1,098 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

    Children’s Mental Health Need and Expenditures in Ontario: Findings from the 2014 Ontario Child Health Study

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    Objective: To estimate the alignment between the Ontario Ministry of Children and Youth Services (MCYS) expenditures for children’s mental health services and population need, and to quantify the value of adjusting for need in addition to population size in formula-based expenditure allocations. Two need definitions are used: “assessed need,” as the presence of a mental disorder, and “perceived need,” as the subjective perception of a mental health problem. Methods: Children’s mental health need and service contact estimates (from the 2014 Ontario Child Health Study), expenditure data (from government administrative data), and population counts (from the 2011 Canadian Census) were combined to generate formula-based expenditure allocations based on 1) population size and 2) need (population size adjusted for levels of need). Allocations were compared at the service area and region level and for the 2 need definitions (assessed and perceived). Results: Comparisons were made for 13 of 33 MCYS service areas and all 5 regions. The percentage of MCYS expenditure reallocation needed to achieve an allocation based on assessed need was 25.5% at the service area level and 25.6% at the region level. Based on perceived need, these amounts were 19.4% and 27.2%, respectively. The value of needs-adjustment ranged from 8.0% to 22.7% of total expenditures, depending on the definition of need. Conclusion: Making needs adjustments to population counts using population estimates of children’s mental health need (assessed or perceived) provides additional value for informing and evaluating allocation decisions. This study provides much-needed and current information about the match between expenditures and children’s mental health need

    Changes in the Prevalence of Child and Youth Mental Disorders and Perceived Need for Professional Help between 1983 and 2014: Evidence from the Ontario Child Health Study

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    Objectives: To examine: 1) changes in the prevalence of mental disorders and perceived need for professional help among children (ages 4 to 11) and youth (ages 12 to 16) between 1983 and 2014 in Ontario and 2) whether these changes vary by age and sex, urban-rural residency, poverty, lone-parent status, and immigrant background. Methods: The 1983 (n = 2836) and 2014 (n = 5785) Ontario Child Health Studies are provincially representative cross-sectional surveys with identical self-report checklist measures of conduct disorder, hyperactivity, and emotional disorder, as well as perceived need for professional help, assessed by integrating parent and teacher responses (ages 4 to 11) and parent and youth responses (ages 12 to 16). Results: The overall prevalence of perceived need for professional help increased from 6.8% to 18.9% among 4- to 16-year-olds. An increase in any disorder among children (15.4% to 19.6%) was attributable to increases in hyperactivity among males (8.9% to 15.7%). Although the prevalence of any disorder did not change among youth, conduct disorder decreased (7.2% to 2.5%) while emotional disorder increased (9.2% to 13.2%). The prevalence of any disorder increased more in rural and small to medium urban areas versus large urban areas. The prevalence of any disorder decreased for children and youth in immigrant but not nonimmigrant families. Conclusions: Although there have been decreases in the prevalence of conduct disorder, increases in other mental disorders and perceived need for professional help underscore the continued need for effective prevention and intervention programs

    Clinical and biochemical characterization of four patients with mutations in ECHS1

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    Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, the first patients with SCEH deficiency have been reported revealing only a defect in valine catabolism. We investigated the role of SCEH in fatty acid and branched-chain amino acid metabolism in four newly identified patients. In addition, because of the Leigh-like presentation, we studied enzymes involved in bioenergetics. Metabolite, enzymatic, protein and genetic analyses were performed in four patients, including two siblings. Palmitate loading studies in fibroblasts were performed to study mitochondrial β-oxidation. In addition, enoyl-CoA hydratase activity was measured with crotonyl-CoA, methacrylyl-CoA, tiglyl-CoA and 3-methylcrotonyl-CoA both in fibroblasts and liver to further study the role of SCEH in different metabolic pathways. Analyses of pyruvate dehydrogenase and respiratory chain complexes were performed in multiple tissues of two patients. All patients were either homozygous or compound heterozygous for mutations in the ECHS1 gene, had markedly reduced SCEH enzymatic activity and protein level in fibroblasts. All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities. The third patient showed a slow neurodegenerative condition with global brain atrophy and the fourth patient showed Leigh-like lesions with a single episode of metabolic acidosis. Clinical picture and metabolite analysis were not consistent with a mitochondrial fatty acid oxidation disorder, which was supported by the normal palmitate loading test in fibroblasts. Patient fibroblasts displayed deficient hydratase activity with different substrates tested. Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein, whereas E2 mRNA was increased. Despite its activity towards substrates from different metabolic pathways, SCEH appears to be only crucial in valine metabolism, but not in isoleucine metabolism, and only of limited importance for mitochondrial fatty acid oxidation. In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentatio

    Poverty, Neighbourhood Antisocial Behaviour, and Children’s Mental Health Problems: Findings from the 2014 Ontario Child Health Study

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    Objectives: To determine if levels of neighbourhood poverty and neighbourhood antisocial behaviour modify associations between household poverty and child and youth mental health problems. Methods: Data come from the 2014 Ontario Child Health Study—a provincially representative survey of 6537 families with 10,802 four- to 17-year-olds. Multivariate multilevel modelling was used to test if neighbourhood poverty and antisocial behaviour interact with household poverty to modify associations with children’s externalizing and internalizing problems based on parent assessments of children (4- to 17-year-olds) and self-assessments of youth (12- to 17-year-olds). Results: Based on parent assessments, neighbourhood poverty, and antisocial behaviour modified associations between household poverty and children’s mental health problems. Among children living in households below the poverty line, levels of mental health problems were 1) lower when living in neighbourhoods with higher concentrations of poverty and 2) higher when living in neighbourhoods with more antisocial behaviour. These associations were stronger for externalizing versus internalizing problems when conditional on antisocial behaviour and generalized only to youth-assessed externalizing problems. Conclusion: The lower levels of externalizing problems reported among children living in poor households in low-income neighbourhoods identify potential challenges with integrating poorer households into more affluent neighbourhoods. More important, children living in poor households located in neighbourhoods exhibiting more antisocial behaviour are at dramatically higher risk for mental health problems. Reducing levels of neighbourhood antisocial behaviour could have large mental health benefits, particularly among poor children
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