Human Cord Blood Stem Cell-Modulated Regulatory T Lymphocytes Reverse the Autoimmune-Caused Type 1 Diabetes in Nonobese Diabetic (NOD) Mice

Background: The deficit of pancreatic islet b cells caused by autoimmune destruction is a crucial issue in type 1 diabetes (T1D). It is essential to fundamentally control the autoimmunity for treatment of T1D. Regulatory T cells (Tregs) play a pivotal role in maintaining self-tolerance through their inhibitory impact on autoreactive effector T cells. An abnormality of Tregs is associated with initiation of progression of T1D. Methodology/Principal Findings: Here, we report that treatment of established autoimmune-caused diabetes in NOD mice with purified autologous CD4 + CD62L + Tregs co-cultured with human cord blood stem cells (CB-SC) can eliminate hyperglycemia, promote islet b-cell regeneration to increase b-cell mass and insulin production, and reconstitute islet architecture. Correspondingly, treatment with CB-SC-modulated CD4 + CD62L + Tregs (mCD4CD62L Tregs) resulted in a marked reduction of insulitis, restored Th1/Th2 cytokine balance in blood, and induced apoptosis of infiltrated leukocytes in pancreatic islets. Conclusions/Significance: These data demonstrate that treatment with mCD4CD62L Tregs can reverse overt diabetes

Vaping in today's pandemic: E-cigarette, or vaping, product use-associated lung injury mimicking COVID-19 in teenagers presenting with respiratory distress.

The clinical presentation of children and adolescents infected with severe acute respiratory syndrome coronavirus 2 can range from asymptomatic to mild or moderate manifestations. We present a case series of three adolescents who presented during the coronavirus disease 2019 (COVID-19) pandemic with symptoms concerning for COVID-19, including fever, abdominal symptoms, cough, respiratory distress, and hypoxemia. Their laboratory results showed elevated inflammatory markers that are also commonly seen in COVID-19. The chest imaging studies mimicked COVID-19 with non-specific ground glass opacities and interstitial prominence patterns. However, severe acute respiratory syndrome coronavirus 2 testing was negative and further questioning of these adolescents and their parents revealed a history of vaping marijuana-related products leading to the eventual diagnosis of e-cigarette, or vaping, product use-associated lung injury. Our patients were successfully treated with corticosteroids. The providers caring for pediatric patients, especially adolescents, should continue to have a high index of suspicion for e-cigarette, or vaping, product use-associated lung injury in patients presenting with unexplained respiratory failure, while ruling out COVID-19

Effect of Clemastine on Neurophysiological Outcomes in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy

Originally approved by the U.S. Food and Drug Administration (FDA) for its antihistamine properties, clemastine can also promote white matter integrity and has shown promise in the treatment of demyelinating diseases such as multiple sclerosis. Here, we conducted an in-depth analysis of the feasibility, safety, and neuroprotective efficacy of clemastine administration in near-term lambs (n = 25, 141–143 days) following a global ischemic insult induced via an umbilical cord occlusion (UCO) model. Lambs were randomly assigned to receive clemastine or placebo postnatally, and outcomes were assessed over a six-day period. Clemastine administration was well tolerated. While treated lambs demonstrated improvements in inflammatory scores, their neurodevelopmental outcomes were unchanged

Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling

The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD using fetal surgical techniques: 1) left pulmonary artery (LPA) ligation primarily resulting in increased PBF and 2) aortopulmonary shunt placement resulting in increased PBF and PAP. Hemodynamic, histologic, and molecular studies were performed on control, LPA, and shunt lambs as well as pulmonary artery endothelial cells (PAECs) derived from each. Physiologically, LPA, and to a greater extent shunt, lambs demonstrated an exaggerated increase in PAP in response to vasoconstricting stimuli compared with controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt lambs but not in control or LPA lambs. Furthermore, in the setting of acutely increased afterload, the right ventricle of control and LPA but not shunt lambs demonstrates ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. In addition, we found hyperproliferation of PAECs from LPA lambs, and to a greater extent shunt lambs, with associated increased angiogenesis and decreased apoptosis in PAECs derived from shunt lambs. A further understanding of mechanical force-specific drivers of pulmonary artery pathology will enable development of precision therapeutics for pulmonary hypertension associated with CHD