YAP activation inhibits inflammatory signalling and cartilage breakdown associated with reduced primary cilia expression.

OBJECTIVE: To clarify the role of YAP in modulating cartilage inflammation and degradation and the involvement of primary cilia and associated intraflagellar transport (IFT). METHODS: Isolated primary chondrocytes were cultured on substrates of different stiffness (6-1000 kPa) or treated with YAP agonist lysophosphatidic acid (LPA) or YAP antagonist verteporfin (VP), or genetically modified by YAP siRNA, all ± IL1ß. Nitric oxide (NO) and prostaglandin E2 (PGE2) release were measured to monitor IL1ß response. YAP activity was quantified by YAP nuclear/cytoplasmic ratio and percentage of YAP-positive cells. Mechanical properties of cartilage explants were tested to confirm cartilage degradation. The involvement of primary cilia and IFT was analysed using IFT88 siRNA and ORPK cells with hypomorphic mutation of IFT88. RESULTS: Treatment with LPA, or increasing polydimethylsiloxane (PDMS) substrate stiffness, activated YAP nuclear expression and inhibited IL1ß-induced release of NO and PGE2, in isolated chondrocytes. Treatment with LPA also inhibited IL1ß-mediated inflammatory signalling in cartilage explants and prevented matrix degradation and the loss of cartilage biomechanics. YAP activation reduced expression of primary cilia, knockdown of YAP in the absence of functional cilia/IFT failed to induce an inflammatory response. CONCLUSIONS: We demonstrate that both pharmaceutical and mechanical activation of YAP blocks pro-inflammatory signalling induced by IL1ß and prevents cartilage breakdown and the loss of biomechanical functionality. This is associated with reduced expression of primary cilia revealing a potential anti-inflammatory mechanism with novel therapeutic targets for treatment of osteoarthritis (OA).

Three-vessel view debridement of the open tibial fracture: a surgical technique.

Adequate debridement of an open fracture is a key component of successful management. Despite having set debridement principles, there is no structured technique available in the literature to guide the surgeon in achieving this. We therefore present a technical note detailing the structured approach to the debridement of any open tibial fracture. Our unit has developed a novel stepwise technique termed locally as the "three-vessel view". Identifying all three primary vessels of the leg facilitates confirmation of inspection of all lower limb compartments thus minimising the risk of missed devitalised tissue or neglected areas of contamination and the potential for consequent disastrous outcomes as a result of inadequate exposure.

Evaluation and management of atypical femoral fractures: an update of current knowledge.

Atypical femoral fractures are often attributed to the use of anti-resorptive medications such as bisphosphonates (BP). Whilst they have proven effects on fragility fracture prevention, clinical and laboratory evidence is evolving linking BP-related suppression of bone remodelling to the development of atypical stress-related sub-trochanteric fractures (Shane et al. in JBMR 29:1-23, 2014; Odvina et al. in JCEM 90:1294-301, 2005; Durchschlag et al. in JBMR 21(10):1581-1590, 2006; Donnelly et al. in JBMR 27:672-678, 2012; Mashiba et al. in Bone 28(5):524-531, 2001; Dell et al. in JBMR 27(12):2544-2550, 2012; Black et al. in Lancet 348:1535-1541, 1996; Black et al. in NEJM 356:1809-1822, 2007; Black et al. in JAMA 296:2927-2938, 2006; Schwartz et al. in JBMR 25:976-82, 2010). Injuries may present asymptomatically or with prodromal thigh pain and most can be successfully managed with cephalomedullary nailing and discontinuation of BP therapy. Such injuries exhibit a prolonged time to fracture union with high rates of non-union and metal-work failure when compared to typical subtrochanteric osteoporotic femoral fractures. Despite emerging literature on AFFs, their management continues to pose a challenge to the orthopaedic and extended multi-disciplinary team. The purpose of this review includes evaluation of the current evidence supporting the management of AFFs, clinical and radiological features associated with their presentation and a review of reported surgical strategies to treat and prevent these devastating injures.

Gastric bands: what the general radiologist should know.

Obesity in the UK is increasing, it is estimated that in England 24% of men and 25% of women are obese.(1,2) In recent years bariatric surgery has become increasingly common and is effective in producing long-term weight loss.(4,5) The most popular form of bariatric surgery in Europe is laparoscopic adjustable gastric banding (LAGB).(6) Radiologists play a key role assessing the normal function of bands, adjusting their filling under fluoroscopic guidance, and in recognizing and managing complications. This review will describe the general principles of LAGB; how they are assessed, how to recognize the most common complications, an overview of the appearances of the bands used in the UK, and novel developments in their use and design.

Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis.

Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

Imaging manifestations of faecal impaction and stercoral perforation.

Stercoral perforation can be defined as perforation of the bowel due to pressure necrosis from a faecal mass. It is an uncommon but life-threatening complication of unresolved faecal impaction. In this review, we highlight the important computed tomography (CT) findings of faecal impaction and stercoral perforation of the colon and subsequent therapeutic options in the adult population.

Reducing Implant Infection in Orthopaedics (RIIiO): Results of a pilot study comparing the influence of forced air and resistive fabric warming technologies on postoperative infections following orthopaedic implant surgery.

BACKGROUND: Active warming during surgery prevents perioperative hypothermia but the effectiveness and postoperative infection rates may differ between warming technologies. AIM: To establish the recruitment and data management strategies needed for a full trial comparing postoperative infection rates associated with forced air warming (FAW) versus resistive fabric warming (RFW) in patients aged >65 years undergoing hemiarthroplasty following fractured neck of femur. METHODS: Participants were randomized 1:1 in permuted blocks to FAW or RFW. Hypothermia was defined as a temperature of <36°C at the end of surgery. Primary outcomes were the number of participants recruited and the number with definitive deep surgical site infections. FINDINGS: A total of 515 participants were randomized at six sites over a period of 18 months. Follow-up was completed for 70.1%. Thirty-seven participants were hypothermic (7.5% in the FAW group; 9.7% in the RFW group). The mean temperatures before anaesthesia and at the end of surgery were similar. For the primary clinical outcome, there were four deep surgical site infections in the FAW group and three in the RFW group. All participants who developed a postoperative infection had antibiotic prophylaxis, a cemented prosthesis, and were operated under laminar airflow; none was hypothermic. There were no serious adverse events related to warming. CONCLUSION: Surgical site infections were identified in both groups. Progression from the pilot to the full trial is possible but will need to take account of the high attrition rate.

Mid- to long-term results of revision total knee replacement using press-fit intramedullary stems with cemented femoral and tibial components.

This was a retrospective analysis of the medium- to long-term results of 46 TC3 Sigma revision total knee replacements using long uncemented stems in press-fit mode. Clinical and radiological analysis took place pre-operatively, at two years post-operatively, and at a mean follow-up of 8.5 years (4 to 12). The mean pre-operative International Knee Society (IKS) clinical score was 42 points (0 to 74), improving to 83.7 (52 to 100) by the final follow-up. The mean IKS score for function improved from 34.3 points (0 to 80) to 64.2 (15 to 100) at the final follow-up. At the final follow-up 30 knees (65.2%) had an excellent result, seven (15.2%) a good result, one (2.2%) a medium and eight (17.4%) a poor result. There were two failures, one with anteroposterior instability and one with aseptic loosening. The TC3 revision knee system, when used with press-fit for long intramedullary stems and cemented femoral and tibial components, in both septic and aseptic revisions, results in a satisfactory clinical and radiological outcome, and has a good medium- to long-term survival rate.

Medial unicompartmental knee replacement in the under-50s.

We retrospectively reviewed 35 cemented unicompartmental knee replacements performed for medial unicompartmental osteoarthritis of the knee in 31 patients

The importance of coded radiographic labelling in clinical practice.

Locating a particular radiograph from a radiographic envelope can be a frustrating and time-consuming process. The aim of this study was to evaluate the role of colour and number coding of radiographs in reducing time taken to locate films and thereby improve efficiency. The time taken by clinicians to retrieve films from a radiographic envelope was measured. The radiographs were coded by number, number and colour or not at all. Results show a statistically significant reduction in time taken to find number coded versus non-coded radiographs. A further benefit was gained by using colour coding in conjunction with number coding. We recommend the use of colour and number coding of radiographs in clinical practice.