Behavioral and Developmental Changes in Rats with Prenatal Exposure of Mirtazapine

Mirtazapine is an often used antidepressant drug; however insufficient information is available regarding its safety during pregnancy. Therefore, this work was initiated to study the effect of prenatal exposure of mirtazapine on postnatal developments of rats. The study was conducted on pregnant rats to observe the safety profile of mirtazapine in comparison to control. The percentage weight gain, gestation period and litter size of the rats treated with double therapeutic dose (DTD) was significantly lower than the rats treated with therapeutic dose (TD) and rats of control group. However the litter size of the TD treated rats was also found smaller than the control. The offspring were examined through battery of test in order to evaluate their developmental neurotoxicity. The test includes the assessment of postnatal growth, reflex ontogeny, neuromotor abilities, activity level, emotional reactivity and learning ability. The DTD exposure negatively affected on overall growth of pups in comparison to TD exposed pups and control group. Further, the amine concentration in brain was also found significantly lower in DTD exposed pups. Therefore, this study reveals that the treatment of pregnant rats with TD and DTD decreases their litter size. In addition the prenatal exposure of DTD of mirtazapine negatively affects on neurodevelopment of rats

Prokaryotic expression of a 750 bp capsid region of bovine immunodeficiency virus gag gene and development of a recombinant capsid (p26) protein based immunoassay for seroprevalence studies

50-55A 750 bp DNA fragment of the gag gene, coding for capsid (p26) protein of bovine immunodeficiency virus (BIV), was cloned in pQE32 vector and expressed as 6 His tagged fusion protein in Escherichia coli. The concentration of affinity purified His tagged capsid protein was 5 mg/mL and its yield was 3.5 g/L of induced culture (E. coli). The recombinant capsid protein of BIV was found to be immunologically reactive with a reference positive serum. Using the purified capsid protein, an indirect ELISA was standardized to test sera of cattle and buffalo for carrying out sero-surveillance of BIV. Of 672 animals tested by capsid based ELISA, 162 were positive and 510 were negative, giving an overall prevalence of 24% in India. In conclusion, the recombinant capsid based indirect ELISA was found suitable to study BIV antibody status. To our knowledge, this is the first seroprevalence study of BIV infection in India

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Not AvailableFoot-and-mouth Disease (FMD) is a highly contagious viral disease of domesticated livestock, primarily cattle, buffalo and pigs. Sheep, goat and different species of wild life are also susceptible to the disease. India has a FMD susceptible livestock population of >500 million (DAHD&F, GoI, 2012). The economic loss to the livestock industry attributed to this dreaded disease is huge. There are direct and indirect losses due to this disease. Direct loss is estimated at >20,000 crore/annum that is due to significant drop in milk yield (up to 80%), loss in drought power, reduction in meat and wool production, abortion in pregnant animals and mortality in calves. Indirect loss could be much more due to trade barrier imposed by the countries free from FMD, and massive expenditure by Government on FMD control and cost of treatment. The causative FMD virus (FMDV) is antigenically diverse having seven distinct serotypes (O, A, C, Asia1) and Southern African Territories (SAT) 1-3 and multiple genetic groups in each serotype. Currently three serotypes (O, A and Asia1) are prevalent in India. Serotype O is the most prevalent one followed by serotypes Asia1 and A.Not Availabl

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Not AvailableBacillus anthracis secretes three secretary proteins; lethal factor (LF), protective antigen (PA) and edema factor (EF). The LF has ability to check proliferation of mammary tumors, chiefly depending on mitogen activated protein kinase (MAPK) signaling pathway. Evaluation of therapeutic potential of recombinant LF (rLF), recombinant PA (rPA) and lethal toxin (rLF + rPA = LeTx) on the primary mammary ductal carcinoma cells revealed significant (p < 0.01) reduction in proliferation of tumor cells with mean inhibition indices of 28.0 ± 1.37% and 19.6 ± 1.47% respectively. However, treatment with rPA alone had no significant anti-proliferative effect as evident by low mean inhibition index of 3.4 ± 3.87%. The higher inhibition index observed for rLF alone as compared to LeTx is contrary to the existing knowledge on LF, which explains the requirement of PA dependent endocytosis for its enzymatic activity. Therefore, the plausible existence of PA independent mode of action of LF including direct receptor mediated endocytosis or modulation of signal transduction cascade via unknown means is hypothesized. In silico protein docking analysis of other cellular receptors for any plausibility to play the role of receptor for LF revealed c-Met receptor showing strongest affinity for LF (H bond = 19; Free energy = -773.96), followed by nerve growth factor receptor (NGFR) and human epidermal growth factor receptor (HER)-1. The study summarizes the use of rLF or LeTx as therapeutic molecule against primary mammary ductal carcinoma cells and also the c-Met as potential alternative receptor for LF to mediate and modulate PA independent signal transduction.Not Availabl

Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARγ Agonists and their Antidiabetic Effects on Type 2 Diabetes

Peroxisome proliferator-activated receptor γ (PPARγ) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARγ and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPARγ. Furthermore, docking experiments revealed that BTZDs interact with PPARγ through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidaemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36 mg/kg/day administered orally for 15 days. Histopathological investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacological agents by selectively targeting PPARγ for further development in the clinical treatment of type 2 diabetes mellitus

Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study

International audienceBackground: Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. Methods: WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. Findings: Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0–4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 day), 457 (10·1%) had intermediate weaning (2–6 days), 433 (9·6%) required prolonged weaning (≥7 days), and 706 (15·6%) had weaning failure. Higher sedation scores were independently associated with delayed initiation of weaning. Delayed initiation of weaning and higher sedation scores were independently associated with weaning failure. 1742 (31·8%) of 5479 patients died in the intensive care unit and 2095 (38·3%) of 5465 patients died in hospital. Interpretation: In critically ill patients receiving at least 2 days of invasive mechanical ventilation, only 65% were weaned at 90 days. A better understanding of factors that delay the weaning process, such as delays in weaning initiation or excessive sedation levels, might improve weaning success rates. Funding: European Society of Intensive Care Medicine, European Respiratory Society

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p&lt;0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p&lt;0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status