Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis.

Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.

A Systematic Review of the Role of Vitamin D on Neuromuscular Remodelling Following Exercise and Injury.

UNLABELLED: Vitamin D is important for skeletal muscle health and deficiency is associated with clinical neuromuscular symptoms of poor strength and gait. Supplementation can independently increase muscle strength in chronically deficient populations. However, the regulatory role of vitamin D on neuromuscular remodelling and adaptation subsequent to exercise conditioning or injury has not been systematically reviewed. OBJECTIVE: to systematically review the available evidence of the role of vitamin D on neuromuscular remodelling following exercise conditioning, exercise- or experimentally induced injury. We searched Medline (OVID platform), PubMed, Embase and Web of Science for randomised controlled trials (RCTs) including measures of neuromuscular function, injury and/or inflammation; a physiologically stressful intervention involving exercise conditioning, exercise- or experimentally induced injury and; vitamin D supplementation. Nine RCTs met the inclusion criteria. Significant heterogeneity of methodological approaches and outcomes meant that meta-analysis of data was limited. Qualitative findings indicated that vitamin D may be an effective accelerant of neuromuscular remodelling in animal models (24-140 % improved recovery vs. control); the effects in humans are inconclusive and likely influenced by baseline vitamin D and supplementation strategy. Results of the meta-analyses indicated no effect of vitamin D supplementation on muscle strength adaptation following resistance training [standardised mean difference (SMD): 0.74, P = 0.42] or muscle damage (SMD: -0.03, P = 0.92), although inflammatory markers were elevated in the latter (SMD: 0.56, P = 0.04). Data from animal models offer promising and plausible mechanisms for vitamin D as an agent for neuromuscular adaptation. Further high-quality research is needed to offer clearer insight into the influential role of vitamin D in human populations.

Periarticular infiltration in total hip replacement: effect on heterotopic ossification, analgesic requirements and outcome.

BACKGROUND: Up to 80% of patients develop heterotopic ossification (HO) following total hip replacement (THR) and high grades may adversely affect outcome. This study investigated the influence of local infiltration of a NSAID (Ketorolac) and local anaesthetic on the incidence and grade of HO following THR, the effect on post-operative opiate analgesic requirement and on patient reported outcome score. METHODS: A retrospective study was performed on 118 THRs performed without periarticular infiltration from 2003 to 2005, and on 211 performed with infiltration from 2005 to 2008. Pre-operative and 12-month radiographs were examined and HO graded according to the Brooker classification. Peri-operative analgesic requirements and NSAID use were noted and outcome was measured at 1 year with the Oxford Hip Score. RESULTS: Univariate and multivariate analysis indicated that single-dose periarticular NSAID infiltration did not reduce the incidence or grade of HO. Preoperative HO (p = 0.005) and enthesopathy (p = 0.027) were significant predictors of post-operative HO. The use of post-operative oral NSAID (except aspirin) significantly reduced HO (p = 0.001). Periarticular infiltration significantly reduced opiate analgesia use in the first 24 h (p < 0.001) and length of inpatient stay (p < 0.001). There was no difference in Oxford Hip Score at 1 year. CONCLUSION: Preoperative enthesopathies are a risk factor for postoperative HO. Periarticular infiltration of NSAID and local anaesthetic does not reduce HO incidence or grade in THR, but does reduce perioperative opiate requirements and length of hospital stay.

Subcapital fracture of the femoral neck in medically unwell patients: technique for fixation using direct infiltration local anaesthetic rather than regional blockade.

INTRODUCTION: Patients presenting with fracture of the femoral neck are usually elderly, and often have extensive co-morbidity. Patients who are considered able to survive an operation under general or regional anaesthesia usually undergo surgical stabilisation of the fracture or hemiarthroplasty of the hip for pain relief, to facilitate mobilisation and minimise the risk of developing the sequelae of bed rest. Patients who are considered too unwell for surgery are often treated non-operatively. These patients have a high morbidity and mortality and present significant nursing difficulties. STUDY: We describe a technique for fixation of subcapital fracture of the femoral neck under local anaesthesia direct infiltration only which is suitable for the medically unwell patient who may otherwise be treated non-operatively. A case series of patients on whom it was performed is presented. RESULTS: None of the patients required a supplementary anaesthetic technique, all survived to discharge from hospital. CONCLUSION: We recommend all patients with a subcapital fracture of the femoral neck are offered surgery to optimise their chance of survival and avoid the morbidity associated with bed rest.