Polyglutamine (polyQ) diseases, including Huntington's disease, are characterized by an expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats encoding for an uninterrupted prolonged polyQ tract. We previously identified TRMT2A as a strong modifier of polyQ-induced toxicity in an unbiased large-scale screen in Drosophila melanogaster. RNAi-mediated silencing of TRMT2A ameliorated polyQ-induced toxicity and polyQ aggregation in flies. This work aimed at identifying and validating pharmacological TRMT2A inhibitors as treatment opportunities for polyQ diseases. An in silico structure- and ligand-based lead discovery approach and computer-aided drug discovery (CADD) was used to identify TRMT2A inhibitors. Additionally, the crystal structure of one protein domain, the RNA recognition motif (RRM), was determined and Biacore experiments with the RRM were performed. The identified inhibitors were functionally validated for their potency to reduce polyQ aggregation and polyQ-induced cell death in human HEK293T cells and patient derived fibroblasts. Several candidate molecules were able to decrease cell death and ameliorate the aggregation of polyQ peptides in cultured cells comparable to the TRMT2A knockdown experiments. Among these, spermidine was identified as able to cause a decrease in the abundance of polyQ aggregates in SCA3-patient derived fibroblasts. Our work provides a first step towards a pharmacological inhibition of this enzyme and indicates TRMT2A as a viable drug target for polyQ diseases.

The inequitable distribution and centralization of resources and services in urban area persists around the world, more so in developing countries. The challenge to meet the health needs of rural population requires health policy makers, government and concerned organization to put extra efforts. Such efforts require innovative, feasible and sustainable strategies to address the social justice of people living in districts away from capital and urban cities. At Patan Academy of Health Sciences, the medial school curriculum is designed to address these issues. Together with health professionals from Patan Hospital, the main teaching hospital on which the academy evolved, have initiated strategies to bring specialist services, starting with surgical services to remote district hospitals to serve the need of rural population. This initiative is 'desirable, doable and feasible'. Further more, this can be modified for replication and promotion by other academic institutions, central hospitals and government health system. KEY WORDSDistrict hospital, public health, return on investment, rural Nepal, specialist service, surgery.

Objective: Infections in surgery are major concern of morbidity, mortality, and costs. Timely antibiotic prophylaxis (AP) before incision ensures optimum concentration of AP in blood and tissues to prevent surgical site infections (SSIs). However, proper timing of AP remains problematic as reported by various studies, though none so far from local institutions in Nepal. Aim of this cross sectional observation study was to assess and address the issues of timing of AP and need for improvements. Material & Methods:Convenient sample target of 100 cases of preoperative AP were studied from Oct 1 to Oct 30, 2010. Data were prospectively entered in predesigned "AP form" for all major elective surgeries, except obstetric cases, who received AP of intravenous Cefazoline 1 g as per existing hospital protocol. Time of AP administration in respect to incision time was analyzed.Results: There were 125 cases during study period. Majority, 81% received AP before incision, while 19% had AP after the incision. Only 1% of patients received AP within recommended period within 60 to 30 minutes before incision. Conclusion:Current practice of antibiotic prophylaxis (AP) at our institutions needs improvement as per standard guidelines of AP within 60 to 30 minutes before incision.