Institution
Nuffield Orthopaedic Centre
Healthcare•Oxford, United Kingdom•
About: Nuffield Orthopaedic Centre is a healthcare organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Arthroplasty. The organization has 2082 authors who have published 2920 publications receiving 145718 citations.
Papers published on a yearly basis
Papers
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TL;DR: High-resolution x-ray structures of the human enzyme in complexes with risedronate and zoledronate, two of the leading N-BPs in clinical use, reveal the molecular binding characteristics of an important pharmacological target and provide a route for further optimization of these important drugs.
Abstract: Osteoporosis and low bone mass are currently estimated to be a major public health risk affecting >50% of the female population over the age of 50. Because of their bone-selective pharmacokinetics, nitrogen-containing bisphosphonates (N-BPs), currently used as clinical inhibitors of bone-resorption diseases, target osteoclast farnesyl pyrophosphate synthase (FPPS) and inhibit protein prenylation. FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. To understand the molecular events involved in inhibition of FPPS by N-BPs, we used protein crystallography, enzyme kinetics, and isothermal titration calorimetry. We report here high-resolution x-ray structures of the human enzyme in complexes with risedronate and zoledronate, two of the leading N-BPs in clinical use. These agents bind to the dimethylallyl/geranyl pyrophosphate ligand pocket and induce a conformational change. The interactions of the N-BP cyclic nitrogen with Thr-201 and Lys-200 suggest that these inhibitors achieve potency by positioning their nitrogen in the proposed carbocation-binding site. Kinetic analyses reveal that inhibition is competitive with geranyl pyrophosphate and is of a slow, tight binding character, indicating that isomerization of an initial enzyme–inhibitor complex occurs with inhibitor binding. Isothermal titration calorimetry indicates that binding of N-BPs to the apoenzyme is entropy-driven, presumably through desolvation entropy effects. These experiments reveal the molecular binding characteristics of an important pharmacological target and provide a route for further optimization of these important drugs.
494 citations
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TL;DR: No clear evidence emerged that primary spinal fusion surgery was any more beneficial than intensive rehabilitation, and the potential risk and additional cost of surgery also need to be considered.
Abstract: Objectives To assess the clinical effectiveness of surgical stabilisation (spinal fusion) compared with intensive rehabilitation for patients with chronic low back pain. Design Multicentre randomised controlled trial. Setting 15 secondary care orthopaedic and rehabilitation centres across the United Kingdom. Participants 349 participants aged 18-55 with chronic low back pain of at least one year9s duration who were considered candidates for spinal fusion. Intervention Lumbar spine fusion or an intensive rehabilitation programme based on principles of cognitive behaviour therapy. Main outcome measure The primary outcomes were the Oswestry disability index and the shuttle walking test measured at baseline and two years after randomisation. The SF-36 instrument was used as a secondary outcome measure. Results 176 participants were assigned to surgery and 173 to rehabilitation. 284 (81%) provided follow-up data at 24 months. The mean Oswestry disability index changed favourably from 46.5 (SD 14.6) to 34.0 (SD 21.1) in the surgery group and from 44.8 (SD14.8) to 36.1 (SD 20.6) in the rehabilitation group. The estimated mean difference between the groups was –4.1 (95% confidence interval –8.1 to –0.1, P = 0.045) in favour of surgery. No significant differences between the treatment groups were observed in the shuttle walking test or any of the other outcome measures. Conclusions Both groups reported reductions in disability during two years of follow-up, possibly unrelated to the interventions. The statistical difference between treatment groups in one of the two primary outcome measures was marginal and only just reached the predefined minimal clinical difference, and the potential risk and additional cost of surgery also need to be considered. No clear evidence emerged that primary spinal fusion surgery was any more beneficial than intensive rehabilitation.
493 citations
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TL;DR: 6 research centers have agreed upon standards for terminology, description and use of RSA arrangement including radiographic set-up and techniques, which will form the basis of a detailed standardization protocol under supervision of ISO and the European Standards Working Group on Joint Replacement Implants.
Abstract: There is a need for standardization of radiostereometric (RSA) investigations to facilitate comparison of outcome reported from different research groups. In this document, 6 research centers have ...
492 citations
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TL;DR: Some principles which might guide the design of knee prostheses are deduced and it is shown that current designs transgress some of these principles.
Abstract: The mechanisms controlling and limiting movement and serving to transmit load between the femur and the tibia are discussed. Having accounted for the transmission of all components of force and couple across the joint and noted the load-bearing role of the menisci, some principles which might guide the design of knee prostheses are deduced. It is shown that current designs transgress some of these principles. An experimental prosthesis is then described, which incorporates analogues of the natural menisci. The possible practical application of this novel principle has been studied in cadaveric human joints and in living patients.
479 citations
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Wellcome Trust Centre for Human Genetics1, University of Oxford2, Wellcome Trust Sanger Institute3, University of Cambridge4, Nuffield Orthopaedic Centre5, University of Queensland6, University of Leicester7, Queen Mary University of London8, University of Leeds9, Peninsula College of Medicine and Dentistry10, King's College London11, University College London12, Western General Hospital13, University of Manchester14, Medical Research Council15, National Health Service16, Wellcome Trust17, National Institute for Health Research18, Churchill Hospital19
TL;DR: In this paper, the authors defined credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs, and showed the value of more detailed mapping to target sequences for functional studies.
Abstract: To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.
468 citations
Authors
Showing all 2120 results
Name | H-index | Papers | Citations |
---|---|---|---|
Douglas G. Altman | 253 | 1001 | 680344 |
George Davey Smith | 224 | 2540 | 248373 |
Cyrus Cooper | 204 | 1869 | 206782 |
James J. Collins | 151 | 669 | 89476 |
Richard J.H. Smith | 118 | 1308 | 61779 |
Andrew Carr | 111 | 842 | 54974 |
Paul Dieppe | 105 | 618 | 53529 |
Matthew A. Brown | 103 | 748 | 59727 |
David W. Murray | 97 | 699 | 43372 |
Ray Fitzpatrick | 95 | 477 | 40322 |
Derrick W. Crook | 92 | 474 | 29885 |
Richard W Morris | 91 | 519 | 35165 |
Richard J. K. Taylor | 91 | 1543 | 43893 |
Sharon J. Peacock | 90 | 494 | 33352 |
Derick T Wade | 90 | 398 | 37413 |