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Dean B.J.F.,Botnar Research Center | Gettings P.,Botnar Research Center | Dakin S.G.,University of Essex | Carr A.J.,University of Essex
British Journal of Sports Medicine | Year: 2016

Background The role of inflammation in tendinopathy has historically been a subject of significant controversy. Our primary aim was to determine whether inflammatory cell numbers were increased in painful human tendinopathy versus healthy control tendons. Our secondary aim was to assess whether the inflammatory cells had been linked with symptoms or disease stage. Methods We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. Only studies measuring inflammatory cells using specific markers in tissue from human patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by 2 independent researchers on review of abstracts or full-text using specific predetermined criteria. The search yielded 5 articles in total. Results There were increased numbers of macrophages (4 studies) and mast cells (3 studies) in tendinopathic versus healthy control tissues. One study demonstrated increased numbers of T cells in tendinopathic tissue versus healthy control tendons. There were reduced numbers of T cells (1 study), macrophages (2 studies) and mast cells (2 studies) in torn tendon versus intact tendinopathic tissue. Conclusions The existing evidence supports the hypothesis that increased numbers of inflammatory cells are present in pathological tendons. The lack of highquality quantitative studies in this area demonstrates a clear need for future research to better understand the role of inflammation in tendinopathy.


Murray D.W.,Nuffield Orthopaedic Center | Murray D.W.,Botnar Research Center | Grammatopoulos G.,Nuffield Orthopaedic Center | Grammatopoulos G.,Botnar Research Center | And 6 more authors.
Journal of Bone and Joint Surgery - Series B | Year: 2012

Recent events have highlighted the importance of implant design for survival and wear-related complications following metal-on-metal hip resurfacing arthroplasty. The mid-term survival of the most widely used implant, the Birmingham Hip Resurfacing (BHR), has been described by its designers. The aim of this study was to report the ten-year survival and patient-reported functional outcome of the BHR from an independent centre. In this cohort of 554 patients (646 BHRs) with a mean age of 51.9 years (16.5 to 81.5) followed for a mean of eight years (1 to 12), the survival and patient-reported functional outcome depended on gender and the size of the implant. In female hips (n = 267) the ten-year survival was 74% (95% confidence interval (CI) 83 to 91), the ten-year revision rate for pseudotumour was 7%, the mean Oxford hip score (OHS) was 43 (SD 8) and the mean UCLA activity score was 6.4 (SD 2). In male hips (n = 379) the ten-year survival was 95% (95% CI 92.0 to 97.4), the ten-year revision rate for pseudotumour was 1.7%, the mean OHS was 45 (SD 6) and the mean UCLA score was 7.6 (SD 2). In the most demanding subgroup, comprising male patients aged < 50 years treated for primary osteoarthritis, the survival was 99% (95% CI 97 to 100). This study supports the ongoing use of resurfacing in young active men, who are a subgroup of patients who tend to have problems with conventional THR. In contrast, the results in women have been poor and we do not recommend metal-on-metal resurfacing in women. Continuous follow-up is recommended because of the increasing incidence of pseudotumour with the passage of time. ©2012 British Editorial Society of Bone and Joint Surgery.


Shafqat N.,University of Oxford | Turnbull A.,University of Oxford | Zschocke J.,Innsbruck Medical University | Oppermann U.,University of Oxford | And 2 more authors.
Journal of Molecular Biology | Year: 2010

3-Hydroxy-3-methylglutaryl coenzyme A (CoA) synthase (HMGCS) catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl CoA. It is ubiquitous across the phylogenetic tree and is broadly classified into three classes. The prokaryotic isoform is essential in Gram-positive bacteria for isoprenoid synthesis via the mevalonate pathway. The eukaryotic cytosolic isoform also participates in the mevalonate pathway but its end product is cholesterol. Mammals also contain a mitochondrial isoform; its deficiency results in an inherited disorder of ketone body formation. Here, we report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. Our data represent the first structures solved for human HMGCS and the mitochondrial isoform, allowing for the first time structural comparison among the three isoforms. This serves as a starting point for the development of isoform-specific inhibitors that have potential cholesterol-reducing and antibiotic applications. In addition, missense mutations that cause mitochondrial HMGCS deficiency have been mapped onto the hHMGCS2 structure to rationalize the structural basis for the disease pathology. © 2010 Elsevier Ltd.


Yue W.W.,University of Oxford | Oppermann U.,University of Oxford | Oppermann U.,Botnar Research Center
Journal of Inherited Metabolic Disease | Year: 2011

The Structural Genomics Consortium (SGC) is a public-private partnership that aims to determine the three-dimensional structures of human proteins of medical relevance and place them into the public domain without restriction. To date, the Oxford Metabolic Enzyme Group at SGC has deposited the structures of more than 140 human metabolic enzymes from diverse protein families such as oxidoreductases, hydrolases, oxygenases and fatty acid transferases. A subset of our target proteins are involved in the inherited disorders of carbohydrate, fatty acid, amino acid and vitamin metabolism. This article will provide an overview of the structural data gathered from our high-throughput efforts and the lessons learnt in the structure-function relationship of these enzymes, small molecule development and the molecular basis of disease mutations. © 2011 SSIEM and Springer.


Oppermann U.,Botnar Research Center | Oppermann U.,University of Oxford
Arthritis Research and Therapy | Year: 2013

In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases. © 2013 BioMed Central Ltd.


Roos E.M.,University of Southern Denmark | Arden N.K.,Botnar Research Center
Nature Reviews Rheumatology | Year: 2016

Osteoarthritis (OA) has been thought of as a disease of cartilage that can be effectively treated surgically at severe stages with joint arthroplasty. Today, OA is considered a whole-organ disease that is amenable to prevention and treatment at early stages. OA develops slowly over 10-15 years, interfering with activities of daily living and the ability to work. Many patients tolerate pain, and many health-care providers accept pain and disability as inevitable corollaries of OA and ageing. Too often, health-care providers passively await final 'joint death', necessitating knee and hip replacements. Instead, OA should be viewed as a chronic condition, where prevention and early comprehensive-care models are the accepted norm, as is the case with other chronic diseases. Joint injury, obesity and impaired muscle function are modifiable risk factors amenable to primary and secondary prevention strategies. The strategies that are most appropriate for each patient should be identified, by selecting interventions to correct - or at least attenuate - OA risk factors. We must also choose the interventions that are most likely to be acceptable to patients, to maximize adherence to - and persistence with - the regimes. Now is the time to begin the era of personalized prevention for knee OA. © 2016 Macmillan Publishers Limited. All rights reserved.


Davies B.M.,Botnar Research Center
Annals of the Royal College of Surgeons of England | Year: 2013

We describe the cases of four patients who presented with painful hips and were found to have fractured cemented Exeter™ V40™ stems. Failure was multifactorial. Fractured Exeter™ stems are rarely reported and this series raises a concern that a population of patients may be at risk of such morbidity.


Pilka E.S.,Old Road Research Campus Building | Kochan G.,Old Road Research Campus Building | Oppermann U.,Old Road Research Campus Building | Oppermann U.,Botnar Research Center | Yue W.W.,Old Road Research Campus Building
Biochemical and Biophysical Research Communications | Year: 2012

Zn2+-dependent carbonic anhydrases (CA) catalyse the reversible hydration of carbon dioxide to bicarbonate and participate in diverse physiological processes, hence having manifold therapeutic potentials. Among the 15 human CAs with wide-ranging sub-cellular localisation and kinetic properties, CA VI is the only secretory isoform. The 1.9å crystal structure of the human CA VI catalytic domain reveals a prototypical mammalian CA fold, and a novel dimeric arrangement as compared to previously-reported CA structures. The active site cavity contains a cluster of non-conserved residues that may be involved in ligand binding and have significant implications for developing the next-generation of isoform-specific inhibitors. © 2012 Elsevier Inc.


Murphy R.J.,Botnar Research Center | Daines M.T.,Botnar Research Center | Carr A.J.,Botnar Research Center | Rees J.L.,Botnar Research Center
Journal of Bone and Joint Surgery - Series A | Year: 2013

Background: There is an evolving interest in shoulder ultrasound performed by orthopaedic surgeons as part of routine clinical assessment of the rotator cuff in a so-called one-stop clinic. This study investigated the accuracy of ultrasound assessment of rotator cuff integrity performed by orthopaedic surgeons without prior experience of ultrasound who were following our proposed learning protocol. Methods: We studied four surgeons without previous experience with shoulder ultrasound and monitored their ability to evaluate rotator cuff integrity using ultrasound compared with findings at arthroscopy. The surgeons attended a formal training course and were taught a protocol to identify and size full-thickness tears of the rotator cuff. The surgeons performed preoperative scans on the day that patients underwent shoulder arthroscopy. This allowed the surgeons to receive same-day feedback with comparison of arthroscopic images and ultrasound images. Results: One hundred and fifty-nine shoulders were scanned by the surgeons in the study. In the initial training period, surgeons who performed >100 scans demonstrated a sensitivity of 94% and a specificity of 88% (a positive predictive value of 79% and a negative predictive value of 97%) for the identification of a full-thickness tear and agreed with intraoperative sizing of the defect in 84% of the scans. In the later training period, the predictive values showed a sensitivity of 90% and a specificity of 97% (a positive predictive value of 95% and a negative predictive value of 94%) for the identification of a full-thickness tear and agreement with intraoperative sizing for 95% of the scans. Conclusions: The predictive values obtained in this study for the evaluation of rotator cuff integrity were comparable with published results from experienced radiologists. This study demonstrates the capacity of our proposed learning protocol to train surgeons without previous ultrasound experience to reliably evaluate rotator cuff integrity using ultrasound within fifty to 100 scans. Level of Evidence: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. COPYRIGHT © 2013 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED.


Goodfellow J.W.,Botnar Research Center | O'Connor J.J.,Botnar Research Center | Murray D.W.,Botnar Research Center
Journal of Bone and Joint Surgery - Series B | Year: 2010

National registers compare implants by their revision rates, but the validity of the method has never been assessed. The New Zealand Joint Registry publishes clinical outcomes (Oxford knee scores, OKS) alongside revision rates, allowing comparison of the two measurements. In the two types of knee replacement, unicompartmental (UKR) had a better knee score than total replacement (TKR), but the revision rate of the former was nearly three times higher than that of the latter. This was because the sensitivity of the revision rate to clinical failure was different for the two implants. For example, of knees with a very poor outcome (OKS < 20 points), only about 12% of TKRs were revised compared with about 63% of UKRs with similar scores. Revision therefore is not an objective measurement and should not be used to compare these two types of implant. Furthermore, revision is much less sensitive than the OKS to clinical failure in both types and therefore exaggerates the success of knee replacements, particularly of TKR. ©2010 British Editorial Society of Bone and Joint Surgery.

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