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1.  Pathogenic Role of Basic Calcium Phosphate Crystals in Destructive Arthropathies 
PLoS ONE  2013;8(2):e57352.
Background
basic calcium phosphate (BCP) crystals are commonly found in osteoarthritis (OA) and are associated with cartilage destruction. BCP crystals induce in vitro catabolic responses with the production of metalloproteases and inflammatory cytokines such as interleukin-1 (IL-1). In vivo, IL-1 production induced by BCP crystals is both dependant and independent of NLRP3 inflammasome. We aimed to clarify 1/ the role of BCP crystals in cartilage destruction and 2/ the role of IL-1 and NLRP3 inflammasome in cartilage degradation related to BCP crystals.
Methodology/ Principal Findings
synovial membranes isolated from OA knees were analysed by alizarin Red and FTIR. Pyrogen free BCP crystals were injected into right knees of WT, NLRP3 -/-, ASC -/-, IL-1α -/- and IL-1β-/- mice and PBS was injected into left knees. To assess the role of IL-1, WT mice were treated by intra-peritoneal injections of anakinra, the IL-1Ra recombinant protein, or PBS. Articular destruction was studied at d4, d17 and d30 assessing synovial inflammation, proteoglycan loss and chondrocyte apoptosis. BCP crystals were frequently found in OA synovial membranes including low grade OA. BCP crystals injected into murine knee joints provoked synovial inflammation characterized by synovial macrophage infiltration that persisted at day 30, cartilage degradation as evidenced by loss of proteoglycan staining by Safranin-O and concomitant expression of VDIPEN epitopes, and increased chondrocyte apoptosis. BCP crystal-induced synovitis was totally independent of IL-1α and IL-1β signalling and no alterations of inflammation were observed in mice deficient for components of the NLRP3-inflammasome, IL-1α or IL-1β. Similarly, treatment with anakinra did not prevent BCP crystal effects. In vitro, BCP crystals elicited enhanced transcription of matrix degrading and pro-inflammatory genes in macrophages.
Conclusions/ Significance
intra-articular BCP crystals can elicit synovial inflammation and cartilage degradation suggesting that BCP crystals have a direct pathogenic role in OA. The effects are independent of IL-1 and NLRP3 inflammasome.
doi:10.1371/journal.pone.0057352
PMCID: PMC3585350  PMID: 23468973
2.  Treatment and management of pseudogout: insights for the clinician 
Pseudogout and the associated calcium pyrophosphate dihydrate (CPPD)- crystal-related arthropathies are common conditions that present particular management problems in clinical practice as they often affect older patients with multiple medical comorbidities. The epidemiology, metabolic and endocrine disease associations, and routine investigations used in the diagnostic workup are briefly reviewed. Current treatment approaches that are mainly directed at relieving the symptoms of joint inflammation are outlined. Unlike gout, there are no agents available that have been shown to decrease crystal load in CPPD-related joint disease. Recent novel insights into the pathogenesis of crystal-induced joint inflammation and subsequent joint degeneration are also discussed. The potential of colchicine as a prophylactic agent in managing recurrent attacks and the likely mechanisms of its effects on the NACHT, LRR and PYD domains-containing protein 3 (NALP-3) inflammasome of the innate immune system are highlighted. The use of agents that directly target the inflammasome, in particular drugs which inhibit the interleukin 1 pathway, in the treatment of severe, refractory pseudogout is also discussed. Finally, there is particular emphasis on the likely pathogenic role of CPPD crystal deposition in degenerative joint disease and the use of targeted anticrystal therapies as potential disease-modifying drugs.
doi:10.1177/1759720X11432559
PMCID: PMC3383522  PMID: 22870500
pseudogout; CPPD; colchicine; osteoarthritis; inflammasome; crystal; interleukin-1
3.  FIRE (facilitating implementation of research evidence): a study protocol 
Background
Research evidence underpins best practice, but is not always used in healthcare. The Promoting Action on Research Implementation in Health Services (PARIHS) framework suggests that the nature of evidence, the context in which it is used, and whether those trying to use evidence are helped (or facilitated) affect the use of evidence. Urinary incontinence has a major effect on quality of life of older people, has a high prevalence, and is a key priority within European health and social care policy. Improving continence care has the potential to improve the quality of life for older people and reduce the costs associated with providing incontinence aids.
Objectives
This study aims to advance understanding about the contribution facilitation can make to implementing research findings into practice via: extending current knowledge of facilitation as a process for translating research evidence into practice; evaluating the feasibility, effectiveness, and cost-effectiveness of two different models of facilitation in promoting the uptake of research evidence on continence management; assessing the impact of contextual factors on the processes and outcomes of implementation; and implementing a pro-active knowledge transfer and dissemination strategy to diffuse study findings to a wide policy and practice community.
Setting and sample
Four European countries, each with six long-term nursing care sites (total 24 sites) for people aged 60 years and over with documented urinary incontinence
Methods and design
Pragmatic randomised controlled trial with three arms (standard dissemination and two different programmes of facilitation), with embedded process and economic evaluation. The primary outcome is compliance with the continence recommendations. Secondary outcomes include proportion of residents with incontinence, incidence of incontinence-related dermatitis, urinary tract infections, and quality of life. Outcomes are assessed at baseline, then at 6, 12, 18, and 24 months after the start of the facilitation interventions. Detailed contextual and process data are collected throughout, using interviews with staff, residents and next of kin, observations, assessment of context using the Alberta Context Tool, and documentary evidence. A realistic evaluation framework is used to develop explanatory theory about what works for whom in what circumstances.
Trial registration
Current Controlled Trials ISRCTN11598502.
doi:10.1186/1748-5908-7-25
PMCID: PMC3356232  PMID: 22453077
4.  New approaches in the detection of calcium-containing microcrystals in synovial fluid 
Bioanalysis  2011;3(10):1085-1091.
Background
The presence of calcium phosphate crystals such as basic calcium phosphate and calcium pyrophosphate dihydrate in intra-articular fluid is linked to a number of destructive arthropathies and detection of these deposits is often pivotal for early diagnosis and appropriate management of such disease.
Results
We describe the use of a calcium-sensitive dye, Fluo-4, to selectively label calcium-containing mineral deposits in synovial fluid, which can then be easily visualized using a standard fluorescence microscope. Furthermore, we have combined the fluorescent properties of the tagged crystals with flow cytometry as a fast and semi-quantitative method of detection.
Conclusion
Dot-plots were used to quantify differences between various types of arthropathies and confirmed by visual observation of the crystals under a fluorescence microscope.
doi:10.4155/bio.11.35
PMCID: PMC3109550  PMID: 21585303
5.  The meniscus, calcification and osteoarthritis: a pathologic team 
Articular calcification correlates with osteoarthritis (OA) severity but its exact role in the disease process is unclear. In examining OA meniscal cell function, Sun and colleagues have shown recently that meniscal cells from end-stage OA subjects can generate calcium crystals and that genes involved in calcification are upregulated in OA meniscal cells. Also, this in vitro calcium deposition by OA menisci is inhibited by phosphocitrate. This study should catalyse further work examining the pathological contribution or otherwise of calcium crystals in OA. This would significantly aid the development of potential disease modifying agents in OA, which are currently unavailable.
doi:10.1186/ar2993
PMCID: PMC2911850  PMID: 20500910
6.  Exercise and manual physiotherapy arthritis research trial (EMPART): a multicentre randomised controlled trial 
Background
Osteoarthritis (OA) of the hip is a major cause of functional disability and reduced quality of life. Management options aim to reduce pain and improve or maintain physical functioning. Current evidence indicates that therapeutic exercise has a beneficial but short-term effect on pain and disability, with poor long-term benefit. The optimal content, duration and type of exercise are yet to be ascertained. There has been little scientific investigation into the effectiveness of manual therapy in hip OA. Only one randomized controlled trial (RCT) found greater improvements in patient-perceived improvement and physical function with manual therapy, compared to exercise therapy.
Methods and design
An assessor-blind multicentre RCT will be undertaken to compare the effect of a combination of manual therapy and exercise therapy, exercise therapy only, and a waiting-list control on physical function in hip OA. One hundred and fifty people with a diagnosis of hip OA will be recruited and randomly allocated to one of 3 groups: exercise therapy, exercise therapy with manual therapy and a waiting-list control. Subjects in the intervention groups will attend physiotherapy for 6–8 sessions over 8 weeks. Those in the control group will remain on the waiting list until after this time and will then be re-randomised to one of the two intervention groups. Outcome measures will include physical function (WOMAC), pain severity (numerical rating scale), patient perceived change (7-point Likert scale), quality of life (SF-36), mood (hospital anxiety and depression scale), patient satisfaction, physical activity (IPAQ) and physical measures of range of motion, 50-foot walk and repeated sit-to stand tests.
Discussion
This RCT will compare the effectiveness of the addition of manual therapy to exercise therapy to exercise therapy only and a waiting-list control in hip OA. A high quality methodology will be used in keeping with CONSORT guidelines. The results will contribute to the evidence base regarding the clinical efficacy for physiotherapy interventions in hip OA.
Trial Registration
Number: NCT00709566
doi:10.1186/1471-2474-10-9
PMCID: PMC2653461  PMID: 19152689
7.  Detection of calcium phosphate crystals in the joint fluid of patients with osteoarthritis - analytical approaches and challenges 
The Analyst  2008;133(3):302-318.
Clinically, osteoarthritis (OA) is characterised by joint pain, stiffness after immobility, limitation of movement and, in many cases, the presence of basic calcium phosphate (BCP) crystals in the joint fluid. The detection of BCP crystals in the synovial fluid of patients with OA is fraught with challenges due to the submicroscopic size of BCP, the complex nature of the matrix in which they are found and the fact that other crystals can co-exist with them in cases of mixed pathology. Routine analysis of joint crystals still relies almost exclusively on the use of optical microscopy, which has limited applicability for BCP crystal identification due to limited resolution and the inherent subjectivity of the technique. The purpose of this Critical Review is to present an overview of some of the main analytical tools employed in the detection of BCP to date and the potential of emerging technologies such as atomic force microscopy (AFM) and Raman microspectroscopy for this purpose.
doi:10.1039/b716791a
PMCID: PMC2625400  PMID: 18299743
8.  Detection of calcium phosphate crystals in the joint fluid of patients with osteoarthritis – analytical approaches and challenges 
The Analyst  2008;133(3):302-318.
The detection of basic calcium phosphate (BCP) crystals in the synovial fluid of patients with osteoarthritis is important as they represent a therapeutic target as well as a potential biomarker for the disease. This review collates the work that has been done on developing analytical assays for BCP crystals.
Clinically, osteoarthritis (OA) is characterised by joint pain, stiffness after immobility, limitation of movement and, in many cases, the presence of basic calcium phosphate (BCP) crystals in the joint fluid. The detection of BCP crystals in the synovial fluid of patients with OA is fraught with challenges due to the submicroscopic size of BCP, the complex nature of the matrix in which they are found and the fact that other crystals can co-exist with them in cases of mixed pathology. Routine analysis of joint crystals still relies almost exclusively on the use of optical microscopy, which has limited applicability for BCP crystal identification due to limited resolution and the inherent subjectivity of the technique. The purpose of this Critical Review is to present an overview of some of the main analytical tools employed in the detection of BCP to date and the potential of emerging technologies such as atomic force microscopy (AFM) and Raman microspectroscopy for this purpose.
doi:10.1039/b716791a
PMCID: PMC2625400  PMID: 18299743
9.  Inflammatory microcrystals induce murine macrophage survival and DNA synthesis 
Arthritis Research  2001;3(4):242-246.
The interaction of particulates with resident macrophages is a consistent feature in certain forms of crystal-induced inflammation, for example, in synovial tissues, lung, and the peritoneum. The mitogenic activity of basic calcium phosphate (BCP) crystals and calcium pyrophosphate dihydrate (CPPD) crystals on synovial fibroblasts has been considered relevant to the synovial hyperplasia observed in crystal-induced arthritis. The aim of the study was to determine whether microcrystals such as these could enhance macrophage survival and induce DNA synthesis, thus indicating that they may contribute to the tissue hyperplasia.
Murine bone-marrow-derived macrophages were treated in vitro with microcrystals, the cell numbers were monitored over time, and DNA synthesis was measured as the incorporation of [methyl-3H]thymidine (TdR). We report here that BCP, monosodium urate, talc, and, to a lesser extent, CPPD crystals promote macrophage survival and DNA synthesis; the latter response is particularly striking in the presence of low concentrations of macrophage-colony stimulating factor (M-CSF, CSF-1). Enhanced macrophage survival or proliferation may contribute to the synovial hyperplasia noted in crystal-associated arthropathies, as well as to talc-induced inflammation and granuloma formation. The crystals studied join the list of particulates having these effects on macrophages, indicating the generality of this type of response.
PMCID: PMC34113  PMID: 11438042
crystals; DNA synthesis; macrophages; survival

Results 1-9 (9)