The effect of calorie restriction on mouse skeletal muscle is sex, strain and time-dependent

Loss of skeletal muscle mass and function occurs with increasing age. Calorie restriction (CR) increases the lifespan of C57Bl/6 mice, but not in the shorter-lived DBA/2 strain. There is some evidence that calorie restriction reduces or delays many of the age-related defects that occur in rodent skeletal muscle. We therefore investigated the effect of short (2.5 month) and longer term (8.5 and 18.5 months) CR on skeletal muscle in male and female C57Bl/6 and DBA/2 mice. We found that short-term CR increased the satellite cell number and collagen VI content of muscle, but resulted in a delayed regenerative response to injury.Consistent with this, the in vitro proliferation of satellite cells derived from these muscles was reduced by CR. The percentage of stromal cells, macrophages, hematopoietic stem cells and fibroadipogenic cells in the mononucleated cell population derived from skeletal muscle was reduced by CR at various stages. But overall, these changes are neither consistent over time, nor between strain and sex. The fact that changes induced by CR do not persist with time and the dissimilarities between the two mouse strains, combined with sex differences, urge caution in applying CR to improve skeletal muscle function across the lifespan in humans

A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs

Familial subvalvular aortic stenosis (SAS) is one of the most common congenital heart defects in dogs and is an inherited defect of Newfoundlands, golden retrievers and human children. Although SAS is known to be inherited, specific genes involved in Newfoundlands with SAS have not been defined. We hypothesized that SAS in Newfoundlands is inherited in an autosomal dominant pattern and caused by a single genetic variant. We studied 93 prospectively recruited Newfoundland dogs, and 180 control dogs of 30 breeds. By providing cardiac screening evaluations for Newfoundlands we conducted a pedigree evaluation, genome-wide association study and RNA sequence analysis to identify a proposed pattern of inheritance and genetic loci associated with the development of SAS. We identified a three-nucleotide exonic insertion in phosphatidylinositol-binding clathrin assembly protein (PICALM) that is associated with the development of SAS in Newfoundlands. Pedigree evaluation best supported an autosomal dominant pattern of inheritance and provided evidence that equivocally affected individuals may pass on SAS in their progeny. Immunohistochemistry demonstrated the presence of PICALM in the canine myocardium and area of the subvalvular ridge. Additionally, small molecule inhibition of clathrin-mediated endocytosis resulted in developmental abnormalities within the outflow tract (OFT) of Xenopus laevis embryos. The ability to test for presence of this PICALM insertion may impact dog-breeding decisions and facilitate reduction of SAS disease prevalence in Newfoundland dogs. Understanding the role of PICALM in OFT development may aid in future molecular and genetic investigations into other congenital heart defects of various species

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Evolución de las lesiones deportivas y correlación con el estilo de afrontamiento

El proceso de rehabilitación y recuperación tras una lesión deportiva es complicado y supone muchos cambios a los que las personas deben adaptarse. Los recursos de afrontamiento que emplean las personas pueden favorecer o, si no son los adecuados, pueden provocar una recuperación más lenta y aumentar la probabilidad de sufrir otra lesión. Actualmente la medicina centra sus esfuerzos en la rehabilitación a nivel física pero en este estudio se ha comprobado que la sintomatología psicopatológica está relacionada con las estrategias de afrontamiento que los deportistas utilizan y la manera como perciben la evolución de su lesión. Se ha estudiado una muestra de pacientes del Institut Català de Traumatologia i Medicina de l’Esport (ICATME), en el Hospital Universitario Dexeus, que practican deporte de manera regular y de competición. Se han encontrado resultados que nos dan información relevante sobre el tipo de respuestas que tienen los deportistas ante la lesión y cómo afecta a la evolución. En primer lugar, el control emocional resulta de gran importancia desde los primeros días después de sufrir la lesión, ya que conlleva sintomatología depresiva, ansiosa, de hostilidad e ideación paranoide, así como somatización. Impide la aceptación y crecimiento personal e influye en la toma de decisiones y la motivación. La negación de la lesión también está implicada en estas respuestas y por ello es importante ofrecer al paciente información de calidad sobre su lesión.El apoyo social es uno de los grandes pilares en la recuperación, ya que evita la sensibilidad interpersonal y la ansiedad fóbica, aspectos que conllevan un sentimiento de inferioridad ante los otros deportistas y miedos irracionales que retrasan la recuperación de la lesión. Con todo esto, se recomienda la investigación en este campo para crear programas de ayuda psciológica a deportistas que han sufrido una lesión

Irradiation dependent inflammatory response may enhance satellite cell engraftment

Skeletal muscle stem (satellite) cells transplanted into host mouse muscles contribute to muscle regeneration. Irradiation of host muscle enhances donor stem cell engraftment by promoting the proliferation of transplanted donor cells. We hypothesised that, similar to other systems, cells damaged by radiation might be effecting this donor cell proliferation. But we found no difference in the percentage of dying (TUNEL+) cells in immunodeficient dystrophic mouse muscles at the times after the irradiation dose that enhances donor cell engraftment. Similarly, irradiation did not significantly increase the number of TUNEL+ cells in non-dystrophic immunodeficient mouse muscles and it only slightly enhanced donor satellite cell engraftment in this mouse strain, suggesting either that the effector cells are present in greater numbers within dystrophic muscle, or that an innate immune response is required for effective donor cell engraftment. Donor cell engraftment within non-irradiated dystrophic host mouse muscles was not enhanced if they were transplanted with either satellite cells, or myofibres, derived from irradiated dystrophic mouse muscle. But a mixture of cells from irradiated muscle transplanted with donor satellite cells promoted donor cell engraftment in a few instances, suggesting that a rare, yet to be identified, cell type within irradiated dystrophic muscle enhances the donor stem cell-mediated regeneration. The mechanism by which cells within irradiated host muscle promote donor cell engraftment remains elusive

Restoration of Functional Full-Length Dystrophin After Intramuscular Transplantation of Foamy Virus-Transduced Myoblasts

Stem cell therapy is a promising strategy to treat muscle diseases such as Duchenne muscular dystrophy (DMD). To avoid immune-rejection of donor cells or donor-derived muscle, autologous cells which have been genetically modified to express dystrophin are preferable to cells derived from healthy donors. Restoration of full-length dystrophin using viral vectors is extremely challenging, due to the limited packaging capacity of the vectors, but we have recently shown that either a foamy viral or lentiviral vector is able to package full-length dystrophin open- reading-frame and transduce myoblasts derived from a DMD patient. Differentiated myotubes derived from these transduced cells produced full-length dystrophin. Here, we transplanted the foamy viral-dystrophin corrected DMD myoblasts intramuscularly into mdx nude mice, and showed that the transduced cells contributed to muscle regeneration, expressing full-length dystrophin in nearly all the muscle fibres of donor origin. Further, we showed that the restored full-length dystrophin recruited members of the dystrophin- associated protein complex and nNOS within donor-derived muscle fibres, evidence that the restored dystrophin protein is functional. Dystrophin-expressing donor-derived muscle fibres expressed lower levels of utrophin than host muscle fibres, providing additional evidence of functional improvement of donor-derived myofibres. This is the first in vivo evidence that foamy virus vector transduced DMD myoblasts can contribute to muscle regeneration and mediate functional dystrophin restoration following their intra-muscular transplantation, representing a promising therapeutic strategy for individual small muscles in DMD

The offline lead thickness measurement system for the ATLAS Electromagnetic Barrel Calorimeter

We describe the apparatus that will be used to measure the thickness of the lead plates that are to be used for the production of the absorbers of the ATLAS Electromagnetic Barrel Calorimeter. Its performance is analysed, and the coherence between these measurements and the X-ray measurements obtained at the factory is studied, using the data that has been taken in view of the construction of Module 0. The results of the measurements that have been done in view of the construction of Module 0 are shown