken. It was confirmed that the cemetery was an Anglo-Saxon execution cemetery, the only known example from northern England, and the site is set into its wider context in the paper