Search

Long non-coding RNAs (lncRNAs) have emerged as an important regulatory control in biological systems. Though the field of lncRNA has been progressing rapidly, a complete understanding of the role of lncRNAs in neuroblastoma pathogenesis is still lacking. To identify the abrogated lncRNAs in primary neuroblastoma and in the metastasized as well as the relapsed form of neuroblastoma, we analyzed an RNA-seq dataset on neuroblastoma that is available online to identify the lncRNAs that could potentially be contributing to the biology of neuroblastoma. The identified lncRNAs were further scrutinized using a publicly available epigenetic dataset of neuroblastoma and a cancer database. After this cross-sectional study, we were able to identify three significant lncRNAs, CASC15 , PPP1R26-AS1 , and USP3-AS1 , which could serve as potential biomarkers in clinical studies of neuroblastoma pathogenesis., (Copyright © 2019 Prajapati, Fatma, Fatima, Khan, Sinha and Seth.)

Statins are first-line therapy drugs for cholesterol lowering. While they are highly effective at lowering cholesterol, they have propensity to induce hyperglycemia in patients. Only limited studies have been reported which studied the impact of statins on (a) whether they can worsen glucose tolerance in a high sucrose fed animal model and (b) if so, what could be the molecular mechanism. We designed studies using high sucrose fed animals to explore the above questions. The high sucrose fed animals were treated with atorvastatin and simvastatin, the two most prescribed statins. We examined the effects of statins on hyperglycemia, glucose tolerance, fatty acid accumulation and insulin signaling. We found that chronic treatment with atorvastatin made the animals hyperglycemic and glucose intolerant in comparison with diet alone. Treatment with both statins lead to fatty acid accumulation and inhibition of insulin signaling in the muscle tissue at multiple points in the pathway.

The diversity of archaeal viruses is severely undersampled compared with that of viruses infecting bacteria and eukaryotes, limiting our understanding on their evolution and environmental impacts. Here, we describe the isolation and characterization of four new viruses infecting halophilic archaea from the saline Lake Retba, located close to Dakar on the coast of Senegal. Three of the viruses, HRPV10, HRPV11 and HRPV12, have enveloped pleomorphic virions and should belong to the family Pleolipoviridae, whereas the forth virus, HFTV1, has an icosahedral capsid and a long non-contractile tail, typical of bacterial and archaeal members of the order Caudovirales. Comparative genomic and phylogenomic analyses place HRPV10, HRPV11 and HRPV12 into the genus Betapleolipovirus, whereas HFTV1 appears to be most closely related to the unclassified Halorubrum virus HRTV-4. Differently from HRTV-4, HFTV1 encodes host-derived minichromosome maintenance helicase and PCNA homologues, which are likely to orchestrate its genome replication. HFTV1, the first archaeal virus isolated on a Haloferax strain, could also infect Halorubrum sp., albeit with an eightfold lower efficiency, whereas pleolipoviruses nearly exclusively infected autochthonous Halorubrum strains. Mapping of the metagenomic sequences from this environment to the genomes of isolated haloarchaeal viruses showed that these known viruses are underrepresented in the available viromes., (© 2019 Society for Applied Microbiology and John Wiley & Sons Ltd.)

In addition to its essential functions within the cytoskeleton, actin also localizes to the cell nucleus, where it is linked to many important nuclear processes from gene expression to maintenance of genomic integrity. However, the molecular mechanisms by which actin operates in the nucleus remain poorly understood. Here, we have used two complementary mass spectrometry (MS) techniques, AP-MS and BioID, to identify binding partners for nuclear actin. Common high-confidence interactions highlight the role of actin in chromatin-remodeling complexes and identify the histone-modifying complex human Ada-Two-A-containing (hATAC) as a novel actin-containing nuclear complex. Actin binds directly to the hATAC subunit KAT14, and modulates its histone acetyl transferase activity in vitro and in cells. Transient interactions detected through BioID link actin to several steps of transcription as well as to RNA processing. Alterations in nuclear actin levels disturb alternative splicing in minigene assays, likely by affecting the transcription elongation rate. This interactome analysis thus identifies both novel direct binding partners and functional roles for nuclear actin, as well as forms a platform for further mechanistic studies on how actin operates during essential nuclear processes.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Long non-coding RNAs have emerged as an important regulatory layer in biological systems. Of the various types of lncRNAs, one class (designated as divergent RNAs/XH), which is in head-to-head overlap with the coding genes, has emerged as a critical biotype that regulates development and cellular differentiation. This work aimed to analyze previously published data on differential expression, epigenetic and network analysis in order to demonstrate the association of divergent lncRNAs, a specific biotype with the differentiation of human neural progenitor cells (hNPCs). We have analyzed various available RNAseq databases that address the neuronal and astrocytic differentiation of hNPCs and identified differentially expressed lncRNAs (DELs) during cell-fate determination. Key DELs identified from the databases were experimentally verified by us in our in-vitro hNPC differentiation system. We also analyzed the change in promoter activity using ChIP-seq datasets of the histone markers H3K4me3 (activation) and H3K27me3 (inactivation) of these DELs. Additionally, we explored the change in the euchromatinization state of DELs (by analyzing DNase-seq data) during lineage-specific differentiation of hNPCs and performed their network analysis. We were able to identify differences between neuronal and astrocytic differentiation of hNPCs at the level of divergent DELs epigenetic markers, DNAase hypersensitive sites and gene expression network. Divergent lncRNAs are more involved in neuronal rather than astrocytic differentiation, while the sense downstream lncRNA biotype appears to be more involved in astrocytic differentiation. By studying the lncRNA involvement of distinct biotypes, we have been able to indicate the preferential role of a particular biotype during lineage-specific differentiation.

Objective: Gut microbiota is currently targeted for various diseases especially metabolic disorders such as diabetes. Our strategy is to alter gut microflora via specific antibiotic to reduce load of inflammation in the liver that increases as a result of high carbohydrate diet. Th1, Th17 and Treg are important immune cell types which decide the type of inflammatory response. Liver is tolerogenic in nature with low Th17/Treg ratio. In diabetics, this ratio decreases even more, and can cause liver trauma., Method: The present study tries to find relationship between gut flora and immune cells such as Th1/Th17/Treg and their role in liver metabolism using diet induced diabetic mice model., Result: Upon alteration of flora using Cefdinir in different forms, one could help lower the level of Treg cells thus increasing the ratio. Gut flora is strongly associated with the immunity in the liver. Targeted alteration of gut flora helps us to restore insulin sensitivity., Conclusion: Colon targeted Cefdinir gives more promising results, opens colonic bacteria as target for improving gut, liver inflammation and insulin sensitivity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Actin has been linked to processes spanning the whole gene expression cascade, from regulating specific transcription factors, such as myocardin-related transcription factor, to chromatin remodeling and RNA polymerase function. However, whether actin controls the transcription of only specific genes or has a global role in gene expression has remained elusive. Our genome-wide analysis reveals, for the first time, that actin interacts with essentially all transcribed genes in Drosophila ovaries. Actin co-occupies the majority of gene promoters together with Pol II, and on highly expressed genes, these two proteins also associate with gene bodies. Mechanistically, actin is required for Pol II recruitment to gene bodies, and manipulation of nuclear transport factors for actin leads to the decreased expression of eggshell genes. Collectively, these results uncover a global role for actin in transcription and demonstrate the in vivo importance of balanced nucleocytoplasmic shuttling of actin in the transcriptional control of a developmental process., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Zika virus (ZV) infects neural stem cells (NSCs) and causes quiescence in NSCs, reducing the pool of brain cells, leading to microcephaly. Despite conscientious efforts, the molecular mechanisms for ZV-mediated effects on NSCs lack clarity. This study aimed to explore the underlying mechanisms for ZV-mediated induction of quiescence in the primary cultures of human fetal neural stem cells (fNSCs). We demonstrate that expression of ZV envelope (E) protein displays maximum quiescence in human fNSCs by accumulating cells in the G0/G1 phase of the cell cycle as compared to other non-structural proteins, viz. NS2A, NS4A and NS4B. E protein induces immature differentiation by induction of pro-neuronal genes in proliferating fNSCs, induces apoptosis in differentiating fNSCs 3 days post differentiation, and disrupts migration of cells from differentiating neurospheres. In utero electroporation of mouse brain with E protein shows drastic downregulation of proliferating cells in ventricular and subventricular zone regions. Global microRNA sequencing suggests that E protein modulates miRNA circuitry. Among differentially expressed miRNAs, we found 14 upregulated and 11 downregulated miRNAs. Mir-204-3p and mir-1273g-3p directly regulate NOTCH2 and PAX3 expression, respectively, by binding to their 3'UTR. Bioinformatic analysis using GO analysis for the targets of differentially expressed miRNAs revealed enrichment of cell cycle and developmental processes. Furthermore, WNT, CCKR, PDGF, EGF, p53, and NOTCH signaling pathways were among the top enriched pathways. Thus, our study provides evidence for the involvement of ZV E protein and novel insights into the molecular mechanism through identification of miRNA circuitry. Art work depicting the effect of Zika virus E protein on human fetal neural stem cells.

Dyslexia is a neurodevelopmental disorder that manifests as a reading disability despite normal intelligence and adequate educational opportunity. Twin and family studies have indicated a genetic component, while genome-wide studies have implicated a number of susceptibility genes, most of which have direct or indirect roles in neuronal migration. Reelin (RELN) has important biological functions facilitating migration of neurons. Polymorphisms in RELN have been implicated in related disorders like autism and schizophrenia but have not been examined in dyslexia. We hypothesized that not only RELN, but its interactors in the neuronal migration pathway may play roles in the etiology of dyslexia. Twenty two functional variants across six RELN signalling genes (RELN, VLDLR, APOER2, DAB1, LIS1 and NDEL1) and two dyslexia candidate genes (DCDC2 and ROBO1) were analyzed for association in twenty six nuclear and three extended families with individuals affected with dyslexia. Univariate association analysis was suggestive of association (p uncorrected  = 0.01) with rs362746 in RELN which however did not withstand Bonferroni corrections (p corrected  = 0.21). Multimarker tests indicated significant association (p = 0.037), based on which we tested for haplotype associations. Although there were no significant haplotypic associations, we found that a three marker unit with rs3808039 and rs2072403 flanking and independently in linkage disequilibrium with rs362746 was significantly overtransmitted (risk allelic combination - TAT) to dyslexia affected individuals in the sample (p = 0.002). Our results suggest preliminary evidence for a new potential risk variant in the RELN locus for dyslexia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background : A sugar rich diet induces inflammation and insulin resistance (IR) mainly through gut microbiota alteration. Gut dysbiosis increases lipopolysaccharide (LPS) and reduces propionate and butyrate levels to impair the insulin signalling cascades by different molecular pathways, which progresses into IR. The present study was designed to investigate the effect of spectrum specific antibiotics on the modulation of gut microbiota and its signalling pathways to prevent diet-induced diabetes. Methods : Healthy male Wistar rats were divided into a non-diabetic group with a control diet (CD), a diabetic group with a high sucrose diet (HSD) and two antibiotic fed groups (linezolid and cefdinir; administered by oral gavage) along HSD. Physiological, biochemical, inflammatory and microbiome parameters were examined. Results : Cefdinir administration in HSD rats reduced fasting glucose, serum triglyceride, and cholesterol levels compared to HSD alone. In addition, cefdinir reduced serum LPS by decreasing the population of Gram-negative phyla, that is, Bacteroidetes and Proteobacteria in the fecal content. Furthermore, cefdinir treatment decreased hepatic/ileal/colonic Tlr4 , Nlr1 , and Nf-κB at the mRNA level. Moreover, cefdinir-treated rats had shown increased fecal butyrate and propionate and reduced acetate levels compared to HSD alone. Cefdinir treatment also induced ileal/colonic Gpr43 and Glut4 at the mRNA level after 12 weeks of administration. Conclusions : Taken together, these data suggest that administration of a Gram-negative spectrum antibiotic, that is, cefdinir, has modulated the gut microbiota, and reduced serum LPS and triglycerides, which prevented the progression of IR and inflammation in HSD rats., Competing Interests: The authors who have taken part in this paper declared that they do not have any disclosures regarding funding or conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Dyslexia is a heritable neurodevelopmental disorder characterized by difficulties in reading and writing. In this study, we describe the identification of a set of 17 polymorphisms located across 1.9Mb region on chromosome 5q31.3, encompassing genes of the PCDHG cluster, TAF7, PCDH1 and ARHGAP26, dominantly inherited with dyslexia in a multi-incident family. Strikingly, the non-risk form of seven variations of the PCDHG cluster, are preponderant in the human lineage, while risk alleles are ancestral and conserved across Neanderthals to non-human primates. Four of these seven ancestral variations (c.460A>C [p.Ile154Leu], c.541G>A [p.Ala181Thr], c.2036G>C [p.Arg679Pro] and c.2059A>G [p.Lys687Glu]) result in amino acid alterations. p.Ile154Leu and p.Ala181Thr are present at EC2: EC3 interacting interface of γA3-PCDH and γA4-PCDH respectively might affect trans-homophilic interaction and hence neuronal connectivity. p.Arg679Pro and p.Lys687Glu are present within the linker region connecting trans-membrane to extracellular domain. Sequence analysis indicated the importance of p.Ile154, p.Arg679 and p.Lys687 in maintaining class specificity. Thus the observed association of PCDHG genes encoding neural adhesion proteins reinforces the hypothesis of aberrant neuronal connectivity in the pathophysiology of dyslexia. Additionally, the striking conservation of the identified variants indicates a role of PCDHG in the evolution of highly specialized cognitive skills critical to reading., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Bacteriocin TSU4 is a novel antimicrobial peptide isolated from Catla catla gut isolate Lactobacillus animalis TSU4. It has been reported for its potential antimicrobial activity against fish pathogens and food spoilage bacteria. In vivo safety evaluation is necessary to determine its immunogenicity, toxicity, and importance in real-life applications. The present study was designed to evaluate the immunogenicity, acute and sub-chronic toxicity of bacteriocin TSU4 in BALB/c mice to ensure its safety in industrial application. Male BALB/c mice were administered intraperitoneally for immunogenicity assessment, by oral gavage with 50, 100, and 200 mg/kg/body weight for acute test and 0.5 mg/kg/day dose of bacteriocin TSU4 for sub-chronic toxicity test. Neither mortality nor any infections were observed during experimental period. There was no major increase in antibody titer during the immunogenicity test, and no mortality was observed during acute or sub-chronic toxicity tests. The LD 50 value of bacteriocin TSU4 was found to be higher than 200 ± 0.45 mg/kg. No significant change in the serum biochemical markers, histopathological analysis and visual observation in spleen sizes was observed. These findings revealed that bacteriocin TSU4 is a non-immunogenic, safe, non-toxic, and could be a potential candidate for industrial applications in food preservation and aquaculture industries.

Background: This study aimed to determine whether the Neonatal Acute Physiology (SNAP) scoring system (SNAP II) and with perinatal extension (SNAP II PE) can be used to predict neonatal deaths in a resource-limited neonatal intensive care unit in Nepal., Methods: A prospective observational study was conducted in a neonatal intensive care unit (NICU) of Kanti Children's Hospital in Kathmandu, Nepal. Data required for the SNAP II and SNAP II PE scores were collected. The relationships between the SNAP II and SNAP II PE scores and neonatal mortality were analyzed., Results: There were 135 neonates admitted during the 6 month study period, of whom 126 met the inclusion criteria. Of these 126 neonates, 29 (23.0%) died. Mortality was 83% (5/6) when SNAP II was >40, and 66.7% (6/9) when SNAP II PE was >50. A SNAP II score of ≥12 had a sensitivity of 75.9%, and specificity of 73.2% for predicting mortality, and a SNAP II PE score of ≥14 had a sensitivity of 82.8% and specificity of 67.0% for it., Conclusions: SNAP II and SNAP II PE scoring of neonates can be used to predict prognosis of neonates in resource-limited NICUs in Nepal., (© The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Astroglia are indispensable component of the tripartite synapse ensheathing innumerous soma and synapses. Its proximity to neurons aids the regulation of neuronal functions, health and survival through dynamic neuroglia crosstalk. Susceptibility of astrocyte to HIV-1 infection and subsequent latency culminates in compromised neuronal health. The viral protein HIV-1 transactivator of transcription (Tat) is neurotoxic. HIV-1 Tat is detected in brain of AIDS patients even in cases where viral load is non-detectable due to successful HAART therapy. Recently, we demonstrated that HIV-1 Tat triggers excess ATP release from astrocytes that causes neuronal death by activating purinergic receptor system. Using well-characterized model system of human primary astrocytes and neurons, we probed into the molecular mechanism for enhanced ATP release in HIV-1 Tat affected astrocytes. HIV-1 Tat modulated the miRNA machinery in astrocytes and perturbed the levels of voltage dependent anion channel 1 (VDAC1), a channel present in the outer mitochondrial membrane and plasma membrane that regulates extracellular ATP release. Our studies with autopsy tissue sections also showed concordantly dysregulated VDAC1 and miR-320a levels in HIV-1 patients suffering from mild cognitive impairment (MCI). We report a novel molecular cascade of miRNA-mediated ATP release through regulation of VDAC1. Downregulation of VDAC1 either with miR-320a mimic or VDAC1 siRNA in HIV-1 Tat-affected astroglia could rescue the neurons from glia-mediated indirect death. Our findings reveal a novel upstream therapeutic target that could be employed to thwart the astroglia-mediated neurotoxicity in HIV-1 neuropathogenesis. GLIA 2017;65:250-263., (© 2016 Wiley Periodicals, Inc.)

Background Diabetic ketoacidosis is one of the life-threatening acute complications of diabetes mellitus. Despite the improvements in diabetic care, it remains a major clinical problem in clinical practice. Objective To assess the clinical and laboratory profile of adults with diabetic ketoacidosis in Dhulikhel hospital. Method This is a descriptive cross-sectional study including adult patients admitted in Dhulikhel hospital from July 2014 to July 2016 with the diagnosis of diabetic ketoacidosis according to the guidelines of American diabetes association. The hospital records of these patients were reviewed for their clinical and biochemical profiles. Result Forty eight patients fulfilled the criteria of diabetic ketoacidosis and were included in the study. Seventy three percent of patients had type 2 diabetes mellitus. Twenty three percent of the patients were cases of newly diagnosed diabetes mellitus. Polyuria and polydipsia as presenting complaint was more common in patients with type 1 diabetes mellitus (p=0.002) whereas fever was more common in type 2 diabetes mellitus patients (p=0.03). Majority of patients had normal serum sodium and potassium level. Forty two percent of the patients have high serum urea level and just over one third had high serum creatinine level. The most common precipitating factor of diabetic ketoacidosis for patients with type 1 diabetes mellitus was omission of insulin whereas in type 2 diabetic patients was infection. Conclusion Diabetic ketoacidosis is complication of both type 1 and type 2 diabetes mellitus. High degree of suspicion is needed for early detection of this life threatening condition especially in patients without history of diabetes mellitus.

The World Health Organization declared India among other 10 countries in South East Region - as 'polio-free' in 2014. Since then, the Government of India (GoI) has scaled up its initiatives against polio endgame which targets virus eradication and sequential withdrawal of type 2 virus from oral polio vaccine (OPV). However, prior to choosing the switch from trivalent OPV (t-OPV) to bivalent OPV (b-OPV), it was suggested to include inactivated poliovirus vaccine (IPV) in the national immunization schedule to protect vaccine naïve population against type 2 poliovirus. The GoI declared introduction of single dose of intramuscular IPV at 14 weeks since October 2015. In addition, anticipating the scarcity of IPV at present in India, GoI also recommended two intradermal doses of IPV in few states since April 2016. This review discusses the programmatic implications of these strategies along with recommendations by the Advisory Committee on Vaccines and Immunization Practices of Indian Academy of Pediatrics (IAP-ACVIP) on polio endgame strategy.

Background Spirometry is a standard test for screening and evaluation of patients with symptoms of cough and shortness of breath. Despite its easy availability, low cost and ease of performance it has not been widely used in clinical practice in Nepal. Objective To assess the prevalence of respiratory diseases in a regional referral centre in patients referred for spirometry. Method This is a descriptive cross-sectional study including patients referred for spirometry to the spirometry unit of Dhulikhel Hospital, Kathmandu University Hospital from 2014 July to 2015 October. The spirometry findings of the patients fulfilling the criteria of American Thoracic Society/European Respitatory Society (ATS/ERS) guidelines were analyzed and categorized as normal, having obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and bronchial asthma or restrictive lung disease. Data were analyzed using SPSS 20.0 software. Result Out of 821 patients, 755 patients (92%) fulfilled ATS/ERS criteria for satisfactory spirometry. The prevalence of COPD was 31.4%, bronchial asthma 24.2% and restrictive lung disease 8.1%. The mean age of patients diagnosed with COPD was 57.8±10.8 years; bronchial asthma 44.3±16.2 years; and restrictive lung disease 44.6±21.5 years. Both COPD and bronchial asthma were common in females. About twenty two percent of the COPD patients were non-smokers and 86.3% of these were females. The most common symptoms for referral was cough and shortness of breath: these symptoms were more likely to be associated with abnormal spirometry findings. Conclusion Spirometry is a crucial preliminary test for evaluation of patients with respiratory symptoms. It should be used more frequently to help stratify patients for appropriate treatment.

Background: Gut microbiota has a significant role in the pathogenesis of diabetes. Colonic microflora modulation using an antibiotic might have an emerging role to treat the metabolic disorders. The present study was aimed to optimize the Moxifloxacin loaded chitosan microspheres (MCMs) by emulsion cross linking method for colon targeted delivery to alter the microflora., Methods: Preliminary optimization of MCMs was carried out using Placket-Burman design (PBD) following by final optimization with Box-Behnken design (BBD). Optimized MCMs were evaluated for yield, particle size, entrapment efficiency and in vitro/ in vivo antimicrobial activities., Results: FTIR spectroscopy of MCMs confirms the absence of chemical interactions during the formulation. MCMs were found to be smooth, spherical with particle size around 20μm. An enteric coating of MCMs prevented the drug release in the acidic environment of the stomach and ileum with complete release at the colon. MCMs had followed the korsmeyer - peppas model of drug release, indicating the drug release by non-fickian diffusion pattern. MCMs showed significant in vitro antimicrobial activity against Lactobacillus casei and Escherichia coli. In vivo results of MCMs exhibited prolonged antimicrobial effect of drug in the cecal content of rats. Significant protective activity observed in the ileum and colon histology in rats treated with MCMs compared to the pure drug., Conclusion: MCMs were formulated by emulsion cross linking method using QBD approach. An enteric coating around the microspheres prevented the premature drug release at upper gastrointestinal tract, while chitosan cross linking has provided the sustain release of the drug in the colonic region over the time.

Uncontrolled inflammation leads to several diseases such as insulin resistance, T2D and several types of cancers. The functional role of microRNAs in inflammation induced insulin resistance is poorly studied. MicroRNAs are post-transcriptional regulatory molecules which mediate diverse biological processes. We here show that miR-16 expression levels are down-regulated in different inflammatory conditions such as LPS/IFNγ or palmitate treated macrophages, palmitate exposed myoblasts and insulin responsive tissues of high sucrose diet induced insulin resistant rats. Importantly, forced expression of miR-16 in macrophages impaired the production of TNF-α, IL-6 and IFN-β leading to enhanced insulin stimulated glucose uptake in co-cultured skeletal myoblasts. Further, ectopic expression of miR-16 enhanced insulin stimulated glucose uptake in skeletal myoblasts via the up-regulation of GLUT4 and MEF2A, two key players involved in insulin stimulated glucose uptake. Collectively, our data highlight the important role of miR-16 in ameliorating inflammation induced insulin resistance., (Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

The mechanisms underlying inflammation induced insulin resistance are poorly understood. Here, we report that the expression of PIMT, a transcriptional co-activator binding protein, was up-regulated in the soleus muscle of high sucrose diet (HSD) induced insulin resistant rats and TNF-α exposed cultured myoblasts. Moreover, TNF-α induced phosphorylation of PIMT at the ERK1/2 target site Ser(298). Wild type (WT) PIMT or phospho-mimic Ser298Asp mutant but not phospho-deficient Ser298Ala PIMT mutant abrogated insulin stimulated glucose uptake by L6 myotubes and neonatal rat skeletal myoblasts. Whereas, PIMT knock down relieved TNF-α inhibited insulin signaling. Mechanistic analysis revealed that PIMT differentially regulated the expression of GLUT4, MEF2A, PGC-1α and HDAC5 in cultured cells and skeletal muscle of Wistar rats. Further characterization showed that PIMT was recruited to GLUT4, MEF2A and HDAC5 promoters and overexpression of PIMT abolished the activity of WT but not MEF2A binding defective mutant GLUT4 promoter. Collectively, we conclude that PIMT mediates TNF-α induced insulin resistance at the skeletal muscle via the transcriptional modulation of GLUT4, MEF2A, PGC-1α and HDAC5 genes.

Background Chronic Obstructive Pulmonary Disease (COPD) affects about 329 million people worldwide, which is nearly 5% of the entire global population. In the context of Nepal, COPD accounts for 43% of the non-communicable disease burden and 2.56% of hospitalizations. Various pre-disposing factors like bacterial, viral, fungal, smoking, occupational exposures and genetic factors have been proposed to precipitate COPD and its exacerbation though, the definitive pre-disposing factors and factors related to acute exacerbation have not been determined in the context of Nepal. Objective To find out the pre-disposing factors and the related causative agents for COPD. Method A cross sectional study was conducted in a tertiary care hospital. Patients of all age group who were diagnosed as COPD and admitted in the hospital were included in this study. Patients were interviewed using structured questionnaire. The sociodemographic data including personal and medical history were recorded from those participants. In addition, sputum from those patients was sent for culture to investigate the possible responsible pathogens as well as its antibiotic sensitivity pattern. Result A total of 150 patients having Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) who have admitted from either emergency or out-patient department of the hospital were included in this study. Among the total number of patients, more than half of them were female (n=82). In addition, analysis of occupations shows that most of them were either farmer (36.0%) or housewife (30.7%). In total studied patients (n=150), most of them were using traditional firewood (83%) for cooking purpose and majority of patients (91%) were smokers. Most of the sputum samples show growth of gram-positive cocci (26.7%) and gram negative bacilli (27.5%). Considering the overall sensitivity pattern, the higher sensitivity was recorded for Co-trimoxazole and Ciprofloxacin while higher rate of resistance was noted for Penicillin group of drugs. The most widely used antibiotics were found to be Cephalosporin group of drugs (68%). Conclusion The present study revealed that the case of COPD is more in female and the commonest pre-disposing factor is found to be smoke/firewood. Cephalosporin group of drugs is the most commonly prescribed drug.

Sugar rich diet induces inflammation and insulin resistance mainly through gut microbiota alteration. Gut microflora dysbiosis increases plasma lipopolysaccharide and reduces short chain fatty acids to impair the insulin signaling cascades by different molecular pathways to progress into diabetes. Chitosan based formulations have major significance in insulin delivery system due to their ability to protect the insulin from enzymatic degradation and its efficient inter-epithelial transport. This study was designed to investigate the effect of chitosan administration on gut microflora mediated signaling pathways to prevent the diet induced diabetes. Male wistar rats were divided into non-diabetic group with a normal diet (CD), diabetic group with high sucrose diet (HSD) and treatment group with HSD and chitosan (60 mg/kg). After 8 weeks of the study, significant alterations in two major gut dominant microbial phyla i.e Firmicutes and Bacteroides and four dominant microbial species i.e. Lactobacilli, Bifidobacteria, Escherichia and Clostridia were observed in HSD group compared to CD. This microbial dysbiosis in dominant phyla was significantly prevented in chitosan administrated HSD group. Chitosan administration had also reduced the HSD induced activation of Toll like receptors and Nod like receptors signaling pathways compared to HSD control group to reduce the inflammation. These suggest that chitosan can prevent the progression of Type 2 Diabetes through gut microbiota alteration, reducing endotoxin and microbes mediated inflammation.

Heat shock proteins (HSPs) play a role in the homeostasis, apoptosis regulation and the maintenance of the various other physiological processes. Aging is accompanied by a decrease in the resistance to environmental stress, while mitochondria are primary targets in the process of aging, their expression decreasing with age. Mitochondrion also plays a significant role in the process of spermatogenesis. HSPs have been shown to be involved in apoptosis with some of acting as apoptotic inhibitors and are involved in cytoprotection. In this review we discuss the roles of Hsp 27, 60, 70, and 90 in aging and male infertility and have concluded that these particular HSPs can be used as a molecular markers for mitochondrially- mediated apoptosis, aging and male infertility.

Obesity and Type 2 diabetes are leading health problems which are characterized by low-grade inflammation with an increase in inflammatory cytokines along with the change in the gut microbiota population. Toll like Receptors (TLRs) and NOD like Receptors (NLRs) are very prominent pathogen recognition receptors, which play a significant role in the innate immune system. Both TLRs and NLRs pathways are mediated through different adaptor proteins; commonly found to activate the NF-kB, which induces the expression of proinflammatory cytokines. It has been suggested that TLRs and NLRs have a significant role in the pathogenesis of inflammation mediated insulin resistance, which further develops metabolic complications. TLRs mediated mechanism for insulin resistance involves activation through TLR ligands such as increased free fatty acids and lipid derivatives from adipocytes as well as the skeletal muscles. Moreover, gut microbiota alteration in the type 2 diabetes also plays a key role by increasing the plasma LPS levels, which specifically activates TLR4 and provokes the inflammation mediated insulin resistance. NOD1 and NOD2 are involved in the pathogenesis of diabetes, possibly through the recognition of the gut microbiota. Gut microbiota modulation by antibiotics plays a crucial role in increasing insulin sensitivity, possibly through the TLRs and NLRs mediated signaling responses, which suggest future therapeutic approaches for obesity, insulin resistance and type 2 diabetes. In this review, we focused on the interdependent role of TLRs and NLRs in metabolic diseases and their cross talk for the pathogenesis of inflammatory diseases.

The objective of present investigation was to study the effect of gut microbiota alteration by oral administration of targeted delivery of pH sensitive cefdinir microspheres to high-fructose-fed (HFD) rats. Rats were fed with a high-fructose diet with or without cefdinir microsphere administration for 30 days. The fecal microbiota community, oral glucose tolerance, the markers of liver injury, plasma and hepatic lipids profile, and histological evaluation were investigated. The levels of blood glucose, liver injury markers, lipid profile in plasma and liver, and fat tissue were significantly increased in high-fructose-fed rats. However, after pH-sensitive cefdinir microsphere administration, the elevation of these parameters was significantly suppressed. Cef EL significantly lowered the increased AST (p < 0.05) and ALT (p < 0.001) levels in HFD group. There is a significant lower (p < 0.01) AUCglucose level in Cef EL group than HFD group The histological changes in the liver and the small and large intestines were more profound in HFD group as compared to cefdinir-treated HFD and control groups. Feeding of cefdinir microsphere sustained lactobacilli and bifidobacteria and significantly decreased (p < 0.05) the number of Enterobacteriaceae induced by HFD. Experimental evidences demonstrated that the effectiveness of pH-specific cefdinir microsphere on reducing insulin resistance and development of metabolic changes in high-fructose-fed rats and suggested that it may be a promising therapeutic agent in treating type 2 diabetes. Intestinal-targeted antibiotic delivery needs to be further explored for its therapeutic applications.

Male wistar rats (weighting 160-180 g) were divided into six groups of six animals per group. Groups A and F served as control. Groups B, C, D, and E received acrylamide at 20 mg/kg body weight for 28 days and groups C and E received additionally vitamin E (50 IU/kg body weight) for 1 to 28 days and 29 to 42 days of experiment, respectively. The animals from groups A, B, and C were sacrificed on day 28 of experiment and from groups D, E, and F on day 42 of experiment, respectively. The FOB (Functional Observational Battery) and histopathological changes were investigated at the end of 4(th) week and 6(th) week. FOB at the end of 4(th) week, of rats given acrylamide alone, or in combination with vitamin E, revealed a significant change in CNS, neuromuscular, and autonomic domains. A marked decrease in grip strength was recorded. A significant increase in foot splay, reduction in width and angle of sequential stride was noticed. Degenerative changes, necrosis, congestion, and kupffer cell proliferation in liver while vacuolar degenerative changes in tubular epithelium, coagulative necrosis, and hemorrhages in kidney were constant findings in acrylamide intoxicated rats. Neuronal degeneration, severe gliosis, congestion were found in brain. Spinal cord revealed demyelination. Acute microscopic softening of lumbar cord, bilateral necrosis with malacia and liquefaction of white matter, and loss of myelin from grey matter were seen. In the recovery period, vitamin E-treated rats revealed improvement in remyelination of spinal cord. In brain mild gliosis was seen. Thus, it appears that vitamin E is not able to protect them from acrylamide toxicity during active feeding, but after cessation of acrylamide feeding treatment with vitamin E revealed faster recovery as compared to the non-treated group.

Purpose: This cross-sectional study was designed to determine whether the academic performance of optometry undergraduates is influenced by enrollment status, learning style or gender., Methods: Three hundred and sixty undergraduates in all 3 years of the optometry degree course at Aston University during 2008-2009 were asked for their informed consent to participate in this study. Enrollment status was known from admissions records. An Index of Learning Styles (http://www4.nscu.edu/unity/lockers/users/f/felder/public/Learning-Styles.html) determined learning style preference with respect to four different learning style axes; active-reflective, sensing-intuitive, visual-verbal and sequential-global. The influence of these factors on academic performance was investigated., Results: Two hundred and seventy students agreed to take part (75% of the cohort). 63% of the sample was female. There were 213 home non-graduates (entrants from the UK or European Union without a bachelor's degree or higher), 14 home graduates (entrants from the UK or European Union with a bachelor's degree or higher), 28 international non-graduates (entrants from outside the UK or European Union without a bachelor's degree or higher) and 15 international graduates (entrants from outside the UK or European Union with a bachelor's degree or higher). The majority of students were balanced learners (between 48% and 64% across four learning style axes). Any preferences were towards active, sensing, visual and sequential learning styles. Of the factors investigated in this study, learning styles were influenced by gender; females expressed a disproportionate preference for the reflective and visual learning styles. Academic performance was influenced by enrollment status; international graduates (95% confidence limits: 64-72%) outperformed all other student groups (home non graduates, 60-62%; international non graduates, 55-63%) apart from home graduates (57-69%)., Conclusion: Our research has shown that the majority of optometry students have balanced learning styles and, from the factors studied, academic performance is only influenced by enrollment status. Although learning style questionnaires offer suggestions on how to improve learning efficacy, our findings indicate that current teaching methods do not need to be altered to suit varying learning style preferences as balanced learning styles can easily adapt to any teaching style (Learning Styles and Pedagogy in Post-16 Learning: A Systematic and Critical Review. London, UK: Learning and Skills Research Centre, 2004)., (© 2010 The College of Optometrists.)

Background: Traditional wisdom is that wound healing is directly related to haemoglobin level in the blood; therefore blood transfusion is given in anaemic patients to raise the haemoglobin level for better wound healing., Methods: Evaluation of wound healing in the form of split thickness skin graft take was done in 35 normovolaemic anaemic patients (haemoglobin level of < 10 gm/ dl) and compared with control group (patients with haemoglobin level of 10 or > 10 gm/ dl)., Results: There was no statistically significant difference in mean graft take between the two groups., Conclusion: It is not mandatory to keep haemoglobin level at or >10 g/dL or PCV value at or >30% for skin graft take, as mild to moderate anaemia per se does not cause any deleterious effect on wound healing; provided perfusion is maintained by adequate circulatory volume. Prophylactic transfusion to increase the oxygen carrying capacity of the blood for the purpose of wound healing is not indicated in asymptomatic normovolemic anaemic patients (with haemoglobin levels greater than 6g/dL) without significant cardiovascular or pulmonary disease.

Nasopharyngeal angiofibroma is a rare, highly vascular locally invasive tumor with a strong tendency to bleed. It usually occurs in young adolescent males. This is a retrospective study of 53 patients with nasopharyngeal angiofibroma. All the cases were treated surgically by different conventional approaches depending upon the extent of the mass. Transpalatal approach was used in 32 cases, lateral rhinotomy in 13 cases and a combination of transpalatine + lateral rhinotomy + caldwel-luc in 8 cases. There is no recurrence in 49 cases till date. However, recurrence was noted in four cases within six months. Three out of four patients with recurrence had to undergo repeat surgery for the removal of angiofibroma within six months while the remaining one was referred to radiotherapy as the mass was invading the cavernous sinus. The various clinical presentation and treatment modalities are discussed.

The purpose of this study was to find out the prevalence and antibiotic sensitivity pattern of Salmonella typhi and paratyphi isolated from children presenting with fever at Kanti Children's Hospital in Kathmandu, Nepal. A total of 9,856 blood samples collected for culture during one year period (April 2007 to March 2008) were included in the study. Out of total, 235 (2.0%) were positive for S. typhi and paratyphi A. Of the total positive, 195 (83.0%) were S. typhi and 40 (17.0%) were S. paratyphi A. The growth positive rate in two genders (M: 53.2% and F: 46.8%) was not significant (P > 0.05). Over two-third of cases were clustered in the age-group of 1-10 years. The occurrence of infections was common in summer months (rainy season). S. typhi was found to be most sensitive to cefotaxime (100.0%) followed by ceftriaxone (98.9%), ofloxacin (93.5%), cotrimoxazole (93.5%) and chloramphenicol (93.2%) and was least sensitive to amoxyccilin (66.7%) followed by ciprofloxacin (86.6%). S. paratyphi also was found to be most sensitive to cefotaxime (100.0%), followed by ceftriaxone (97.4%), cotrimoxazole (97.1%) and chloramphenicol (92.5%) and was least sensitive to amoxycillin (15.0%) followed by ciprofloxacin (51.3%) and ofloxacin (70.3%).

Background: The aim of study is to evaluate the Endoscopic dacryocystorhinostomy (DCR) with conventional instruments, its results and advantage over external dacryocystorhinostomy (DCR)., Methods: The study group comprised of 127 patients who underwent consecutive endoscopic dacryocystorhinostomy. The cases operated by one team were included in the study to make the uniform analysis and its result. There were 48 males and 79 female in this study and male female ratio was 1:1.6. The mean age of the patient was 37 years (range from 16 years to 58 years). There were wide variety of cases like epiphora, lacrimal sac abscess, lacrimal sac fistula, acute dacryocystitis and road vehicular accident. All the patients had undergone non-laser, non-powered conventional instruments surgery under local anesthesia. The lighted probe was not used in any case for sac identification. The free flow of saline through newly created stoma during sac syringing was considered as successful criteria. The stent was used in two cases of road vehicular accident and in remaining 125 cases no stent was used. There were 66 cases of epiphora, 30 cases of lacrimal sac abscess, 26 cases of acute dacryocystitis, 3 cases of lacrimal fistula and 2 case of road traffic accident with multiple fractures. The average follow up period was 17 months (maximum follow up 3 years and minimum 4 months.), Results: The success rate was 96 %., Conclusion: The endoscopic DCR with conventional instruments is safe with very high success rate without any complications. It can be done in acute cases and very much suited for lacrimal sac abscess and lacrimal sac fistula.

Inhalation of foreign body into the tracheobronchial tree is a medical emergency sometimes resulting into sudden death. The current mortality rate due to foreign body inhalation ranges from 0% to 1.8%. Children with or without positive history of aspiration were examined and diagnosis was made on the basis of history, clinical findings, radiological evaluation and strong index of suspicion. A review of 30 cases of suspected foreign body aspiration revealed, children between 6 months were found to be very vulnerable to aspiration. Majority of children were boys. 80% of the patients had positive history of inhalation. Only 50% of the patients presented immediately i.e. within 24 hours after aspiration. Common symptoms were cough and respiratory distress. Decreased air entry was the significant clinical sign (50%). Obstructive emphysema and mediastinal shift were found in the majority of cases (50%). Rigid bronchoscopy under general anaesthesia and patient ventilating using a jet ventilator is a very safe and effective technique.

Background: The aim of study is to compare the external osteotomy vs. internal osteotomy in patients undergoing rhinoplasty., Methods: The study group comprised of 45 patients that had undergone rhinoplasty surgery. The 25 patients had undergone internal / endonasal continuous lateral osteotomy and 20 patients had undergone external / percutaneous perforating digital osteotomy. The internal osteotomy was done high to low to high using 4 mm. curved guarded osteotome. The external osteotomy was done by 2 mm sharp osteotome. The scoring system of Kara and Gokalan was followed for edema and ecchymosis., Conclusion: External osteotomy is an easy approach to carryout and makes fracture with high precision along preset lines. The bone stump is stable. The damage to the nasal mucosa is much less. There is reduced bleeding, reduced edema and reduced ecchymosis around eyes. The cutaneous scar at the entry site of osteotome is invisible.

The case series presents the pattern of association of different co-morbid conditions of Plummer Vinson's Syndrome. The commonest morbidity is web at post cricoid level. The symptoms of dysphagia are more common and there appears to be a female preponderance. The presenting age us usually 5th decade. Although association with post cricoid carcinoma has been reported but only 10% of cases in the present series had carcinoma at the time of presentation. The effect of iron and B-complex supplementation has been clinically appraised and good symptomatic relief has been seen. Maybe this measure can prevent the progression to malignancy. Bouginage was effective in relieving symptoms in all the cases it was tried.

Buccal adhesive patches containing 20 mg of propranolol hydrochloride were prepared using solvent casting method. Chitosan was used as a natural bioadhesive polymer. Patches were prepared at different ratios of PVP K-30 and evaluated for various physicochemical characteristics such as weight variation, drug content uniformity, folding endurance, surface pH, ex-vivo mucoadhesive strength, ex-vivo residence time, in vitro drug release and in vitro buccal permeation study. Patches exhibited sustained release over a period of 7 hours. The mechanism of drug release was found to be Non-Fickian diffusion. Addition of PVP K-30 generally enhanced the releasing rate. The ex-vivo mucoadhesive strength was performed using sheep buccal mucosa on modified physical balance. Optimized patches (batch F4) showed satisfactory bioadhesive strength (9.6 degrees 2.0 gram) and ex vivo residence time (272 degrees 0.25 minutes). Swelling index was proportional to PVP K-30. The surface pH of all batches was within satisfactory limit (7.0+/-1.5) and hence patches would not cause irritation in the buccal cavity. Good correlation was observed between in vitro drug release and in vitro drug permeation with correlation coefficient of 0.9364. Stability of optimized patches was performed in natural human saliva showed that both drug and dosage forms were stable in human saliva.