Requirement of NOX2 and Reactive Oxygen Species for Efficient RIG-I-Mediated Antiviral Response through Regulation of MAVS Expression

The innate immune response is essential to the host defense against viruses, through restriction of virus replication and coordination of the adaptive immune response. Induction of antiviral genes is a tightly regulated process initiated mainly through sensing of invading virus nucleic acids in the cytoplasm by RIG-I like helicases, RIG-I or Mda5, which transmit the signal through a common mitochondria-associated adaptor, MAVS. Although major breakthroughs have recently been made, much remains unknown about the mechanisms that translate virus recognition into antiviral genes expression. Beside the reputed detrimental role, reactive oxygen species (ROS) act as modulators of cellular signaling and gene regulation. NADPH oxidase (NOX) enzymes are a main source of deliberate cellular ROS production. Here, we found that NOX2 and ROS are required for the host cell to trigger an efficient RIG-I-mediated IRF-3 activation and downstream antiviral IFNβ and IFIT1 gene expression. Additionally, we provide evidence that NOX2 is critical for the expression of the central mitochondria-associated adaptor MAVS. Taken together these data reveal a new facet to the regulation of the innate host defense against viruses through the identification of an unrecognized role of NOX2 and ROS

Análisis sincrónico de la gobernanza universitaria: una mirada teórica a los años sesenta y setenta

Resumen Estudiar las perspectivas en el campo del gobierno de las universidades tiene cada día mayor preeminencia, especialmente si se toma en cuenta la incuestionable necesidad de avanzar hacía organizaciones más eficientes, conectadas con las expectativas que sobre ellas tiene la sociedad. Considerando este escenario, el trabajo se ha planteado como propósito central realizar un análisis de carácter sincrónico del concepto de gobernanza y la constitución de los gobiernos universitarios. Desde el punto de vista metodológico se utilizaron fuentes secundarias: una revisión de papers publicados esencialmente en revistas de habla inglesa. El estudio comprende las décadas del sesenta y el setenta. Se centra en las raíces del concepto de gobernanza universitaria, en la delineación de los actores que participan en sus gobiernos y en las relaciones de poder que fluyen entre ellos.Entre las principales conclusiones, se pueden destacar como el estamento académico desde el principio de las universidades ha ocupado el rol casi plenipotenciario en su respectivo gobierno, producto de esto, en el correr del desarrollo y mientras la complejidad organizacional se incrementaba, es que fue necesario incorporar nuevos actores a los sistemas de gestión; todo lo anterior, teniendo en cuenta que dos elementos han sido fundamentales para la sobrevivencia de este tipo de instituciones, la legitimidad otorgada por la sociedad y los principios de estrategias del ámbito de la gestión

Proteomic Modeling for HIV-1 Infected Microglia-Astrocyte Crosstalk

Background: HIV-1-infected and immune competent brain mononuclear phagocytes (MP; macrophages and microglia) secrete cellular and viral toxins that affect neuronal damage during advanced disease. In contrast, astrocytes can affect disease by modulating the nervous system’s microenvironment. Interestingly, little is known how astrocytes communicate with MP to influence disease. Methods and Findings: MP-astrocyte crosstalk was investigated by a proteomic platform analysis using vesicular stomatitis virus pseudotyped HIV infected murine microglia. The microglial-astrocyte dialogue was significant and affected microglial cytoskeleton by modulation of cell death and migratory pathways. These were mediated, in part, through F-actin polymerization and filament formation. Astrocyte secretions attenuated HIV-1 infected microglia neurotoxicity and viral growth linked to the regulation of reactive oxygen species. Conclusions: These observations provide unique insights into glial crosstalk during disease by supporting astrocytemediated regulation of microglial function and its influence on the onset and progression of neuroAIDS. The results open new insights into previously undisclosed pathogenic mechanisms and open the potential for biomarker discovery an

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

Trouble Shooting the Extracorporeal Membrane Oxygenator Circuit and Patient

Patients requiring extracorporeal membrane oxygenation (ECMO) often become totally dependent on the mechanical life support. The Extracorporeal Life Support Organization (ELSO) reports 2486 incidents of mechanical complications in 5905 ECMO supports. To help decrease the number of mechanical complications, an active quality assurance program was initiated at our institution. This resulted in identification of only 14 incidents of mechanical complications in 100 patients (neonate, pediatric, adult, and cardiac). Techniques for dealing with problems such as loss of roller pump occlusion, changing out of the membrane lung or heat exchanger without interrupting ECMO support, venous air lock, tamponade, emergency transfusion, and other situations were generated into written policies and procedures. We routinely review and practice problem solving techniques with specific emphasis on monitoring patient hemodyanmics and appearance. We conclude that written policies and procedures, “water drills,” and continuing education can be beneficial in early recognition, intervention, and/or prevention of ECMO mechanical complications

Extracorporeal Life Support of Neonates with Congenital Cardiac Defects: Techniques Used During Cardiac Catheterization and Surgery

Neonatal patients with congenital cardiac defects require proper diagnosis often by cardiac catheterization before surgical repair. In our institution, patients whose echocardiograms reveal surgically correctable lesions, but who are severely decompensated, have been placed on Extracorporeal Life Support (ECLS) prior to catheterization or surgery. Subsequent management of ECLS and cardiopulmonary bypass (CPB) are dictated by the surgical procedure. Hypothermia can be utilized while on ECLS to facilitate low-flow CPB, or circulatory arrest. Total extracorporeal circulation may be performed with the ECLS circuit, or the patient may be transferred to a conventional CPB circuit during the procedure. If required, post surgical ECLS can be facilitated through prior cannulation. We have found pre-operative institution ofECLS, in the neonate with severe congenital cardiac defects, provides immediate control of hemodynamic and respiratory problems, lowers the risk of cardiac catheterization, and reduces the usage of blood products during surgery