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    ABSTRACT: To develop enzyme-activatable Förster resonance energy transfer (FRET) substrate probes to detect matrix metalloproteinase 12 (MMP-12) and MMP-13 activities in vivo in mouse models of inflammatory arthritis. Peptidic FRET probes activated by MMP-12 and MMP-13 were reverse designed from inhibitors selected from a phosphinic peptide inhibitor library. Selectivity of the probes was demonstrated in vitro using MMP-1, MMP-2, MMP-3, MMP-12, and MMP-13. In vivo activation of the probes was tested in the zymosan-induced mouse model of inflammation, and probe specificity was evaluated by the MMP inhibitor GM6001 and specific synthetic inhibitors of MMP-12 and MMP-13. The probes were used to monitor these enzyme activities in the collagen-induced arthritis (CIA) model in vivo. The MMP-12 and MMP-13 activity probes (MMP12ap and MMP13ap, respectively) discriminated between the activities of the 2 enzymes. The in vivo activation of these probes was inhibited by GM6001 and by their respective specific inhibitors. In the CIA model, MMP12ap activation peaked 5 days after disease onset and showed strong correlation with disease severity during this time (r = 0.85, P < 0.0001). MMP13ap activation increased gradually after disease onset and correlated with disease severity over a longer period of 15 days (r = 0.58, P < 0.0001). We generated two selective FRET probes that can be used to monitor MMP-12 and MMP-13 activities in live animals. MMP12ap follows the initial stage of inflammation in CIA, while MMP13ap follows the progression of the disease. The specificity of these probes is useful in monitoring the efficacy of MMP inhibitors.
    Arthritis & rheumatology (Hoboken, N.J.). 03/2014; 66(3):589-98.
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    ABSTRACT: We investigated whether, in the management of stable paediatric fractures of the forearm, flexible casts that can be removed at home are as clinically effective, cost-effective and acceptable to both patient and parent as management using a cast conventionally removed in hospital. A single-centre randomised controlled trial was performed on 317 children with a mean age of 9.3 years (2 to 16). No significant differences were seen in the change in Childhood Health Assessment Questionnaire index score (p = 0.10) or EuroQol 5-Dimensions domain scores between the two groups one week after removal of the cast or the absolute scores at six months. There was a significantly lower overall median treatment cost in the group whose casts were removed at home (£150.88 (sem 1.90) vs £251.62 (sem 2.68); p < 0.001). No difference was seen in satisfaction between the two groups (p = 0.48). Cite this article: Bone Joint J 2013;95-B:1714-20.
    The bone & joint journal. 12/2013; 95-B(12):1714-20.
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    ABSTRACT: To compare 10 year mortality rates among patients undergoing metal-on-metal hip resurfacing and total hip replacement in England. Retrospective cohort study. English hospital episode statistics database linked to mortality records from the Office for National Statistics. All adults who underwent primary elective hip replacement for osteoarthritis from April 1999 to March 2012. The exposure of interest was prosthesis type: cemented total hip replacement, uncemented total hip replacement, and metal-on-metal hip resurfacing. Confounding variables included age, sex, Charlson comorbidity index, rurality, area deprivation, surgical volume, and year of operation. All cause mortality. Propensity score matching was used to minimise confounding by indication. Kaplan-Meier plots estimated the probability of survival up to 10 years after surgery. Multilevel Cox regression modelling, stratified on matched sets, described the association between prosthesis type and time to death, accounting for variation across hospital trusts. 7437 patients undergoing metal-on-metal hip resurfacing were matched to 22 311 undergoing cemented total hip replacement; 8101 patients undergoing metal-on-metal hip resurfacing were matched to 24 303 undergoing uncemented total hip replacement. 10 year rates of cumulative mortality were 271 (3.6%) for metal-on-metal hip resurfacing versus 1363 (6.1%) for cemented total hip replacement, and 239 (3.0%) for metal-on-metal hip resurfacing versus 999 (4.1%) for uncemented total hip replacement. Patients undergoing metal-on-metal hip resurfacing had an increased survival probability (hazard ratio 0.51 (95% confidence interval 0.45 to 0.59) for cemented hip replacement; 0.55 (0.47 to 0.65) for uncemented hip replacement). There was no evidence for an interaction with age or sex. Patients with hip osteoarthritis undergoing metal-on-metal hip resurfacing have reduced mortality in the long term compared with those undergoing cemented or uncemented total hip replacement. This difference persisted after extensive adjustment for confounding factors available in our data. The study results can be applied to matched populations, which exclude patients who are very old and have had complex total hip replacements. Although residual confounding is possible, the observed effect size is large. These findings require validation in external cohorts and randomised clinical trials.
    BMJ (online) 11/2013; 347:f6549.
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    ABSTRACT: To describe short-term (up to 12 months) and long-term (up to 7 years) damage in patients with newly diagnosed antineutrophil-cytoplasm antibody-associated vasculitis (AAV). Data were combined from six European Vasculitis Study group trials (n=735). Long-term follow-up (LTFU) data available for patients from four trials (n=535). Damage accrued was quantified by the Vasculitis Damage Index (VDI). Sixteen damage items were defined a priori as being potentially treatment-related. VDI data were available for 629 of 735 patients (85.6%) at baseline, at which time 217/629 (34.5%) had ≥1 item of damage and 32 (5.1%) ≥5 items, reflecting disease manifestations prior to diagnosis and trial enrolment. LTFU data were available for 467/535 (87.3%) at a mean of 7.3 years postdiagnosis. 302/535 patients (56.4%) had VDI data at LTFU, with 104/302 (34.4%) having ≥5 items and only 24 (7.9%) no items of damage. At 6 months and LTFU, the most frequent items were proteinuria, impaired glomerular filtration rate, hypertension, nasal crusting, hearing loss and peripheral neuropathy. The frequency of damage, including potentially treatment-related damage, rose over time (p<0.01). At LTFU, the most commonly reported items of treatment-related damage were hypertension (41.5%; 95% CI 35.6 to 47.4%), osteoporosis (14.1%; 9.9 to 18.2%), malignancy (12.6%; 8.6 to 16.6%), and diabetes (10.4%; 6.7 to 14.0%). In AAV, renal, otolaryngological and treatment-related (cardiovascular, disease, diabetes, osteoporosis and malignancy) damage increases over time, with around one-third of patients having ≥5 items of damage at a mean of 7 years postdiagnosis.
    Annals of the rheumatic diseases 11/2013;
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    ABSTRACT: Seminal research over the past 20 years has revealed atherosclerosis to be a chronic inflammatory process that shares features with traditional inflammatory diseases including rheumatoid arthritis. More recently, emphasis has been placed on the role of innate immunity in the development and progression of atherosclerosis. In particular, pattern recognition receptors, including Toll-like receptors (TLRs), have been the focus of much attention as modulators of atherogenesis. This review provides an update on the developments in this area of research in the past 2 years, with a specific focus on the current controversies and how these may affect the design of therapeutics. Specifically, we will address the recent evidence that TLRs elicit both protective and detrimental effects in atherosclerosis and the emerging observation that the outcome of TLR signaling is dependent on the agonist and responding cell type.
    Trends in Pharmacological Sciences 10/2013;
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    ABSTRACT: To evaluate the risk of aortic aneurysm in patients with giant cell arteritis (GCA) compared with age-, gender- and location-matched controls. A UK General Practice Research Database (GPRD) parallel cohort study of 6999 patients with GCA and 41 994 controls, matched on location, age and gender, was carried out. A competing risk model using aortic aneurysm as the primary outcome and non-aortic-aneurysm-related death as the competing risk was used to determine the relative risk (subhazard ratio) between non-GCA and GCA subjects, after adjustment for cardiovascular risk factors. Comparing the GCA cohort with the non-GCA cohort, the adjusted subhazard ratio (95% CI) for aortic aneurysm was 1.92 (1.52 to 2.41). Significant predictors of aortic aneurysm were being an ex-smoker (2.64 (2.03 to 3.43)) or a current smoker (3.37 (2.61 to 4.37)), previously taking antihypertensive drugs (1.57 (1.23 to 2.01)) and a history of diabetes (0.32 (0.19 to 0.56)) or cardiovascular disease (1.98 (1.50 to 2.63)). In a multivariate model of the GCA cohort, male gender (2.10 (1.38 to 3.19)), ex-smoker (2.20 (1.22 to 3.98)), current smoker (3.79 (2.20 to 6.53)), previous antihypertensive drugs (1.62 (1.00 to 2.61)) and diabetes (0.19 (0.05 to 0.77)) were significant predictors of aortic aneurysm. Patients with GCA have a twofold increased risk of aortic aneurysm, and this should be considered within the range of other risk factors including male gender, age and smoking. A separate screening programme is not indicated. The protective effect of diabetes in the development of aortic aneurysms in patients with GCA is also demonstrated.
    Annals of the rheumatic diseases 10/2013;
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    ABSTRACT: Infection in external fixator pins is known to be a significant problem with incidences between 3 and 80% in the literature. An infection occurs when planktonic bacteria adhere to external fixator pins and subsequently produce a biofilm which protects the bacteria from host defences. The most commonly implicated organisms are Staphylococcus aureus and Staphylococcus epidermidis. Once an infection occurs, treatment is difficult. Systemic antibiotics have limited benefits and considerable side effects. The only definitive management is removal of the pin. This review will consider the current and potential future strategies for reducing pin site infection. Techniques to prevent infection must prevent bacterial adhesion, allow good osteointegration and have a low toxicity. Current areas of interest reviewed are titanium-copper alloys, nanosilver coatings, nitric oxide coatings, chitosan coatings, chlorhexidine and iodine, hydroxyapatite and antibiotic coatings. At present there is no consensus on the prevention of pin site infection, and there is a paucity of randomised controlled trials on which to make conclusion. Whilst a number of these strategies have potential future use, many of the above strategies need further studies in animal models to ensure no cytotoxicity and prevention of osteointegration. Following this, well designed randomised controlled clinical trials are required to give future ways to prevent external fixator pin site infections.
    Acta biomaterialia 09/2013;
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    ABSTRACT: Our primary objective was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells. We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. The search yielded 50 articles, which consisted of 13 human studies, 36 animal studies and one combined human/animal study. Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen necrosis (3 studies). The proliferation (8 studies) and viability (9 studies) of fibroblasts was reduced. Collagen synthesis was decreased in 17 studies. An increased inflammatory cell infiltrate was shown in 4 studies. Increased cellular toxicity was demonstrated by 3 studies. The mechanical properties of tendon were investigated by 18 studies. Descriptively, 6 of these studies showed a decrease in mechanical properties, 3 showed an increase, while the remaining 9 showed no significant change. A meta-analysis of the mechanical data revealed a significant deterioration in mechanical properties, with an overall effect size of -0.67 (95% CI = 0.01 to -1.33) (data from 9 studies). Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, including reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by in vivo studies. The mechanical properties of tendon are also significantly reduced. This review supports the emerging clinical evidence that shows significant long-term harms to tendon tissue and cells associated with glucocorticoid injections.
    Seminars in arthritis and rheumatism 09/2013;
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    ABSTRACT: The best approach for surgical treatment of an infected THA remains controversial. Two-stage revision is believed to result in lower reinfection rates but may result in significant functional impairment. Some authors now suggest that single-stage revision may provide comparable results in terms of infection eradication while providing superior functional outcomes. We performed a systematic review to determine whether single- or two-stage revision for an infected THA provides lower reinfection rates and higher functional outcome scores. We conducted a comprehensive search of PubMed and Embase, using the search string [Infection AND ("total hip replacement" OR "total hip arthroplasty") AND revision]. All studies comparing reinfection rates or functional scores for single- and two-stage revision were retrieved and reviewed. A systematic review was performed according to the PRISMA checklist. The initial search retrieved 1128 studies. Following strict exclusion criteria, we identified nine comparative studies comparing reinfection rates (all nine studies) or functional scores (four studies) between single- and two-stage revisions. The overall quality of studies was poor with no randomized studies being identified. Groups often varied in their baseline characteristics. There was no consensus among the studies regarding the relative incidence of reinfection between the two procedures. There was a trend toward better functional outcomes in single-stage surgery, but this reached significance in only one study. In appropriate patients, single-stage revision appears to be associated with similar reinfection rates when compared with two-stage revision with superior functional outcomes. This concurs with earlier studies, but given the methodologic quality of the included studies, these findings should be treated with caution. High-quality randomized studies are needed to compare the two approaches to confirm these findings, and, if appropriate, to determine which patients are appropriate for single-stage revision.
    Clinical Orthopaedics and Related Research 09/2013;
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    ABSTRACT: Mesenchymal stem cells (MSCs) have become an area of intense interest in the treatment of musculoskeletal conditions, such as muscle and tendon injury, as various animal and human trials have demonstrated that implantation with MSCs leads to improved healing and function. However, these trials have usually been relatively small scale and lacking in adequate controls. Additionally, the optimum source of these cells has yet to be determined, partly due to a lack of understanding as to how MSCs produce their beneficial effects when implanted. Scaffolds have been shown to improve tissue-engineering repairs but require further work to optimize their interactions with both native tissue and implanted MSCs. Robust, well-controlled trials are therefore required to determine the usefulness of MSCs in musculoskeletal tissue repair.
    Regenerative Medicine 09/2013; 8(5):613-30.
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