72 research outputs found

    A Replication Study of GWAS-Derived Lipid Genes in Asian Indians: The Chromosomal Region 11q23.3 Harbors Loci Contributing to Triglycerides

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    Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p = 2.03×10−26). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p = 1.74×10−17; rs12286037: p = 1.58×10−2). We further explored 45 SNPs in a ∼195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: p = 1.06×10−39). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD

    15-Deoxy-Δ12,14 Prostaglandin J2 Reduces the Formation of Atherosclerotic Lesions in Apolipoprotein E Knockout Mice

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    AIM: 15-deoxy-Δ¹²,¹⁴ prostaglandin J₂ (15d-PGJ₂) is a ligand of peroxisome proliferator-activated receptor γ (PPARγ) having diverse effects such as the differentiation of adipocytes and atherosclerotic lesion formation. 15d-PGJ₂ can also regulate the expression of inflammatory mediators on immune cells independent of PPARγ. We investigated the antiatherogenic effect of 15d-PGJ₂. METHODS: We fed apolipoprotein (apo) E-deficient female mice a Western-type diet from 8 to 16 wk of age and administered 1 mg/kg/day 15d-PGJ₂ intraperitoneally. We measured atherosclerotic lesions at the aortic root, and examined the expression of macrophage and inflammatory atherosclerotic molecules by immunohistochemical and real-time PCR in the lesion. RESULTS: Atherosclerotic lesion formation was reduced in apo E-null mice treated with 15d-PGJ₂, as compared to in the controls. Immunohistochemical and real-time PCR analyses showed that the expression of MCP-1, TNF-α, and MMP-9 in atherosclerotic lesions was significantly decreased in 15d-PGJ₂ treated mice. The 15d-PGJ₂ also reduced the expression of macrophages and RelA mRNA in atherosclerotic lesions. CONCLUSION: This is the first report 15d-PGJ₂, a natural PPARγ agonist, can improve atherosclerotic lesions in vivo. 15d-PGJ₂ may be a beneficial therapeutic agent for atherosclerosis

    Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

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    Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p

    Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

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    BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

    Nanoparticles-A Thoracic Toxicology Perspective

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    A substantial literature demonstrates that the main ultrafine particles found in ambient urban air are combustion-derived nanoparticles (CDNP) which originate from a number of sources and pose a hazard to the lungs. For CDNP, three properties appear important-surface area, organics and metals. All of these can generate free radicals and so induce oxidative stress and inflammation. Inflammation is a process involved in the diseases exhibited by the individuals susceptible to the effects of PM-development and exacerbations of airways disease and cardiovascular disease. It is therefore possible to implicate CDNP in the common adverse effects of increased PM. The adverse effects of increases in PM on the cardiovascular system are well-documented in the epidemiological literature and, as argued above, these effects are likely to be driven by the combustion-derived NP. The epidemiological findings can be explained in a number of hypotheses regarding the action of NP:-1) Inflammation in the lungs caused by NP causes atheromatous plaque development and destabilization; 2) The inflammation in the lungs causes alteration in the clotting status or fibrinolytic balance favouring thrombogenesis; 3) The NP themselves or metals/organics released by the particles enter the circulation and have direct effects on the endothelium, plaques, the clotting system or the autonomic nervous system/ heart rhythm. Environmental nanoparticles are accidentally produced but they provide a toxicological model for a new class of purposely 'engineered' NP arising from the nanotechnology industry, whose effects are much less understood. Bridging our toxicological knowledge between the environmental nanoparticles and the new engineered nanoparticles is a considerable challenge
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