Role of a functional polymorphism in the F2R gene promoter in sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology characterized by increased inflammation, and results from gene-environment interactions. Proteinase-activated receptor-1 mediates the interplay between coagulation and inflammation. The rs2227744G > A promoter single nucleotide polymorphism has been linked to inflammation, cardiovascular disease and chronic obstructive pulmonary disease exacerbations. Using a case-control study (184 cases with sarcoidosis and 368 controls), we show that the rs2227744A allele significantly associates with protection from sarcoidosis (P = 0.003, OR = 0.68 (0.52-0.88))

Impact of a functional polymorphism in the PAR-1 gene promoter in COPD and COPD exacerbations.

Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (P A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted

Tracing Noble Gas Radionuclides in the Environment

Trace analysis of radionuclides is an essential and versatile tool in modern science and technology. Due to their ideal geophysical and geochemical properties, long-lived noble gas radionuclides, in particular, 39Ar (t1/2 = 269 yr), 81Kr (t1/2 = 2.3x10^5 yr) and 85Kr (t1/2 = 10.8 yr), have long been recognized to have a wide range of important applications in Earth sciences. In recent years, significant progress has been made in the development of practical analytical methods, and has led to applications of these isotopes in the hydrosphere (tracing the flow of groundwater and ocean water). In this article, we introduce the applications of these isotopes and review three leading analytical methods: Low-Level Counting (LLC), Accelerator Mass Spectrometry (AMS) and Atom Trap Trace Analysis (ATTA)

On the effects of friction modelling on small punch creep test responses: a numerical investigation

This paper shows the results of finite element (FE) analyses of Small Punch Creep Testing (SPCT) of a P91 steel at 600°C using two different approaches to model the friction between the specimen and the punch. The numerical results obtained by using the “classical” Coulomb friction model (i.e. constant friction coefficient) have been compared with those obtained by a more modern formulation, which takes into account the effects of local loading conditions, i.e. the contact pressure, between the contacting bodies (the small disc specimen and the punch) on the coefficient of friction. The aim of the work is to investigate the effects of the friction formulation used for the calculations on the numerical results representing the output of the test, i.e. the variation of the punch displacement versus time and the time to rupture. The calculations, carried out for various load levels, showed that the friction coefficient is not constant at all positions on the contacting surface between the punch and the specimen during the deformation process. The maximum value for the coefficient of friction is reached at the contact edge, which is a very important region in the specimen, because this is the position at which most of the creep deformation occurs. As expected, the displacement versus time curve (that is usually the only output obtained from experimental SPCTs) is affected by friction formulation which is used, as this directly influences the stress and strain fields in the specimen

Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder

Domiciliary pulse-oximetry at exacerbation of chronic obstructive pulmonary disease: prospective pilot study

The ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD) from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this

Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets

Acknowledgements We thank Sian Williams of the International Primary Care Respiratory Group for her help and encouragement with the project. The OPCRD database was made available courtesy of the Respiratory Effectiveness Group and RIRL and the data were kindly prepared for analysis by Julie von Ziegenweidt. Funding The International Primary Care Respiratory Group (IPCRG) provided funding for this research project as an UNLOCK group study for which the funding was obtained through an unrestricted grant by Novartis AG, Basel, Switzerland. The latter funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Database access for the OPCRD was provided by the Respiratory Effectiveness Group (REG) and Research in Real Life; the OPCRD statistical analysis was funded by REG. The Bocholtz Study was funded by PICASSO for COPD, an initiative of Boehringer Ingelheim, Pfizer and the Caphri Research Institute, Maastricht University, The Netherlands.Peer reviewedPublisher PD

A Candidate Subspecies Discrimination System Involving a Vomeronasal Receptor Gene with Different Alleles Fixed in M. m. domesticus and M. m. musculus

Assortative mating, a potentially efficient prezygotic reproductive barrier, may prevent loss of genetic potential by avoiding the production of unfit hybrids (i.e., because of hybrid infertility or hybrid breakdown) that occur at regions of secondary contact between incipient species. In the case of the mouse hybrid zone, where two subspecies of Mus musculus (M. m. domesticus and M. m. musculus) meet and exchange genes to a limited extent, assortative mating requires a means of subspecies recognition. We based the work reported here on the hypothesis that, if there is a pheromone sufficiently diverged between M. m. domesticus and M. m. musculus to mediate subspecies recognition, then that process must also require a specific receptor(s), also sufficiently diverged between the subspecies, to receive the signal and elicit an assortative mating response. We studied the mouse V1R genes, which encode a large family of receptors in the vomeronasal organ (VNO), by screening Perlegen SNP data and identified one, Vmn1r67, with 24 fixed SNP differences most of which (15/24) are nonsynonymous nucleotide substitutions between M. m. domesticus and M. m. musculus. We observed substantial linkage disequilibrium (LD) between Vmn1r67 and Abpa27, a mouse salivary androgen-binding protein gene that encodes a proteinaceous pheromone (ABP) capable of mediating assortative mating, perhaps in conjunction with its bound small lipophilic ligand. The LD we observed is likely a case of association rather than residual physical linkage from a very recent selective sweep, because an intervening gene, Vmn1r71, shows significant intra(sub)specific polymorphism but no inter(sub)specific divergence in its nucleotide sequence. We discuss alternative explanations of these observations, for example that Abpa27 and Vmn1r67 are coevolving as signal and receptor to reinforce subspecies hybridization barriers or that the unusually divergent Vmn1r67 allele was not a product of fast positive selection, but was derived from an introgressed allele, possibly from Mus spretus