Androgen regulation of the androgen receptor coregulators

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Neuroprotective Effect of Inhaled Nitric Oxide on Excitotoxic-Induced Brain Damage in Neonatal Rat

BACKGROUND: Inhaled nitric oxide (iNO) is one of the most promising therapies used in neonates. However, little information is known about its impact on the developing brain submitted to excitotoxic challenge. METHODOLOGY/PRINCIPAL FINDINGS: We investigated here the effect of iNO in a neonatal model of excitotoxic brain lesions. Rat pups and their dams were placed in a chamber containing 20 ppm NO during the first week of life. At postnatal day (P)5, rat pups were submitted to intracranial injection of glutamate agonists. At P10, rat pups exposed to iNO exhibited a significant decrease of lesion size in both the white matter and cortical plate compared to controls. Microglia activation and astrogliosis were found significantly decreased in NO-exposed animals. This neuroprotective effect was associated with a significant decrease of several glutamate receptor subunits expression at P5. iNO was associated with an early (P1) downregulation of pCREB/pAkt expression and induced an increase in pAkt protein concentration in response to excitotoxic challenge (P7). CONCLUSION: This study is the first describe and investigate the neuroprotective effect of iNO in neonatal excitotoxic-induced brain damage. This effect may be mediated through CREB pathway and subsequent modulation of glutamate receptor subunits expression

Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States

Vincent Lo Re III,1,2,* Noelle M Cocoros,3,4,* Rebecca A Hubbard,2 Sarah K Dutcher,5 Craig W Newcomb,2 John G Connolly,3,4 Silvia Perez-Vilar,5 Dena M Carbonari,2 Maria E Kempner,3,4 José J Hernández-Muñoz,5 Andrew B Petrone,3,4 Allyson M Pishko,6 Meighan E Rogers Driscoll,3,4 James T Brash,7 Sean Burnett,8,9 Catherine Cohet,10 Matthew Dahl,8,11 Terese A DeFor,12 Antonella Delmestri,13 Djeneba Audrey Djibo,14 Talita Duarte-Salles,15,16 Laura B Harrington,17 Melissa Kampman,18 Jennifer L Kuntz,19 Xavier Kurz,10 Núria Mercadé-Besora,15 Pamala A Pawloski,12 Peter R Rijnbeek,16 Sarah Seager,7 Claudia A Steiner,20,21 Katia Verhamme,16 Fangyun Wu,8,22 Yunping Zhou,23 Edward Burn,13 J Michael Paterson,8,22,* Daniel Prieto-Alhambra13,16,* 1Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Population Medicine, Harvard Medical School, Boston, MA, USA; 4Harvard Pilgrim Healthcare Institute, Boston, MA, USA; 5Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA; 6Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 7IQVIA, Real World Solutions, Brighton, UK; 8Canadian Network for Observational Drug Effect Studies (CNODES), Toronto, Ontario, Canada; 9Therapeutics Initiative, University of British Columbia, Vancouver, British Columbia, Canada; 10Data Analytics and Methods Task Force, European Medicines Agency, Amsterdam, Netherlands; 11Manitoba Centre for Health Policy, University of Manitoba, Winnipeg, Manitoba, Canada; 12HealthPartners Institute, Bloomington, MN, USA; 13Pharmaco- and Device Epidemiology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK; 14CVS Health, Blue Bell, PA, USA; 15Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain; 16Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands; 17Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA; 18Health Canada, Ottawa, Ontario, Canada; 19Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA; 20Kaiser Permanente Colorado Institute for Health Research, Aurora, CO, USA; 21Colorado Permanente Medical Group, Denver, CO, USA; 22ICES, Toronto, Ontario, Canada; 23Humana Healthcare Research, Inc., Louisville, KY, USA*These authors contributed equally to this workCorrespondence: Vincent Lo Re III, Division of Infectious Diseases, Department of Medicine, Division of Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA, Fax +1 215 573 5315, Email [email protected]: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability.Patients and Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE.Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09– 0.13%) in Canada to 1.01% (0.97– 1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21– 0.26%) in Canada to 0.84% (0.80– 0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06– 0.07%) in England to 1.04% (1.01– 1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24– 0.26%) in England to 1.02% (0.99– 1.04%) in the US.Conclusion: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability.Plain Language Summary: Cohort studies of patients diagnosed with COVID-19 in both the ambulatory and hospital settings have suggested that SARS-CoV-2 infection promotes hypercoagulability that could lead to arterial or venous thromboembolism. However, few studies have examined how the risk of thromboembolism with COVID-19 has evolved over time across different countries. A new collaboration was established among the regulatory authorities of Canada, Europe, and the US within the International Coalition of Medicines Regulatory Authorities to evaluate the 90-day risk of both arterial and venous thromboembolism after initial diagnosis of COVID-19 in the ambulatory or hospital setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. The study found that there was variability in the risk of both arterial and venous thromboembolism by month across the countries among patients initially diagnosed with COVID-19 in the ambulatory or hospital setting. Differences in the healthcare systems, prevalence of comorbidities in the study cohorts, and approaches to the case definitions of thromboembolism likely contributed to the variability in estimates of thromboembolism risk across the countries.Keywords: COVID-19, ischemic stroke, myocardial infarction, thromboembolism, venous thromboembolis