Nuffield Orthopaedic Centre

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.

Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4

Abstract: Hypoxia and the hypoxia-inducible factor (HIF) transcription factor regulate angiogenic-osteogenic coupling and osteoclast-mediated bone resorption. To determine how HIF might coordinate osteoclast and osteoblast function, we studied angiopoietin-like 4 (ANGPTL4), the top HIF target gene in an Illumina HumanWG-6 v3.0 48k array of normoxic vs. hypoxic osteoclasts differentiated from human CD14+ monocytes (14.3-fold induction, P<0.0004). ANGPTL4 mRNA and protein were induced by 24 h at 2% O2 in human primary osteoclasts, monocytes, and osteoblasts. ANGPTL4 protein was observed by immunofluorescence in osteoclasts and osteoblasts in vivo. Normoxic inducers of HIF (CoCl2, desferrioxamine, and l-mimosine) and 100 ng/ml ANGPTL4 stimulated osteoclastic resorption 2- to 3-fold in assays of lacunar dentine resorption, without affecting osteoclast viability. Isoform-specific HIF-1α small interfering RNA ablated hypoxic induction of ANGPTL4 and of resorption, which was rescued by addition of exogenous ANGPTL4 (P<0.001). In the osteoblastic Saos2 cell line, ANGPTL4 caused a dose-dependent increase in proliferation (P<0.01, 100 ng/ml) and, at lower doses (1–25 ng/ml), mineralization. These results demonstrate that HIF is sufficient to enhance osteoclast-mediated bone resorption and that ANGPTL4 can compensate for HIF-1α deficiency with respect to stimulation of osteoclast activity and also augments osteoblast proliferation and differentiation.—Knowles, H. J., Cleton-Jansen, A.-M., Korsching, E., and Athanasou, N.A. Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4.

The effect of local antibiotic prophylaxis when treating open limb fractures: A systematic review and meta-analysis.

Abstract: Objectives As well as debridement and irrigation, soft-tissue coverage, and osseous stabilization, systemic antibiotic prophylaxis is considered the benchmark in the management of open fractures an...

WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome

Abstract: Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2 , WNT5A , and more recently, DVL1 and DVL3 . However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered –1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3 , both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

A meta-ethnography of patients’ experience of chronic non-malignant musculoskeletal pain

Abstract: Background The alleviation of pain is a key aim of health care yet pain can often remain a puzzle as it is not always explained by a specific pathology. Musculoskeletal (MSK) pain is one of the most predominant kinds of chronic pain and its prevalence is increasing. One of the aims of qualitative research in health care is to understand the experience of illness, and make sense of the complex processes involved. However, the proliferation of qualitative studies can make it difficult to use this knowledge. There has been no attempt to systematically review and integrate the findings of qualitative research in order to increase our understanding of chronic MSK pain. A synthesis of qualitative research would help us to understand what it is like to have chronic MSK pain. Specifically, it would help us understand peoples' experience of health care with the aim of improving it. Aim The aim of this study was to increase our understanding of patients’ experience of chronic non-malignant MSK pain; utilise existing research knowledge to improve understanding and, thus, best practice in patient care; and contribute to the development of methods for qualitative research synthesis. Methods We used the methods of meta-ethnography, which aim to develop concepts that help us to understand a particular experience, by synthesising research findings. We searched six electronic bibliographic databases (including MEDLINE, EMBASE and PsycINFO) and included studies up until the final search in February 2012. We also hand-searched particular journals known to report qualitative studies and searched reference lists of all relevant qualitative studies for further potential studies. We appraised each study to decide whether or not to include it. The full texts of 321 potentially relevant studies were screened, of which 77 qualitative studies that explored adults’ experience of chronic non-malignant MSK pain were included. Twenty-eight of these studies explored the experience of fibromyalgia. Results Our findings revealed the new concept of an adversarial struggle that explains the experience of people with chronic MSK pain. This included the struggle to affirm self and construct self over time; find an explanation for pain; negotiate the health-care system while feeling compelled to stay in it; be valued and believed; and find the right balance between sick/well and hiding/showing pain. In spite of this struggle, our model showed that some people were able to move forward alongside their pain by listening to their body rather than fighting it; letting go of the old self and finding a new self; becoming part of a community and not feeling like the only one; telling others about pain and redefining relationships; realising that pain is here to stay rather than focusing on diagnosis and cure; and becoming the expert and making choices. We offer unique methodological innovations for meta-ethnography, which allowed us to develop a conceptual model that is grounded in 77 original studies. In particular, we describe a collaborative approach to interpreting the primary studies. Conclusion Our model helps us to understand the experience of people with chronic MSK pain as a constant adversarial struggle. This may distinguish it from other types of pain. This study opens up possibilities for therapies that aim to help a person to move forward alongside pain. Our findings call on us to challenge some of the cultural notions about illness, in particular the expectation of achieving a diagnosis and cure. Cultural expectations are deep-rooted and can deeply affect the experience of pain. We therefore should incorporate cultural categories into our understanding of pain. Not feeling believed can have an impact on a person’s participation in everyday life. The qualitative studies in this meta-ethnography revealed that people with chronic MSK pain still do not feel believed. This has clear implications for clinical practice. Our model suggests that central to the relationship between patient and practitioner is the recognition of the patient as a person whose life has been deeply changed by pain. Listening to a person’s narratives can help us to understand the impact of pain. Our model suggests that feeling valued is not simply an adjunct to the therapy, but central to it. Further conceptual syntheses would help us make qualitative research accessible to a wider relevant audience. Further primary qualitative research focusing on reconciling acceptance with moving forward with pain might help us to further understand the experience of pain. Our study highlights the need for research to explore educational strategies aimed at improving patients’ and clinicians’ experience of care. Funding The National Institute for Health Research Health Services and Delivery Research programme.

Evidence-Based Recommendations for Local Antimicrobial Strategies and Dead Space Management in Fracture-Related Infection.

Abstract: Fracture-related infection (FRI) remains a challenging complication that imposes a heavy burden on orthopaedic trauma patients. The surgical management eradicates the local infectious focus and if necessary facilitates bone healing. Treatment success is associated with debridement of all dead and poorly vascularized tissue. However, debridement is often associated with the formation of a dead space, which provides an ideal environment for bacteria and is a potential site for recurrent infection. Dead space management is therefore of critical importance. For this reason, the use of locally delivered antimicrobials has gained attention not only for local antimicrobial activity but also for dead space management. Local antimicrobial therapy has been widely studied in periprosthetic joint infection, without addressing the specific problems of FRI. Furthermore, the literature presents a wide array of methods and guidelines with respect to the use of local antimicrobials. The present review describes the scientific evidence related to dead space management with a focus on the currently available local antimicrobial strategies in the management of FRI. LEVEL OF EVIDENCE:: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.