Assessment of pain in older people : where are we now and what needs to be done?

The purpose of this paper is to present the findings of a review of the literature into pain and older people. The funded study was part of the development of an annotated bibliography published in August 2005. The review included all major databases and involved the collection of 214 papers between the dates of 1995 and 2005. The papers were divided into several major themes, which include experiences, management (pharmacological and non-pharmacological), assessment, and attitudes. Within this paper, the results of the review into pain assessment will be discussed, which includes 42 of the collected papers. The other sections will be published later. The paper will discuss issues pertaining to the development of specific tools for older people, a discussion of tools already available, comparisons of staff versus older people’s perceptions of pain scales, and articles with cognitive impairment as a focus. Recommendations for further study are made.University of Sheffiel

Assessment of Pain in adults with cognitive impairment : a review of the tools

The aim of this paper is to discuss the results of a review into the literature related to chronic pain and the older adult. Several themes within the review have been identified and reported elsewhere and the final report has been published by the University of Sheffield in the form of an annotated bibliography. This report focuses upon the findings of the in relation to the assessment of pain in the adult with cognitive impairment. Issues surrounding assessment in the non-cognitively impaired older adult have also been reported elsewhere. For this paper nine studies will be discussed which report the development and testing of pain assessment scales the focus of which is upon behavioural indicators of pain. Some scales have been omitted from the review and the rationale for this decision will be discussed. Each of the selected scales will be discussed and the authors will make recommendations for both clinical practice and for future research based upon the validity, reliability and user friendliness of the scales. From the paper it can be concluded that the Abbey, DOLOPLUS-2 and PACSLAC appear to be the most reliable and valid and in terms of the “user friendliness” would be appropriate to explore further. Recommendations are made for further multi-centre evaluation of these scales.University of Sheffiel

Effects of Metallicity on the Rotation Rates of Massive Stars

Recent theoretical predictions for low metallicity massive stars predict that these stars should have drastically reduced equatorial winds (mass loss) while on the main sequence, and as such should retain most of their angular momentum. Observations of both the Be/(B+Be) ratio and the blue-to-red supergiant ratio appear to have a metallicity dependence that may be caused by high rotational velocities. We have analyzed 39 archival Hubble Space Telescope Imaging Spectrograph (STIS), high resolution, ultraviolet spectra of O-type stars in the Magellanic Clouds to determine their projected rotational velocities V sin i. Our methodology is based on a previous study of the projected rotational velocities of Galactic O-type stars using International Ultraviolet Explorer (IUE) Short Wavelength Prime (SWP) Camera high dispersion spectra, which resulted in a catalog of V sin i values for 177 O stars. Here we present complementary V sin i values for 21 Large Magellanic Cloud and 22 Small Magellanic Cloud O-type stars based on STIS and IUE UV spectroscopy. The distribution of V sin i values for O type stars in the Magellanic Clouds is compared to that of Galactic O type stars. Despite the theoretical predictions and indirect observational evidence for high rotation, the O type stars in the Magellanic Clouds do not appear to rotate faster than their Galactic counterparts.Comment: accepted by ApJ, to appear 20 December 2004 editio

Transforming growth factor-beta promotes rhinovirus replication in bronchial epithelial cells by suppressing the innate immune response

Rhinovirus (RV) infection is a major cause of asthma exacerbations which may be due to a deficient innate immune response in the bronchial epithelium. We hypothesized that the pleiotropic cytokine, TGF-?, influences interferon (IFN) production by primary bronchial epithelial cells (PBECs) following RV infection. Exogenous TGF-?(2) increased RV replication and decreased IFN protein secretion in response to RV or double-stranded RNA (dsRNA). Conversely, neutralizing TGF-? antibodies decreased RV replication and increased IFN expression in response to RV or dsRNA. Endogenous TGF-?(2) levels were higher in conditioned media of PBECs from asthmatic donors and the suppressive effect of anti-TGF-? on RV replication was significantly greater in these cells. Basal SMAD-2 activation was reduced when asthmatic PBECs were treated with anti-TGF-? and this was accompanied by suppression of SOCS-1 and SOCS-3 expression. Our results suggest that endogenous TGF-? contributes to a suppressed IFN response to RV infection possibly via SOCS-1 and SOCS-3

Physical activity attitudes, intentions and behaviour among 18-25 year olds: a mixed method study

Peer reviewedPublisher PD

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

IntroductionMany autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development.MethodsWe blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras.ResultsGC block failed to curb autoimmune progression in the R848 model based on anti-dsDNA and plasma cell output, superoligomeric DNA complexes, and immune complex deposition in glomeruli. The 564Igi model confirmed this based on anti-dsDNA and plasma cell output. In vitro, loss of Bcl-6 prevented GC B cell expansion and accelerated plasma cell differentiation. In a competitive scenario in vivo, B cells harboring the genetic GC block contributed disproportionately to the plasma cell output.DiscussionWe identified the extrafollicular pathway as a key contributor to autoimmune progression. We propose that therapeutic targeting of low quality and poorly controlled extrafollicular responses could be a desirable strategy to curb autoreactivity, as it would leave intact the more stringently controlled and high-quality GC responses providing durable protection against infection

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.This work was supported by the NHMRC Project Grant (ID#1031333). This work was also supported by Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692)This is the published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00439-014-1515-4