Direct electrical stimulation promotes growth and enhances survival of aneurogenic muscles of the chick embryo

Analyses of embryonic aneurogenic muscles indicate that several processes associated with early myogenesis in vivo proceed in the absence of peripheral nerves. However, aneurogenic muscles demonstrate impaired growth and limited survival. To investigate whether neurally mediated activity is responsible for these phenomena, aneurogenic muscles of the chick embryo were directly stimulated in vivo via implanted electrodes. Volumetric analyses of stimulated aneurogenic brachial (latissimus dorsi) muscles from Stage (St) 33 (7.5 to 8 days) through St 37 (11 days) demonstrated that growth was enhanced significantly beyond the level characteristic of unstimulated aneurogenic muscles. Moreover, for the majority of embryos, the stimulation regimen actually rescued the posterior latissimus dorsi muscle which characteristically does not survive beyond St 32 (7.5 days) in the aneurogenic state. Thus, our results implicate activity per se as an important factor necessary for the proper growth and survival of brachial muscles during early embryogenesis. The stimulation regimen, however, did not alter myosin ATPase profiles.     

Pathogenic Mitochondrial tRNA Point Mutations: Nine Novel Mutations Affirm Their Importance as a Cause of Mitochondrial Disease

Mutations in the mitochondrial genome, and in particular the mt‐tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counseling for patients and their families. The use of weighted criteria based on functional studies—outlined in a validated pathogenicity scoring system—is therefore invaluable in determining whether novel or rare mt‐tRNA variants are pathogenic. Here, we describe the identification of nine novel mt‐tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes, isolated progressive external ophthalmoplegia, epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT‐TI; m.5541C>T, MT‐TW; m.5690A>G, MT‐TN; m.7451A>T, MT‐TS1; m.7554G>A, MT‐TD; m.8304G>A, MT‐TK; m.12206C>T, MT‐TH; m.12317T>C, MT‐TL2; m.16023G>A, MT‐TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as “definitely pathogenic” mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C, and m.16023G>A), whereas the remaining three currently lack sufficient evidence and are therefore classed as ‘possibly pathogenic’ (m.4289T>C, m.7554G>A, and m.8304G>A).     

Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain

The actions of IGF-I and IGF-II are thought to be largely due to their activation of the IGF-I receptor. However, IGF-II can also bind with high affinity to, and effectively activate, an isoform of the insulin receptor (IR-A) that lacks a sequence at the carboxyl-terminal end of the extracellular alpha subunit due to the alternative splicing of exon 11. This isoform is poorly activated by IGF-I. Here, we show that IGF-II, but not IGF-I, induces potent autophosphorylation of residues Y1158, Y1162, and Y1163 in the activation loop of the kinase domain and tyrosine 960 in the juxtamembrane region of both IR-A and IR-B (exon 11+) isoforms. We have also found, by using IGF chimeras, that the C domain of IGF-II completely accounts for the ability of IGF-II to stimulate IR autophosphorylation compared with IGF-I. We further show that the C domains are responsible for the differential abilities of IGF-II and IGF-I to activate phosphorylation of insulin receptor substrate-1 and Akt, as well as their ability to induce migration and cell survival via the IR-A. Finally, we show for the first time that IGF signaling through the IR-A can protect cells from butyrate-induced apoptosis. In summary, our studies define the structural determinants that allow potent IGF-II signaling and regulation of cellular functions through the IR-A and provide novel insights into IGF signaling via the IR.     

Healthcare Access and Health Beliefs of the Indigenous Peoples in Remote Amazonian Peru

Little is published about the health issues of traditional communities in the remote Peruvian Amazon. This study assessed healthcare access, health perceptions, and beliefs of the indigenous population along the Ampiyacu and Yaguasyacu rivers in north-eastern Peru. One hundred and seventy-nine adult inhabitants of 10 remote settlements attending health clinics were interviewed during a medical services trip in April 2012. Demographics, health status, access to healthcare, health education, sanitation, alcohol use, and smoke exposure were recorded. Our findings indicate that poverty, household overcrowding, and poor sanitation remain commonplace in this group. Furthermore, there are poor levels of health education and on-going barriers to accessing healthcare. Healthcare access and health education remain poor in the remote Peruvian Amazon. This combined with poverty and its sequelae render this population vulnerable to disease.     

Thrombopoiesis‐stimulating agents and myelodysplastic syndromes

Thrombocytopenia in patients with myelodysplastic syndromes (MDS) is a frequent cause of haemorrhage‐related morbidity and mortality, and is associated with increased risk of leukaemic transformation and reduced overall survival. In addition, thrombocytopenia in MDS limits the tolerability and therapeutic efficacy of disease‐modifying therapies, such as azacitidine or lenalidomide. The recombinant human erythropoietin (rHuEPO) erythropoiesis‐stimulating agents, epoetin and darbepoetin, are an established component of anaemia management in lower‐risk MDS. Their success has, in turn, driven the development of haematopoietic growth factors targeting thrombocytopenia. While recombinant thrombopoietin (THPO) proved too immunogenic for clinical use, novel thrombopoiesis‐stimulating agents (TSAs) have the potential to reduce bleeding events, decrease dependency on platelet transfusions and extend exposure to disease‐modifying therapies. Two TSAs, eltrombopag and romiplostim, have demonstrated benefit in chronic immune thrombocytopenia purpura (ITP) and safety and efficacy data for use of these agents in MDS is growing. However, important safety concerns remain, such as the potential for stimulation of neoplastic myeloid clones by THPO agonists. In this narrative review, we discuss the rationale and biological mechanism for TSAs in MDS, describe the agents currently available and their mechanism of action, and present current clinical data relating to TSA safety and efficacy in the context of MDS.