Heme Mediated STAT3 Activation in Severe Malaria

The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated.We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

What happens at the party : Jane Austen converses with Charlotte Smith

IN JANE AUSTEN’S ART OF MEMORY, Jocelyn Harris concludes that “in memory [Austen] found origins for art,” following the eighteenth-century vogue for imitation in her synthesizing of what she had read: “her practice often looks to me like ‘imitation’ . . . which, says Howard Weinbrot, ‘fosters literary borrowing and encourages modernization’” (221, 219). Harris bases her book on Austen’s “tenacious” memory, a trait also discussed by most of the critics who investigate how Austen made use of what she read (Harris x), and is generous is allowing for how much she may have overlooked. For Harris, “Austen’s recollections of books gave her languages to speak with” (218), a telling phrase, conjuring up a mute, or at least tongue-tied Austen for whom reading performed its highest function of instruction, enabling a layering of meaning and event, filling the blank page. What is striking, however, is the reluctance readers show to compromise on what is often presented as Austen’s superiority, despite her debts. Thus she “better[s] the novel” (Siskin 137); she “almost single-handedly . . . has made most of her contemporaries seem excessive, artificial, or absurd” (Todd 18); she “created a new kind of novel which put all her predecessors and contemporaries more or less in the shade and ensured her work outlived theirs” (Waldron 3). These encomiums, and others, derive from scholars who are willing to admit that Austen read her contemporaries and that this reading is visible in her work. Others insist that Austen’s unique genius is untainted by such associations; hence, “she is little given to direct imitation” (Grundy 191, in an article on “Jane Austen and Literary Traditions”); she is “extraordinarily isolated from contemporary writers” (Gillie 55). As Austen sets about perfecting the novel, she is somehow also isolated from the novelistic world, always doing better, always going furthe

Smith, Wordsworth, and the Model of the Romantic Poet

This essay examines how Charlotte Smith and William Wordsworth manipulate the autobiographical and elements of poetical voicing as they explore the figure of the Romantic Poet. Focusing on Beachy Head (1807) and The Prelude (1805), I suggest that in devising separate, competing but eventually equal “personal” voices in Beachy Head, and in interrogating tropes of genre and composition in The Prelude, the two poets signal their interest in using poetry to provide an answer to Wordsworth’s famous question, “What is a Poet?” For each, the model of the Romantic poet is most viable when, like wet clay, it is still able to be shaped