The effect of surges in COVID-19 caseload on COVID-19 survival rates is unclear, especially independent of temporal changes in survival. This retrospective cohort study used data from a large U.S. ... Visual Association Between Caseload Surge and COVID-19 Survival in U.S. Hospitals. The effect of surges in COVID-19 caseload on COVID-19 survival rates is unclear, especially independent o... Background: Several U.S. hospitals had surges in COVID-19 caseload, but their effect on COVID-19 survival rates remains unclear, especially independent of temporal changes in survival. Objective: T...

Meta-analyses of N-acetylcysteine (NAC) for preventing contrast-induced nephrotoxicity (CIN) have led to disparate conclusions. Here we examine and attempt to resolve the heterogeneity evident among these trials.

Reactive oxygen species can function as intracellular messengers, but linking these signaling events with specific enzymes has been difficult. Purified endothelial nitric-oxide synthase (eNOS) can generate superoxide (O⨪₂) under special conditions but is only known to participate in cell signaling through NO. Here we show that eNOS regulates tumor necrosis factor α (TNFα) through a mechanism dependent on the production of O⨪₂ and completely independent of NO. Expression of eNOS in transfected U937 cells increased phorbol 12-myristate 13-acetate-induced TNFα promoter activity and TNFα production.N ^ω-Methyl-l-arginine, an inhibitor of eNOS that blocks NO production but not its NADPH oxidase activity, did not prevent TNFα up-regulation. Likewise, Gln³⁶¹eNOS, a competent NADPH oxidase that lacks NOS activity, retained the ability to increase TNFα. Similar to the effect of eNOS, a O⨪₂ donor dose-dependently increased TNFα production in differentiated U937 cells. In contrast, cotransfection of superoxide dismutase with eNOS prevented TNFα up-regulation, as did partial deletion of the eNOS NADPH binding site, a mutation associated with loss of O⨪₂ production. Thus, eNOS may straddle a bifurcating pathway that can lead to the formation of either NO or O⨪₂, interrelated but often opposing free radical messengers. This arrangement has possible implications for atherosclerosis and septic shock where endothelial dysfunction results from imbalances in NO and O⨪₂ production.

Significance: Caveolin-1 (CAV1) loss-of-function mutations are a hereditary cause of pulmonary arterial hypertension (PAH), but wild-type CAV1 is also decreased in the vascular lesions of idiopathic and disease-associated PAH. Using human pulmonary artery endothelium, lung tissue, and serum from Cav1 ^−/− mice, as well as fibroblasts and serum from patients with CAV1 mutations, CAV1 deficiency produced a dysfunctional, PAH-like endothelial phenotype driven by an interferon-biased inflammatory response with constitutive STAT and AKT activation. Inhibiting JAK/STAT and PI3K/AKT reversed the aberrant endothelial phenotype of CAV1 loss and may similarly ameliorate pathologic vascular remodeling in PAH. Exogenous interferon alone reduced CAV1 expression and activated these same signaling pathways, suggesting that CAV1 insufficiency may contribute to the development of autoimmune and autoinflammatory disease-associated PAH.

Peroxisome Proliferator-Activated Receptor γ (PPARγ) ligands have been widely used to treat type 2 diabetes mellitus. However, knowledge of PPARγ signaling remains incomplete. In addition to PPARγ, these drugs also activate G protein-coupled receptor 40 (GPR40), a Gαq-coupled free fatty acid receptor linked to MAPK networks and glucose homeostasis. Notably, p38 MAPK activation has been implicated in PPARγ signaling. Here, rosiglitazone (RGZ) activation of GPR40 and p38 MAPK was found to boost PPARγ-induced gene transcription in human endothelium. Inhibition or knockdown (KD) of p38 MAPK or expression of a dominant-negative (DN)-p38 MAPK mutant all blunted RGZ-induced PPARγ DNA binding and reporter activity in EA.hy926 human endothelial cells. GPR40 inhibition or KD, or expression of a DN-Gαq mutant likewise blocked RGZ activation of both p38 MAPK and PPARγ reporters. Importantly, RGZ induction of PPARγ target genes in primary human pulmonary artery endothelial cells (PAECs) was suppressed by KD of either p38 MAPK or GPR40. GPR40/p38 MAPK/PPARγ signal transduction was dependent on the activation and induction of PPARγ co-activator-1 (PGC1α). KD of p38 MAPK or GPR40 abolished the ability of RGZ to induce phosphorylation and expression of PGC1α in PAECs. KD of PGC1α, its essential activator SIRT1, or its binding partner/co-activator EP300 inhibited RGZ induction of PPARγ target genes in PAECs. RGZ/GPR40/p38 MAPK signaling also led to EP300 phosphorylation, an event that enhances PPARγ target gene transcription. Thus, GPR40 and PPARγ can function as an integrated two-receptor signal transduction pathway, a finding with implications for rational drug development.