Incidence of decision to delivery interval delay in emergency LSCS and its impact on fetal and maternal outcome: a prospective observational study

Background: Caesarean delivery is a complex multidisciplinary procedure. Decision to delivery interval is supposed to play a significant role in maternal and neonatal outcomes. The present study was undertaken to determine the incidence of DDI delay among pregnant women undergoing Emergency LSCS in tertiary care centres. Methods: This study was conducted on 400 subjects who underwent emergency LSCS in category I and category II during a period from November 2020 to August 2021. Results: The maximum patients were from the age group of 25-29 years (43%), primigravida (59.1%), gestational age between 37-40 weeks (78%). 29% have undergone category-1 LCSC and 71.2% have undergone category-2 LSCS. Out of 116 patients underwent category-1 LSCS, 11 (9.5%) patient delay was present whereas in category-2 LSCS out of 284,12 (4.2%) patient delay was present. Among Category-I LSCS the most common indication was Fetal distress and among Category-II LSCS the major indication was non reassuring CTG. Maximum babies have APGAR scores between 7-10 at 1 (N=369) and 5 min (N=398). The mean cord PH was 7.31, ranged from 6.9-7.47. 98 babies required NICU admission and most of them admitted for respiratory distress. 11 patients required blood transfusion. There was no significant association found between various parameters and DDI delay, (p>0.05). Conclusions: In the present study, the interval between the decision to delivery interval has no significant impact on feto-maternal outcome in Category-I LSCS. Among Category-II LSCS there was a delay in 12 cases, among them 7 babies required NICU admission, the complications among neonates were significantly more when DDI was >75 minutes

Characterization of HSP90 isoforms in transformed bovine leukocytes infected with Theileria annulata

HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterisation was undertaken for three and localisation confirmed for cytoplasmic (TA12105); endoplasmic reticulum (TA06470) and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin, were demonstrated for recombinant TA12105 and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata-infected counterpart was utilised to test the effects of geldanamycin and the derivative 17-AAG. T. annulata-infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17-AAG. These findings suggest that parasite HSP90 isoform (s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation

A Novel C-Terminal Homologue of Aha1 Co-Chaperone Binds to Heat Shock Protein 90 and Stimulates Its ATPase Activity in Entamoeba histolytica

Cytosolic heat shock protein 90 (Hsp90) has been shown to be essential for many infectious pathogens and is considered a potential target for drug development. In this study, we have carried out biochemical characterization of Hsp90 from a poorly studied protozoan parasite of clinical importance, Entamoeba histolytica. We have shown that Entamoeba Hsp90 can bind to both ATP and its pharmacological inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin), with K-d values of 365.2 and 10.77 mu M, respectively, and it has a weak ATPase activity with a catalytic efficiency of 4.12 x 10(-4) min(-1) mu M-1. Using inhibitor 17-AAG, we have shown dependence of Entamoeba on Hsp90 for its growth and survival. Hsp90 function is regulated by various co-chaperones. Previous studies suggest a lack of several important co-chaperones in E. histolytica. In this study, we describe the presence of a novel homologue of co-chaperone Aha1 (activator of Hsp90 ATPase), EhAha1c, lacking a canonical Aha1 N-terminal domain. We also show that EhAha1c is capable of binding and stimulating ATPase activity of EhHsp90. In addition to highlighting the potential of Hsp90 inhibitors as drugs against amoebiasis, our study highlights the importance of E. histolytica in understanding the evolution of Hsp90 and its co-chaperone repertoire. (C) 2014 Elsevier Ltd. All rights reserved

Inheritance and maintenance of small RNA‐mediated epigenetic effects

International audienceHeritable traits are predominantly encoded within genomic DNA, but it is now appreciated that epigenetic information is also inherited through DNA methylation, histone modifications, and small RNAs. Several examples of transgenerational epigenetic inheritance of traits have been documented in plants and animals. These include even the inheritance of traits acquired through the soma during the life of an organism, implicating the transfer of epigenetic information via the germline to the next generation. Small RNAs appear to play a significant role in carrying epigenetic information across generations. This review focuses on how epigenetic information in the form of small RNAs is transmitted from the germline to the embryos through the gametes. We also consider how inherited epigenetic information is maintained across generations in a small RNA-dependent and independent manner. Finally, we discuss how epigenetic traits acquired from the soma can be inherited through small RNAs

Heat Shock Protein 90 Inhibitors as Broad Spectrum Anti-Infectives

Combating stress is one of the prime requirements for any organism. For parasitic microbes, stress levels are highest during the growth inside the host. Their survival depends on their ability to acclimatize and adapt to new environmental conditions. Robust cellular machinery for stress response is, therefore, both critical and essential especially for pathogenic microorganisms. Microbes have cleverly exploited stress proteins as virulence factors for pathogenesis in their hosts. Owing to its ability to sense and respond to the stress conditions, Heat shock protein 90 (Hsp90) is one of the key stress proteins utilized by parasitic microbes. There are growing evidences for the critical role played by Hsp90 in the growth of pathogenic organisms like Candida, Giardia, Plasmodium, Trypanosoma, and others. This review, therefore, explores potential of exploiting Hsp90 as a target for the treatment of infectious diseases. This molecular chaperone has already gained attention as an effective anti-cancer drug target. As a result, a lot of research has been done at laboratory, preclinical and clinical levels for several Hsp90 inhibitors as potential anti-cancer drugs. In addition, lot of data pertaining to toxicity studies, pharmacokinetics and pharmacodynamics studies, dosage regime, drug related toxicities, dose limiting toxicities as well as adverse drug reactions are available for Hsp90 inhibitors. Therefore, repurposing/repositioning strategies are also being explored for these compounds which have gone through advanced stage clinical trials. This review presents a comprehensive summary of current status of development of Hsp90 as a drug target and its inhibitors as candidate anti-infectives. A particular emphasis is laid on the possibility of repositioning strategies coupled with pharmaceutical solutions required for fulfilling needs for ever growing pharmaceutical infectious disease market

The Potential of Lactobacillus casei and Entercoccus faecium Combination as a Preventive Probiotic Against Entamoeba

Travellers' diarrhoea caused by enteric protozoa like Entamoeba histolytica is among the most common protozoan diseases in developing countries. In developing countries, amoebiasis is the second most prevalent protozoan disease. This protozoan parasite is often known to coexist as a part of the normal gut microbiota. It is estimated that around 50-60 % of population in developing countries might be harbouring Entamoeba in an asymptomatic manner. Due to physiological perturbation or upon immuno-compromise, it can become virulent and then cause diarrhoea, bloody stools and may invade other organs if left untreated. Nitroimidazole drugs, namely metronidazole and tinidazole, are widely used to treat protozoan infections. These drugs often show dose-dependent side effects. With emerging antibiotic resistance, novel therapeutics to prevent parasitic infections is required. This study aims to study effect of probiotics on prevention of Amoebiasis. In this study, we have investigated the effect of selected probiotics on the growth of Entamoeba. From the list of probiotics being currently used, five bacterial strains were selected for testing. These probiotic strains were co-cultured with Entamoeba, and their effect on Entamoeba proliferation was checked. Of the five probiotics chosen, individual treatments of Lactobacillus casei and Enterococcus faecium showed a significant reduction of up to 71 % in parasite survival only at higher CFUs. When the two probiotics were used in combination, the percentage of survival reduced gradually further to 80 % at a total CFU of 10(9) cells/ ml of bacteria. The study lays the foundation for providing cost-effective prophylactic treatment for amoebiasis without the overuse of antibiotics

First Structural View of a Peptide Interacting with the Nucleotide Binding Domain of Heat Shock Protein 90

The involvement of Hsp90 in progression of diseases like cancer, neurological disorders and several pathogen related conditions is well established. Hsp90, therefore, has emerged as an attractive drug target for many of these diseases. Several small molecule inhibitors of Hsp90, such as geldanamycin derivatives, that display antitumor activity, have been developed and are under clinical trials. However, none of these tested inhibitors or drugs are peptide-based compounds. Here we report the first crystal structure of a peptide bound at the ATP binding site of the N-terminal domain of Hsp90. The peptide makes several specific interactions with the binding site residues, which are comparable to those made by the nucleotide and geldanamycin. A modified peptide was designed based on these interactions. Inhibition of ATPase activity of Hsp90 was observed in the presence of the modified peptide. This study provides an alternative approach and a lead peptide molecule for the rational design of effective inhibitors of Hsp90 function

Heat shock protein 90 as a potential drug target against surra

Trypanosomiasis is caused by Trypanosoma species which affect both human and animal populations and pose a major threat to developing countries. The incidence of animal trypanosomiasis is on the rise. Surra is a type of animal trypanosomiasis, caused by Trypanosoma evansi, and has been included in priority list B of significant diseases by the World Organization of Animal Health (OIE). Control of surra has been a challenge due to the lack of effective drugs and vaccines and emergence of resistance towards existing drugs. Our laboratory has previously implicated Heat shock protein 90 (Hsp90) from protozoan parasites as a potential drug target and successfully demonstrated efficacy of an Hsp90 inhibitor in cell culture as well as a pre-clinical mouse model of trypanosomiasis. This article explores the role of Hsp90 in the Trypanosoma life cycle and its potential as a drug target. It appears plausible that the repertoire of Hsp90 inhibitors available in academia and industry may have value for treatment of surra and other animal trypanosomiasis

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Not AvailableTrypanosoma evansi is a haemo-protozoan parasite responsible for the disease surra, an economically important disease of wide range of domestic and wild animals. The present diagnostic methods using soluble antigens have inherent problems like lack of standardized and reproducible antigens, as well as ethical issues. This entails further efforts for search of defined antigenic molecules with satisfying sensitivity and specificity for sero-epidemiology of trypanosomosis. In present investigation, we have identified and purified 52–55 kDa immunodominant protein cluster in molecular mass ranges by preparatory SDS-PAGE methods from T. evansi proteome. The purified protein was further characterized by hyper immune serum raised in rabbits and also further evaluated for its immunodiagnostic potential using experimentally infected horse serum samples by different immunological tests. The immunoblot, ELISA and dot blot assay using purified cluster in infected pooled serum samples showed detection of infection early as 10th days post infection till termination of experiment. The observations revealed that purified cluster is expressed not only at early stage but also persisted and detected throughout course of infection. Further, whole cell lysate antigen separated out and detected 141 spots by 2-D gel electrophoresis. The isoelectric focussing (PI) of 52–55 kDa was determined in pH range between 6.9 and 7.5 along with two other cluster of proteins recognised by immune sera of ponies infected with T. evansi. MS/MS analysis of the purified protein cluster identified five proteins i.e. pyruvate kinase 1, beta tubulin, paraflagellar rod protein, alanine aminotransferase and variable surface glycoprotein showing homology to protein present in Trypanosome database. These identified proteins may be useful for development of vaccines and diagnostic targets against animal trypanosomosis.Not Availabl

Argonaute catalytic activity is required for maternal mRNA clearance in embryos

Argonaute proteins and their interacting small RNAs play a key role in regulating complementary mRNA targets during animal development. Here, we investigate a novel and essential function of the catalytically active Argonaute protein CSR-1 in maternal mRNA degradation during early embryogenesis in Caenorhabditis elegans. We show that CSR-1 interacts with endogenous small RNAs antisense to hundreds of cleared maternal mRNAs in embryos, and preferentially cleaves mRNAs no longer engaged in translation. The depletion of CSR-1 during maternal to zygotic transition leads to embryonic lethality in a catalytic-dependent manner and impairs the degradations of its embryonic mRNA targets. Given the conservation of Argonaute catalytic activity, we propose that a similar mechanism operate to clear maternal mRNAs during maternal to zygotic transition across species