Calpain 3 is important for muscle regeneration: Evidence from patients with limb girdle muscular dystrophies

<p>Abstract</p> <p>Background</p> <p>Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration.</p> <p>Methods</p> <p>We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers.</p> <p>Results</p> <p>We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the <it>CAPN3 </it>gene.</p> <p>Conclusions</p> <p>Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.</p

The GTN patch: a simple and effective new approach to cardioprotection?

This is a post-peer-review, pre-copyedit version of an article published in Basic Research in Cardiology . The final authenticated version is available online at: https://doi.org/10.1007/s00395-018-0681-2There remains a significant un-met need to reduce the extent of myocardial injury caused by ischaemia and reperfusion injury in patients experiencing an ST-elevation MI. Although nitric oxide is central to many cardioprotective strategies currently undergoing investigation, cardioprotection from the delivery of nitrates/nitrites has been inconsistently observed. The route of administration appears to be a critical variable. The glyceryl trinitrate (GTN) patch is commonly used as a simple and practical means of delivering nitric oxide to patients with ischaemic heart disease, but whether acute cardioprotection can be achieved by application of a GTN patch has not been investigated before. Here, we use a mouse model to demonstrate that a GTN patch is highly cardioprotective when applied immediately prior to 40 min occlusion of the left anterior coronary artery followed by 2 h reperfusion, reducing infarct size from 54 ± 4% in control mice, to 28 ± 4% (P < 0.001, N = 7). The degree of protection was similar to that achieved with a standard remote ischaemic preconditioning protocol. Furthermore, and of greater potential clinical relevance, a GTN patch was also protective when applied well after the initiation of ischaemia and 15 min prior to reperfusion (28 ± 4 vs 59 ± 4%; P < 0.01, N = 5). Confirmatory experiments verified the expected effect increase in plasma nitrite levels and decrease in blood pressure. The simplicity and rapidity of GTN patch application (easily applied in an ambulance or cardiac catheterization laboratory), and low cost (potentially relevant to low-income countries), make it attractive for further investigation.NIHR Biomedical Research Council (SD), British Heart Foundation PG/15/52/31598 (SD, DH) and the The Hatter Foundation

Allergic Comorbidity Is a Risk Factor for Not Attending Scheduled Outpatient Visits in Children with Asthma

Asthma is one of the most common chronic diseases in children globally. Previous studies have shown that not attending asthma primary care consultations is associated with poorer treatment adherence and increased risk of loss of asthma control on a short-term basis. Here, we investigated long-term patterns and predictors of not attending scheduled asthma outpatient visits during 5-years of follow-up in 146 children with asthma. Of the 146 children, 67 (46%) did not attend at least one scheduled appointment, amounting to a total of 122 (10.8%) missed of 1133 scheduled appointments. In a multivariate analysis adjusting for total scheduled visits in the 5-year period any allergic sensitization was a significant risk factor for not attending &ge;1 scheduled appointment (aOR = 6.6 (95% CI, 1.3&ndash;39.7), p = 0.03), which was not the case for asthma treatment step or lung function. Furthermore, atopic predisposition decreased the risk of non-attendance (aOR = 0.36 (0.13&ndash;0.92), p = 0.04). We found no association between non-attendance, treatment adherence or loss of asthma control. This study highlights that allergic comorbidity, but not degree of asthma severity, identifies a group of children with asthma who are prone to not attend scheduled outpatient appointments