Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy.

International audienceAs a strategy to treat Duchenne muscular dystrophy, we used arginine butyrate, which combines two pharmacological activities: nitric oxide pathway activation, and histone deacetylase inhibition. Continuous intraperitoneal administration to dystrophin-deficient mdx mice resulted in a near 2-fold increase in utrophin (protein homologous to dystrophin) in skeletal muscle, heart, and brain, accompanied by an improvement of the dystrophic phenotype in both adult and newborn mice (45 and 70% decrease in creatine kinase level, respectively; 14% increase in tidal volume, 30% decrease in necrotic area in limb and 23% increase in isometric force). Intermittent administration, as performed in clinical trials, was then used to reduce the frequency of injections and to improve safety. This also enhanced utrophin level around 2-fold (EC50=284 mg/ml) and alleviated the dystrophic phenotype (inverted grid and grip test performance near to wild-type values, creatine kinase level decreased by 50%). Skin biopsies were used to monitor treatment efficacy, instead of invasive muscle biopsies, and this could be done a few days after the start of treatment. A 2-fold increase in utrophin expression was also shown in cultured human myotubes. In vivo and in vitro experiments demonstrated that the drug combination acts synergistically. Together, these data constitute a proof of principle of the beneficial effects of arginine butyrate on muscular dystrophy

Scaling up quality-assured psychotherapy : The role of therapist competence on perinatal depression and anxiety outcomes

Objectives: To examine: (1) the psychometric properties of two therapist competence measures-multiple choice questionnaire (MCQ) and standardized role-plays; (2) whether therapist competence differed between non-specialist (NSPs) and specialist (SPs) providers; and (3) the relations between therapist competence and pa-tient outcomes among perinatal patients receiving brief psychotherapy.Methods: This study is embedded within the SUMMIT Trial-a large, ongoing psychotherapy trial for perinatal women with depressive and anxiety symptoms. We assessed the: (1) psychometric properties of therapist competence measures using Cronbach's alpha and inter-class correlation; (2) differences in therapist competence scores between n = 23 NSPs and n = 22 SPs using a two-sample t-test; and (3) relations between therapist competence measures and perinatal patient outcomes through a linear regression model.Results: Internal consistency for role-play was acceptable (alpha = 0.71), whereas MCQ was excellent (alpha = 0.97). Role-play showed good inter-rater reliability (ICC = 0.80) and scores were higher for SPs compared with NSPs (t (2,38) =-2.86, p = 0.0069) and associated with outcomes of anxiety (B = 1.52, SE = 0.60, p = 0.01) and depressive (B = 0.96, SE = 0.55, p = 0.08) symptom scores.Conclusions: Our study highlights the importance of demonstrating psychological treatment skills through standardized role-plays over knowledge-based competence to predict perinatal patient outcomes. Using well-defined evidence-based tools is critical for deploying NSPs to provide high-quality psychotherapy and increase accessibility to psychological treatments for perinatal populations worldwide.Peer reviewe

Mice Lacking Dystrophin or α Sarcoglycan Spontaneously Develop Embryonal Rhabdomyosarcoma with Cancer-Associated p53 Mutations and Alternatively Spliced or Mutant Mdm2 Transcripts

Altered expression of proteins in the dystrophin-associated glycoprotein complex results in muscular dystrophy and has more recently been implicated in a number of forms of cancer. Here we show that loss of either of two members of this complex, dystrophin in mdx mice or α sarcoglycan in Sgca−/− mice, results in the spontaneous development of muscle-derived embryonal rhabdomyosarcoma (RMS) after 1 year of age. Many mdx and Sgca−/− tumors showed increased expression of insulin-like growth factor 2, retinoblastoma protein, and phosphorylated Akt and decreased expression of phosphatase and tensin homolog gene, much as is found in a human RMS. Further, all mdx and Sgca−/− RMS analyzed had increased expression of p53 and murine double minute (mdm)2 protein and contained missense p53 mutations previously identified in human cancers. The mdx RMS also contained missense mutations in Mdm2 or alternatively spliced Mdm2 transcripts that lacked an exon encoding a portion of the p53-binding domain. No Pax3:Fkhr or Pax7:Fkhr translocation mRNA products were evident in any tumor. Expression of natively glycosylated α dystroglycan and α sarcoglycan was reduced in mdx RMS, whereas dystrophin expression was absent in almost all human RMS, both for embryonal and alveolar RMS subtypes. These studies show that absence of members of the dystrophin-associated glycoprotein complex constitutes a permissive environment for spontaneous development of embryonal RMS associated with mutation of p53 and mutation or altered splicing of Mdm2