2D/3D-QSAR, DOCKING AND OPTIMIZATION OF 5-SUBSTITUTED-1H-INDAZOLE AS INHIBITORS OF GSK-3β

Objective: Glycogen synthase kinase-3 beta (GSK-3β) plays a crucial role in several human diseases. GSK-3β is being one of the most attractive therapeutic targets for several decades across the research communities to discover new potent and selective inhibitors of GSK-3β. The objective of the research is to develop new compounds based on the QSAR and molecular docking studies. Methods: 2D/3D QSAR studies were conducted on a series of 5-substituted Indazole derivatives in order to optimize the GSK-3β inhibitors. Optimized inhibitors were subjected to molecular docking studies to find best inhibitors towards GSK-3β. Results: The significant QSAR model-3 (2D) and model-6 (3D) elucidate that T_C_N_5, T_2_N_0, SlogP, electrostatic potential (E_451, E_229) and hydrophobicity (H_1052) are important descriptors to conclude the biological activities of compounds. Docking study illustrates Val135, Gln185, Arg141 and Asp200 were essential interacting residues in the active site of the receptor with ligands. Based on QSAR models, 450 compounds were optimized and validated through docking studies. Conclusion: The best 31 optimized compounds, which showed good interaction energy, docking score and preferred interactions were selected as GSK-3β inhibitors

IN SILICO STUDIES ON NEW INDAZOLE DERIVATIVES AS GSK-3β INHIBITORS

Objective: In silico studies were conducted on newly proposed Indazole derivatives as GSK-3β inhibitors to select the best possible drug candidates based on drug properties and bioactivity score of the compounds. Methods: 31 Indazole derivatives and active GSK-3β Indazole inhibitor 3-(5-chloro-1-methyl-indol-3-yl)-4-[1-[3-(triazol-1-yl)propyl]indazol-3-yl]pyrrole-2,5-dione(IC50 of 0.003 μM) were subjected to predict the mutagenic, tumorigenic, irritant, reproductive risks, and drug-relevant properties using OSIRIS Property Explorer. Further bioactivity scores were determined using Molinspiration online tools. Results: The results of new GSK-3β inhibitors were compared with potent GSK-3β Indazole inhibitor to examine the prospective of the optimized compounds. The best possible drug candidates were reported after comprehensive analysis on predicted cLogP, solubility, molecular weight, topological molecular polar surface area (TPSA), drug- likeness, drug score properties and bioactivity score for different human targets like GPCR, ion channel, kinase, nuclear receptor, protease and enzymes. Conclusion: Five compounds 282, 141, 161, 108 and 456 were reported as the best drug like candidates for GSK-3β regulation

Field Evaluation of Three Entomopathogenic fungi on Groundnut Pest

Entomopathogenic fungi Beauveria bassiana (Balsamo) Vuillemin (Deuteromycotina: Hyphomycetes), Paecilomyces fumosoroseus (Wize) (Deuteromycotina: Hyphomycetes), Verticillium lecani Viegas (Deuteromycotina: Hyphomycetes) were tested against groundnut pests, Aphis craccivora (Koch) (Homoptera: Aphididae), Aproarema modicella (Deventer) (Lepidoptera: Gelechiidae), Mylabris pustulata Faust (Coleoptera: Meloidae) and Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae) in field conditions. Among the tested fungi, V. lecanii suppressed 62% of A. craccivora population at 39 Days After Seedling Emergence (DASE). During the same period, B. bassiana reduced 72% of S. litura larval population (0.73 larvae). The infestation of S. litura and A. modicella were greatly reduced after the treatment of B. bassiana; subsequently the yield (1721.31 kg/ha-1) and cost benefit ratio (1: 1.93) were increased. P. fumosoroseus and V. lecanii were less effective than B. bassiana. The persistence of fungal pathogens was found to be higher in soil than the phyllosphere indicating that they can be naturally favored for the control of pests in groundnut

BIS monitoring versus clinical assessment for sedation in mechanically ventilated adults in the intensive care unit and its impact on clinical outcomes and resource utilization.

BACKGROUND: Patients admitted to intensive care and on mechanical ventilation, are administered sedative and analgesic drugs to improve both their comfort and interaction with the ventilator. Optimizing sedation practice may reduce mortality, improve patient comfort and reduce cost. Current practice is to use scales or scores to assess depth of sedation based on clinical criteria such as consciousness, understanding and response to commands. However these are perceived as subjective assessment tools. Bispectral index (BIS) monitors, which are based on the processing of electroencephalographic signals, may overcome the restraints of the sedation scales and provide a more reliable and consistent guidance for the titration of sedation depth.The benefits of BIS monitoring of patients under general anaesthesia for surgical procedures have already been confirmed by another Cochrane review. By undertaking a well-conducted systematic review our aim was to find out if BIS monitoring improves outcomes in mechanically ventilated adult intensive care unit (ICU) patients. OBJECTIVES: To assess the effects of BIS monitoring compared with clinical sedation assessment on ICU length of stay (LOS), duration of mechanical ventilation, any cause mortality, risk of ventilator-associated pneumonia (VAP), risk of adverse events (e.g. self-extubation, unplanned disconnection of indwelling catheters), hospital LOS, amount of sedative agents used, cost, longer-term functional outcomes and quality of life as reported by authors for mechanically ventilated adults in the ICU. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, ProQuest, OpenGrey and SciSearch up to May 2017 and checked references citation searching and contacted study authors to identify additional studies. We searched trial registries, which included clinicaltrials.gov and controlled-trials.com. SELECTION CRITERIA: We included all randomized controlled trials comparing BIS versus clinical assessment (CA) for the management of sedation in mechanically ventilated critically ill adults. DATA COLLECTION AND ANALYSIS: We used Cochrane's standard methodological procedures. We undertook analysis using Revman 5.3 software. MAIN RESULTS: We identified 4245 possible studies from the initial search. Of those studies, four studies (256 participants) met the inclusion criteria. One more study is awaiting classification. Studies were, conducted in single-centre surgical and mixed medical-surgical ICUs. BIS monitor was used to assess the level of sedation in the intervention arm in all the studies. In the control arm, the sedation assessment tools for CA included the Sedation-Agitation Scale (SAS), Ramsay Sedation Scale (RSS) or subjective CA utilizing traditional clinical signs (heart rate, blood pressure, conscious level and pupillary size). Only one study was classified as low risk of bias, the other three studies were classified as high risk.There was no evidence of a difference in one study (N = 50) that measured ICU LOS (Median (Interquartile Range IQR) 8 (4 to 14) in the CA group; 12 (6 to 18) in the BIS group; low-quality evidence).There was little or no effect on the duration of mechanical ventilation (MD -0.02 days (95% CI -0.13 to 0.09; 2 studies; N = 155; I2 = 0%; low-quality evidence)). Adverse events were reported in one study (N = 105) and the effects on restlessness after suction, endotracheal tube resistance, pain tolerance during sedation or delirium after extubation were uncertain due to very low-quality evidence. Clinically relevant adverse events such as self-extubation were not reported in any study. Three studies reported the amount of sedative agents used. We could not measure combined difference in the amount of sedative agents used because of different sedation protocols and sedative agents used in the studies. GRADE quality of evidence was very low. No study reported other secondary outcomes of interest for the review. AUTHORS' CONCLUSIONS: We found insufficient evidence about the effects of BIS monitoring for sedation in critically ill mechanically ventilated adults on clinical outcomes or resource utilization. The findings are uncertain due to the low- and very low-quality evidence derived from a limited number of studies

Adverse Events Sustained by Children in The Intensive Care Unit: Guiding local quality improvement

Objective: To determine the frequency, nature and consequence of adverse events sustained by children admitted to a combined general and cardiac paediatric intensive care unit (PICU). Design: Retrospective analysis of data collected between January 1st 2008 and December 31st 2017 from PICU. Setting: The Royal Children’s Hospital, a paediatric tertiary referral centre in Melbourne, Victoria, Australia. The PICU has thirty beds. Results: During the study period, PICU received 15208 admissions, of which 73% sustained at least one adverse event with a frequency of 67 adverse events per 100 PICU-days and 3 per admission. One adverse event was sustained for every 35 hours of care. The risk of an adverse event was highest in children less than a month of age, or if mechanically ventilated, a high Pediatric Index of Mortality (PIM2) score, longer PICU length of stay, had a pre-existing disability or a high risk adjustment for congenital heart surgery (RACHS) score. Those patients who sustained an adverse event, as compared to those who did not, were mechanically ventilated for longer (80 hrs Vs. 7 hrs, p=<0.001), had a longer PICU length of stay (131 hrs Vs. 35 hrs, p=<0.001), had a longer hospital length of stay (484 hrs Vs. 206 hrs, p=<0.001) and had a higher mortality rate (3% vs. 0.1%, p=<0.001). Conclusion: Whilst admission to PICU is an essential aspect of care for many patients, the risk of adverse events is high and is associated with significant clinical consequences. Monitoring of adverse events as part of quality improvement enables targeted intervention to improve patient safety

Supplementation of Madhuca longifolia Seed oil augments diclofenac-induced organ toxicities: A biochemical and histopathological approach

Diclofenac medication has been extensively used for anti-inflammatory, anti-pyretic, and analgesic actions. Its abiding usage and overdose have induced toxicity and harmful effects on the liver, kidney, and gastrointestinal tract. The research aims to scrutinize the protective effect of Madhuca longifolia seed oil against diclofenac-induced toxicity in female Wistar albino rats. A period of 10 days of study was aimed at 7 groups; Group 1 was assigned as normal control. Group 2 has been administered diclofenac (50 mg/kg b.w. /day, i.p.) only on the last two days of each study period. Group 3 and Group 4 have been pre-treated with 1 mL, and 2 mL of Madhuca longifolia seed oil, respectively, and diclofenac was induced as per Group 2. Group 5 was treated with the standard drug silymarin and diclofenac. Group 6 and Group 7 were given 1 mL and 2 mL of Madhuca longifolia seed oil alone. After the study period, parameters like liver enzyme markers, renal enzyme markers, and antioxidants were measured, and tissue samples were analyzed for histopathological changes. The results proved that pre-treatment of 1 mL of Madhuca longifolia seed oil has efficacy against diclofenac-induced toxicity

Prenatal Diagnosis of Oculocutaneous Albinism by Electron Microscopy of Fetal Skin

Oculocutaneous albinism was diagnosed prenatally by electron microscopic examination of fetal skin samples taken during fetoscopy at 20 weeks of gestation. Melanosome development in hair bulb melanocytes progressed no further than stage II, indicating a lack of melanin synthesis. In 4 age-matched control fetuses, numerous stage IV melanosomes, signifying active melanin synthesis, were identified. The diagnosis was confirmed after the pregnancy was terminated at 22 weeks. Examination of the fetal eye showed absence of pigment in the retinal epithelium and uvea at a stage when ocular melanogenesis would normally be active. This study shows that oculocutaneous albinism can be detected in the second trimester using similar techniques to those employed in the prenatal diagnosis of epidermolysis bullosa and ichthyosis