13 research outputs found

    EVALUATION OF IN VITRO ANTI-UROLITHIATIC ACTIVITY OF METHANOLIC EXTRACT OF CUCUMIS MELO SEEDS ON CALCIUM OXALATE CRYSTALS

    Get PDF
    Objective: This in vitro study was carried out to evaluate the anti-urolithiatic activity of the methanolic extract of the Cucumismelo seeds on experimentally prepared calcium oxalate crystals which was prepared by the homogeneous precipitation method in the laboratory.Methods: The crude extract was prepared by the soxhlet extraction method and the extraction was done until all the compounds get extracted into the solution and solvent was evaporated by rotary evaporator. Extracts were stored in an airtight light-resistant container at 4 °C in a refrigerator for further analysis.Results: Seed extract of Cucumismelo showed maximum efficiencies in the dissolution of the calcium oxalate crystals. Cystone drug was used as the standard. This in vitro study has shown that the methanolic extract of the seeds of Cucumismelo has the potential anti-urolithiatic activity when compared with the standard.Conclusion: This in vitro study has given the primary evidence that the extract of seeds of Cucumismelo has the anti-urolithiatic activity. In vivo studies can be carried out on the seed extract of Cucumismelo for further investigations

    Whole-genome sequencing reveals host factors underlying critical COVID-19

    Get PDF
    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

    Genetic mechanisms of critical illness in COVID-19.

    Get PDF
    Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

    Heterozygous transcriptional and nonsense decay signatures in blood outgrowth endothelial cells from patients with hereditary haemorrhagic telangiectasia

    No full text
    In order to identify cellular phenotypes resulting from nonsense (gain of stop/premature termination codon) variants, we devised a framework of analytic methods that minimised confounder contributions, and applied to blood outgrowth endothelial cells (BOECs) derived from controls and patients with heterozygous nonsense variants in ACVRL1 , ENG or SMAD4 causing hereditary haemorrhagic telangiectasia (HHT). Following validation of 48 pre-selected genes by single cell qRT-PCR, discovery RNASeq ranked HHT-differential alignments of 16,807 Ensembl transcripts. Consistent gene ontology (GO) processes enriched compared to randomly-selected gene lists included bone morphogenetic protein, transforming growth factor-β and angiogenesis GO processes already implicated in HHT, further validating methodologies. Additional terms/genes including for endoplasmic reticulum stress could be attributed to a generic process of inefficient nonsense mediated decay (NMD). NMD efficiency ranged from 78-92% (mean 87%) in different BOEC cultures, with misprocessed mutant protein production confirmed by pulse chase experiments. Genes in HHT-specific and generic nonsense decay (ND) lists displayed differing expression profiles in normal endothelial cells exposed to an additional stress of exogenous 10μmol/L iron which acutely upregulates multiple mRNAs: Despite differing donors and endothelial cell types, >50% of iron-induced variability could be explained by the magnitude of transcript downregulation in HHT BOECs with less efficient NMD. The Genotype Tissue Expression (GTEx) Project indicated ND list genes were usually most highly expressed in non-endothelial tissues. However, across 5 major tissues, although 18/486 nonsense and frameshift variants in highly expressed genes were captured in GTEx, none were sufficiently prevalent to obtain genome-wide significant p values for expression quantitative trait loci (GnomAD allele frequencies <0.0005). In conclusion, RNASeq analytics of rare genotype-selected, patient-derived endothelial cells facilitated identification of natural disease-specific and more generic transcriptional signatures. Future studies should evaluate wider relevance and whether injury from external agents is augmented in cells with already high burdens of defective protein production

    Mapping the human genetic architecture of COVID-19

    Get PDF
    The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

    Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

    No full text
    The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management

    Evaluation of prognostic risk models for postoperative pulmonary complications in adult patients undergoing major abdominal surgery: a systematic review and international external validation cohort study

    Get PDF
    Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society
    corecore