Progressive limb and girdle muscle atrophy leading to loss of ambulation is a hallmark of dysferlinopathies, which include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. However, animal models fail to fully reproduce the disease severity observed in humans, with dysferlin-null (Dysf) mice exhibiting minor muscle damage and weakness without dramatic ambulatory dysfunction. As we have previously reported significant Dysf expression in blood vessels, we investigated the role of vascular function in development of muscle pathology by generating a Dysf-deficient mouse model with vascular disease. This was achieved by crossing Dysf mice with ApoE mice, which have high levels of nonHDL-associated cholesterol. Double-knockout DysfApoE mice exhibited severe ambulatory dysfunction by 11 months of age. In limb-girdle muscles, histology confirmed dramatic muscle wasting, fibrofatty replacement, and myofiber damage in DysfApoE mice without affecting the ratio of centrally nucleated myofibers. Although there were no major changes in ex vivo diaphragm and soleus muscle function, histological analyses revealed these muscles to be untouched by damage and remodelling. In all, these data suggest that cholesterol may be deleterious to dysferlinopathic muscle and lead to ambulatory dysfunction. Moreover, differences in plasma lipid handling between mice and humans could be a key factor affecting dysferlinopathy severity.

Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal-regulated kinase signaling. In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo. Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.

Introduction: The burn treatment room at our tertiary-care centre is run by a multidisciplinary team, providing care to primarily burn patients who require moderate to deep sedation to undergo dressing changes in a monitored setting outside the operating room. There is little literature on the safety, efficacy, and logistics of treating outpatient pediatric burn patients in this manner. This study reviews the safety of deep sedation in the burn treatment room. Methods: A retrospective chart review of patients with burns treated in the burn treatment room from 2013 to 2015 was conducted. Patient demographics, diagnosis, procedure details, sedation, and adverse events were recorded. Data were analyzed descriptively. Results: Sevety-four patients with burns had a total of 308 visits in the burn treatment room for burn bath and/or dressing changes. Scald burns were the most common mechanism of injury (n = 56). Most burns were superficial and mid-dermal (54%), initially estimated at 5% to 10% TBSA (50%). Of the 308 visits, 304 required sedation. Adverse events were recorded in 11 (3.6%) of 304 sedated procedures. None of these events were critical: 7 patients required intravenous conversion due to inadequate oral sedation, 2 experienced brief apnea episodes but recovered spontaneously, and 2 had delayed discharge of more than 2 hours due to residual sedation. Conclusion: The burn treatment room is a safe and effective setting for treating pediatric burn patients, bypassing what might historically require operating suite inpatient management.