1,077 research outputs found

    Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology

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    Objective Proteinase-activated receptor 2 (PAR2) deficiency protects against cartilage degradation in experimental osteoarthritis (OA). The wider impact of this pathway upon OA-associated pathologies such as osteophyte formation and pain is unknown. Herein, we investigated early temporal bone and cartilage changes in experimental OA in order to further elucidate the role of PAR2 in OA pathogenesis. Methods OA was induced in wild-type (WT) and PAR2-deficient (PAR2−/−) mice by destabilisation of the medial meniscus (DMM). Inflammation, cartilage degradation and bone changes were monitored using histology and microCT. In gene rescue experiments, PAR2−/− mice were intra-articularly injected with human PAR2 (hPAR2)-expressing adenovirus. Dynamic weight bearing was used as a surrogate of OA-related pain. Results Osteophytes formed within 7 days post-DMM in WT mice but osteosclerosis was only evident from 14 days post induction. Importantly, PAR2 was expressed in the proliferative/hypertrophic chondrocytes present within osteophytes. In PAR2−/− mice, osteophytes developed significantly less frequently but, when present, were smaller and of greater density; no osteosclerosis was observed in these mice up to day 28. The pattern of weight bearing was altered in PAR2−/− mice, suggesting reduced pain perception. The expression of hPAR2 in PAR2−/− mice recapitulated osteophyte formation and cartilage damage similar to that observed in WT mice. However, osteosclerosis was absent, consistent with lack of hPAR2 expression in subchondral bone. Conclusions This study clearly demonstrates PAR2 plays a critical role, via chondrocytes, in osteophyte development and subchondral bone changes, which occur prior to PAR2-mediated cartilage damage. The latter likely occurs independently of OA-related bone changes

    Using and Joining a Franchised Private Sector Provider Network in Myanmar

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    BACKGROUND: Quality is central to understanding provider motivations to join and remain within a social franchising network. Quality also appears as a key issue from the client's perspective, and may influence why a client chooses to use a franchised provider over another type of provider. The dynamic relationships between providers of social franchising clinics and clients who use these services have not been thoroughly investigated in the context of Myanmar, which has an established social franchising network. This study examines client motivations to use a Sun Quality Health network provider and provider motivations to join and remain in the Sun Quality Health network. Taken together, these two aims provide an opportunity to explore the symbiotic relationship between client satisfaction and provider incentives to increase the utilization of reproductive health care services. METHODS AND FINDINGS: Results from a series of focus group discussions with clients of reproductive health services and franchised providers shows that women chose health services provided by franchised private sector general practitioners because of its perceived higher quality, associated with the availability of effective, affordable, drugs. A key finding of the study is associated with providers. Provider focus group discussions indicate that a principle determinate for joining and remaining in the Sun Quality Health Network was serving the poor

    ‘Change Today, Choose Fairtrade’ Fairtrade Fortnight and the citizen-consumer

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    The Fairtrade consumer is widely represented as an individual who intentionally and reflexively consumes Fairtrade goods in order to register their support for the plight of producers in the developing world. This figure is imagined to ‘vote’ with her/his pocket every time they visit the supermarket thus demonstrating their commitment to the Fairtrade trading model. However, this image of the Fairtrade citizen-consumer does not emerge automatically as a response to the increasing availability of Fairtrade goods in the market-place but has to be made by various intermediary actors and organizations. This paper examines how the Fairtrade consumer was constructed and called to action by the Fairtrade Fortnight promotional campaign that occurred within the UK in 2008 and was co-ordinated by the Fairtrade Foundation. This annual event offers a unique window into the processes and actors involved in the mobilization of the Fairtrade citizen-consumer. Through a close focus on the promotional material distributed to different audiences and the events that occurred during this Fortnight, this paper reveals the contingent and shifting nature of the citizen-consumer identity. In so doing, it highlights how varying degrees of reflexivity and action are demanded of different audiences and how this shapes the way that Fairtrade goods are qualified and distributed in the market

    Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

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    INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS

    P2X7 receptors induce degranulation in human mast cells.

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    Mast cells play important roles in host defence against pathogens, as well as being a key effector cell in diseases with an allergic basis such as asthma and an increasing list of other chronic inflammatory conditions. Mast cells initiate immune responses through the release of newly synthesised eicosanoids and the secretion of pre-formed mediators such as histamine which they store in specialised granules. Calcium plays a key role in regulating both the synthesis and secretion of mast-cell-derived mediators, with influx across the membrane, in particular, being necessary for degranulation. This raises the possibility that calcium influx through P2X receptors may lead to antigen-independent secretion of histamine and other granule-derived mediators from human mast cells. Here we show that activation of P2X7 receptors with both ATP and BzATP induces robust calcium rises in human mast cells and triggers their degranulation; both effects are blocked by the P2X7 antagonist AZ11645373, or the removal of calcium from the extracellular medium. Activation of P2X1 receptors with αβmeATP also induces calcium influx in human mast cells, which is significantly reduced by both PPADS and NF 449. P2X1 receptor activation, however, does not trigger degranulation. The results indicate that P2X7 receptors may play a significant role in contributing to the unwanted activation of mast cells in chronic inflammatory conditions where extracellular ATP levels are elevated
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