Targeting Nfix to fix muscular dystrophies

Muscular dystrophies (MDs) are still incurable heterogeneous diseases, characterized by muscle wasting, replacement by fibrotic tissue, and increasing weakness, which in severe cases, such as Duchenne MD, lead to premature death. MDs are due to mutations encompassing different dystrophin-glycoprotein complex (DGC) genes, which code for structural proteins that anchor the cytoskeleton to the extracellular matrix, thus conferring myofiber stability. All mutations destabilizing this complex result in different MD forms, with varying levels of severity. Independently of the genetic defect, MDs share common hallmarks, characterized by continuous cycles of muscle degeneration, due to lack of structural support during contraction, followed by regeneration cycles by satellite cells (SCs), the canonical myogenic stem cells of adult muscle. However, dystrophic SCs generate new fibres which are also prone to degeneration so that, after many cycles of degeneration/regeneration, this cell population is exhausted and muscle is replaced by connective and adipose tissue. At this stage, any therapeutic intervention is likely to fail

The transcription factor NF-Y participates to stem cell fate decision and regeneration in adult skeletal muscle

Satellite cells represent myogenic stem cells that allow the homeostasis and repair of adult skeletal muscle. Here the authors report that the transcription factor NF-Y is expressed in satellite cells and is important for their maintenance and proper myogenic differentiation

miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors

miR669a and miR669q inhibit postnatal cardiac progenitor differentiation by directly targeting the 3′UTR of MyoD

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

The origin of embryonic and fetal myoblasts: a role of Pax3 and Pax7

Skeletal muscle is a heterogeneous tissue composed of individual muscle fibers, diversified in size, shape, and contractile protein content, to fulfill the different functional needs of the vertebrate body. This heterogeneity derives from and depends at least in part on distinct classes of myogenic progenitors; i.e., embryonic and fetal myoblasts and satellite cells whose origin and lineage relationship have been elusive so far. In this issue of Genes & Development, Hutcheson and colleagues (pp. 997-1013) provide a first answer to this question

Nuclear Factor One X in development and disease

The past decade has seen incredible advances in the field of stem cell biology that have greatly improved our understanding of development and provided important insights into pathological processes. Transcription factors (TFs) play a central role in mediating stem cell proliferation, quiescence, and differentiation. One TF that contributes to these processes is Nuclear Factor One X (NFIX). Recently, NFIX activity has been shown to be essential in multiple organ systems and to have important translational impacts for human health. Here, we describe recent studies showing the contribution of NFIX to muscle development and muscular dystrophies, hematopoiesis, cancer, and neural stem cell biology, highlighting the importance of this knowledge in the development of therapeutic targets

Reporter-based isolation of developmental myogenic progenitors

The formation and activity of mammalian tissues entail finely regulated processes, involving the concerted organization and interaction of multiple cell types. In recent years the prospective isolation of distinct progenitor and stem cell populations has become a powerful tool in the hands of developmental biologists and has rendered the investigation of their intrinsic properties possible. In this protocol, we describe how to purify progenitors with different lineage history and degree of differentiation from embryonic and fetal skeletal muscle by fluorescence-activated cell sorting (FACS). The approach takes advantage of a panel of murine strains expressing fluorescent reporter genes specifically in the myogenic progenitors. We provide a detailed description of the dissection procedures and of the enzymatic dissociation required to maximize the yield of mononucleated cells for subsequent FACS-based purification. The procedure takes ∼6–7 h to complete and allows for the isolation and the subsequent molecular and phenotypic characterization of developmental myogenic progenitors

Inside and outside the liver: hepatitis-associated aplastic anaemia (haaa) in three paediatric cases.

Background: Hepatitis-associated aplastic anemia (HAAA) is a variant of aplastic anemia (AA) in which pancytopenia appears two to three months after an acute hepatitis [1]. The etiology of this syndrome is still uncompletely clarified: a role of various hepatitis and non hepatitis viruses (i.e. CMV, EBV and Parvovirus B19) has been detected; genetic predisposition and immune-mediated mechanisms (including imbalance of the T cell immune system and the response to immunosuppressive therapy) are also considered to have a pivotal role. Specific aim:We report three paediatric cases with HAAA who where successfully treated with haematopoietic stem cell transplantation (HSCT) or with administration of anti-lymphocyte globulins. Case serie: (1) A formerly healthy 9 year old boy was admitted to our Unit of Paediatric Gastroenterology and Hepatology for detection of elevated transaminases and GGT at blood tests prescribed for sudden appearance of hecchymoses and petechiae at his limbs, feet and face. No trauma had occurred. In the previous two months, asthenia had been referred. Blood tests showed pancytopenia and repeated transfusions of immunoglobulines and platelets were required. CRP-DNA for Parvovirus B19 was positive both on blood and on bone marrow aspirate. Bone marrow aspirate and bone biopsy confirmed AA. Given the absence of any recovery of the medullar function within one month of follow-up, a HSCT was successfully performed thank to the HLA compatibility of one sibling. (2) A 12 year old boy was evaluated at our Unit for jaundice with acute onset. A diagnosis of Type 1 Autoimmune Hepatitis (AIH 1) was based on both serologic profile and liver biopsy. The genetic screening for thiopurine methyltransferase excluded mutations, so a treatment with azathioprine was began to withdrawal corticosteroids. Pancytopenia was detected after two weeks of therapy. The CRPDNA for Parvovirus B19, initially negative at the time of AIH 1 diagnosis, turned out to be positive on both peripheral blood Oral Communications / Digestive and Liver Disease 44 Suppl. 4 (2012) S241\u2013S257 S251 and bone marrow. Pancytopenia persisted with a worsening trend until the appearance of clinical signs (major epistaxis, ecchymoses) and repeated administrations of immunoglobulins, platelets and erythrocytes were needed. A bone biopsy evidenced AA. HSCT was finally required, and the existence of a HLA compatible twin made it feasible. (3) A 3 year old boy was admitted at our Unit for acute jaundice and detection of leucopenia, thrombocytopenia and elevated transaminases. Infusions of platelets and erythrocytes were required, given a progressive worsening of the bone marrow function. A bone biopsy evidenced AA. An immunosuppressive treatment with anti-lymphocyte globulins, cyclosporine, methylprednisolone was administered, together with G-CSF. No infective causes were detected. The bone marrow and liver function increased significantly until a final recovery, so that no bone marrow transplantation was needed. Discussion: Diagnosis of HAAA includes clinical manifestations, blood profiling, viral testing, immune functioning and bone marrow examination. Patients presenting the features of HAAA are mostly treated with HSCT from HLA matched donor. Immunosuppressive therapy has a minor efficacy, as far as it is currently demonstrated. Table Pts Clinical onset AST/ ALT (U/L) GGT (U/L) Parvovirus B19 DNA PCR on blood and bone marrow Ig adm. and blood component transfusions Anti-lymphocyte globulins and/or G-CSF Adm. Allogeneic HSCT Follow-up since diagnosis Current clinical and haemat. outcome Pt 1 Hecchymoses and petechiae at limbs, feet and face Asthenia 1284/ 2949 111 Positive Yes No Yes 1 year Good Pt 2 Jaundice major epistaxis ecchymoses at limbs 540/ 780 94 Positive Yes No Yes 5 months Good Pt 3 Jaundice 1357/ 2322 230 No Yes Yes No 10 years Good Pt: Patient, Adm.: Administration, Ig: Immunoglobulines, Transpl: Transplantation, Haemat.: Haematological, HSCT: Haematopoietic Stem Cell Transplantation. Reference(s) [1] Rauff B, Idrees M, Shah SA, Butt S, Butt AM, Ali L, Hussain A, Irshad- Ur-Rehman, Ali M. Hepatitis associated aplastic anemia: a review. Virol J. 2011 Feb 28;8: 87