Engaging patients and families to transform heart failure care.

For patients with advanced heart failure involvement as a member of the healthcare team is critical to safe, high-quality and goal-directed care. While recognized as an important aspect of care, patient engagement is not yet a standard practice. This presents an opportunity for professional education and development in team-based care. This short report describes the development of a Community and Patient Advisory Team (CPAT) formed to support patient involvement in interprofessional collaborative practice. The CPAT, composed of patient and family advisors, researchers, care team members, and grant operations staff, served as a core team within the structure of a project to shape a new vision of care delivery. This was accomplished through participation in quarterly leadership workshops and facilitation of team training focused on patient-provider communication strategies to improve patient safety. The advisory team led the co-development of patient materials to support patient engagement during the new implementation of structured interprofessional bedside rounds. Involving community members as partners helped shape our work to more effectively and directly address gaps in current patient care.

Autophagy as a new therapeutic target in Duchenne muscular dystrophy.

A resolutive therapy for Duchene muscular dystrophy, a severe degenerative disease of the skeletal muscle, is still lacking. Because autophagy has been shown to be crucial in clearing dysfunctional organelles and in preventing tissue damage, we investigated its pathogenic role and its suitability as a target for new therapeutic interventions in Duchenne muscular dystrophy (DMD). Here we demonstrate that autophagy is severely impaired in muscles from patients affected by DMD and mdx mice, a model of the disease, with accumulation of damaged organelles. The defect in autophagy was accompanied by persistent activation via phosphorylation of Akt, mammalian target of rapamycin (mTOR) and of the autophagy-inhibiting pathways dependent on them, including the translation-initiation factor 4E-binding protein 1 and the ribosomal protein S6, and downregulation of the autophagy-inducing genes LC3, Atg12, Gabarapl1 and Bnip3. The defective autophagy was rescued in mdx mice by long-term exposure to a low-protein diet. The treatment led to normalisation of Akt and mTOR signalling; it also reduced significantly muscle inflammation, fibrosis and myofibre damage, leading to recovery of muscle function. This study highlights novel pathogenic aspects of DMD and suggests autophagy as a new effective therapeutic target. The treatment we propose can be safely applied and immediately tested for efficacy in humans.

Nitric oxide inhibition of Drp1-mediated mitochondrial fission is critical for myogenic differentiation.

During myogenic differentiation the short mitochondria of myoblasts change into the extensively elongated network observed in myotubes. The functional relevance and the molecular mechanisms driving the formation of this mitochondrial network are unknown. We now show that mitochondrial elongation is required for myogenesis to occur and that this event depends on the cellular generation of nitric oxide (NO). Inhibition of NO synthesis in myogenic precursor cells leads to inhibition of mitochondrial elongation and of myogenic differentiation. This is due to the enhanced activity, translocation and docking of the pro-fission GTPase dynamin-related protein-1 (Drp1) to mitochondria, leading also to a latent mitochondrial dysfunction that increased sensitivity to apoptotic stimuli. These effects of NO inhibition were not observed in myogenic precursor cells containing a dominant-negative form of Drp1. Both NO-dependent repression of Drp1 action and maintenance of mitochondrial integrity and function were mediated through the soluble guanylate cyclase. These data uncover a novel level of regulation of differentiation linking mitochondrial morphology and function to myogenic differentiation.