Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a rare hematopoietic disease characterized by a block in red cell differentiation. Most DBA cases are caused by mutations in ribosomal proteins and characterized by higher than normal activity of the tumor suppressor p53. Higher p53 activity is thought to contribute to DBA phenotypes by inducing apoptosis during red blood cell differentiation. Currently, there are few therapies available for patients with DBA. We performed a chemical screen using zebrafish ribosomal small subunit protein 29 (rps29) mutant embryos that have a p53-dependent anemia and identified calmodulin inhibitors that rescued the phenotype. Our studies demonstrated that calmodulin inhibitors attenuated p53 protein amount and activity. Treatment with calmodulin inhibitors led to decreased p53 translation and accumulation but does not affect p53 stability. A U.S. Food and Drug Administration-approved calmodulin inhibitor, trifluoperazine, rescued hematopoietic phenotypes of DBA models in vivo in zebrafish and mouse models. In addition, trifluoperazine rescued these phenotypes in human CD34+ hematopoietic stem and progenitor cells. Erythroid differentiation was also improved in CD34+ cells isolated from a patient with DBA. This work uncovers a potential avenue of therapeutic development for patients with DBA

Do people with benign joint hypermobility syndrome (BJHS) have reduced joint proprioception?:A systematic review and meta-analysis

Joint proprioceptive deficit is documented in a variety of musculoskeletal conditions including osteoarthritis, ligament and meniscal injuries, and individuals with increased joint hypermobility, such as those with Ehlers-Danlos. No systematic reviews have assessed joint proprioception in people with benign joint hypermobility syndrome (BJHS). This study addresses this to determine whether people with BJHS exhibit reduced joint proprioception, and, if so, whether this is evident in all age groups. The search strategy was conducted on 31st January 2013. The published literature was assessed using the databases: AMED, CINAHL, MEDLINE, EMBASE, PubMed and the Cochrane Library. Unpublished literature and trial registries were assessed including: OpenGrey, the WHO International Clinical Trials Registry Platform, Current Controlled Trials, the UK National Research Register Archive. All studies comparing the proprioceptive capability of people with and without BJHS were included. Study methodological quality was assessed using the CASP appraisal tool. Meta-analysis techniques were used when study homogeneity permitted. Five studies including 254 people were identified. People with BJHS demonstrated statistically significantly poorer lower limb joint position sense (JPS) (