Calcium Homeostasis in Myogenic Differentiation Factor 1 (MyoD)-Transformed, Virally-Transduced, Skin-Derived Equine Myotubes

Dysfunctional skeletal muscle calcium homeostasis plays a central role in the pathophysiology of several human and animal skeletal muscle disorders, in particular, genetic disorders associated with ryanodine receptor 1 (RYR1) mutations, such as malignant hyperthermia, central core disease, multiminicore disease and certain centronuclear myopathies. In addition, aberrant skeletal muscle calcium handling is believed to play a pivotal role in the highly prevalent disorder of Thoroughbred racehorses, known as Recurrent Exertional Rhabdomyolysis. Traditionally, such defects were studied in human and equine subjects by examining the contractile responses of biopsied muscle strips exposed to caffeine, a potent RYR1 agonist. However, this test is not widely available and, due to its invasive nature, is potentially less suitable for valuable animals in training or in the human paediatric setting. Furthermore, increasingly, RYR1 gene polymorphisms (of unknown pathogenicity and significance) are being identified through next generation sequencing projects. Consequently, we have investigated a less invasive test that can be used to study calcium homeostasis in cultured, skin-derived fibroblasts that are converted to the muscle lineage by viral transduction with a MyoD (myogenic differentiation 1) transgene. Similar models have been utilised to examine calcium homeostasis in human patient cells, however, to date, there has been no detailed assessment of the cells’ calcium homeostasis, and in particular, the responses to agonists and antagonists of RYR1. Here we describe experiments conducted to assess calcium handling of the cells and examine responses to treatment with dantrolene, a drug commonly used for prophylaxis of recurrent exertional rhabdomyolysis in horses and malignant hyperthermia in humans

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Local synaptic inhibition mediates cerebellar granule cell pattern separation and enables learned sensorimotor associations

The cerebellar cortex has a key role in generating predictive sensorimotor associations. To do so, the granule cell layer is thought to establish unique sensorimotor representations for learning. However, how this is achieved and how granule cell population responses contribute to behavior have remained unclear. To address these questions, we have used in vivo calcium imaging and granule cell-specific pharmacological manipulation of synaptic inhibition in awake, behaving mice. These experiments indicate that inhibition sparsens and thresholds sensory responses, limiting overlap between sensory ensembles and preventing spiking in many granule cells that receive excitatory input. Moreover, inhibition can be recruited in a stimulus-specific manner to powerfully decorrelate multisensory ensembles. Consistent with these results, granule cell inhibition is required for accurate cerebellum-dependent sensorimotor behavior. These data thus reveal key mechanisms for granule cell layer pattern separation beyond those envisioned by classical models

UK DRAFFT: A randomised controlled trial of percutaneous fixation with Kirschner wires versus volar locking-plate fixation in the treatment of adult patients with a dorsally displaced fracture of the distal radius

Background: In high-income countries, 6% of all women will have sustained a fracture of the wrist (distal radius) by the age of 80 years and 9% by the age of 90 years. Advances in orthopaedic surgery have improved the outcome for patients: many such fractures can be treated in a plaster cast alone, but others require surgical fixation to hold the bone in place while they heal. The existing evidence suggests that modern locking-plate fixation provides improved functional outcomes, but costs more than traditional wire fixation. Methods: In this multicentre trial, we randomly assigned 461 adult patients having surgery for an acute dorsally displaced fracture of the distal radius to either percutaneous Kirschner-wire fixation or locking-plate fixation. The primary outcome measure was the Patient-Rated Wrist Evaluation © (PRWE) questionnaire at 12 months after the fracture. In this surgical trial, neither the patients nor the surgeons could be blind to the intervention. We also collected information on complications and combined costs and quality-adjusted life-years (QALYs) to assess cost-effectiveness. Results: The baseline characteristics of the two groups were well balanced and over 90% of patients completed follow-up. Both groups of patients recovered wrist function by 12 months. There was no clinically relevant difference in the PRWE questionnaire score at 3 months, 6 months or 12 months [difference at 12 months: –1.3; 95% confidence interval (CI) –4.5 to 1.8; p = 0.398]. There was no difference in the number of complications in each group and small differences in QALY gains (0.008; 95% CI –0.001 to 0.018); Kirschner-wire fixation represents a cost-saving intervention (–£727; 95% CI –£588 to –£865), particularly in younger patients. Conclusions: Contrary to the existing literature, and against the increasing use of locking-plate fixation, this trial shows that there is no difference between Kirschner wires and volar locking plates for patients with dorsally displaced fractures of the distal radius. A Kirschner-wire fixation is less expensive and quicker to perform. Trial registration: Current Controlled Trials ISRCTN31379280