Citations

Significance Endocytic sorting of amyloid precursor protein (APP) governed by the vacuolar protein sorting (Vps10) family of receptors plays a decisive role in controlling the outcome of APP proteolytic processing and the generation of amyloid β (Aβ) peptides, the key pathogenic factor of Alzheimer's disease (AD). This study provides the first evidence to our knowledge that a G protein-coupled receptor, namely, the α 2A adrenergic receptor, modulates APP endocytic sorting and promotes Aβ generation through disrupting APP interaction with a Vps10 family protein, sorting-related receptor with A repeat. Significantly, blockade of α 2A AR by a clinical antagonist reduces AD-related pathology and ameliorates cognitive deficits in an AD transgenic model, suggesting repurposing clinical α 2 AR antagonists as a new direction for AD treatment.

ABSTRACT Human respiratory syncytial virus (RSV) is a major cause of morbidity and severe lower respiratory tract disease in the elderly and very young, with some infants developing bronchiolitis, recurrent wheezing, and asthma following infection. Previous studies in humans and animal models have shown that vaccination with formalin-inactivated RSV (FI-RSV) leads to prominent airway eosinophilic inflammation following RSV challenge; however, the roles of pulmonary eosinophilia in the antiviral response and in disease pathogenesis are inadequately understood. In vivo studies in mice with eotaxin and/or interleukin 5 (IL-5) deficiency showed that FI-RSV vaccination did not lead to enhanced pulmonary disease, where following challenge there were reduced pulmonary eosinophilia, inflammation, Th2-type cytokine responses, and altered chemokine (TARC and CCL17) responses. In contrast to wild-type mice, RSV was recovered at high titers from the lungs of eotaxin- and/or IL-5-deficient mice. Adoptive transfer of eosinophils to FI-RSV-immunized eotaxin- and IL-5-deficient (double-deficient) mice challenged with RSV was associated with potent viral clearance that was mediated at least partly through nitric oxide. These studies show that pulmonary eosinophilia has dual outcomes: one linked to RSV-induced airway inflammation and pulmonary pathology and one with innate features that contribute to a reduction in the viral load. IMPORTANCE This study is critical to understanding the mechanisms attributable to RSV vaccine-enhanced disease. This study addresses the hypothesis that IL-5 and eotaxin are critical in pulmonary eosinophil response related to FI-RSV vaccine-enhanced disease. The findings suggest that in addition to mediating tissue pathology, eosinophils within a Th2 environment also have antiviral activity.

ObjectiveTo propose an anatomic classification for fetal nuchal lymphatic anomalies that will be clinically useful and to evaluate the classification’s value in predicting chromosomal abnormalities, pregnancy outcomes, other associated fetal anomalies, and spontaneous resolution of these lesions.Study DesignRetrospective cohort study.SettingTertiary academic hospital and affiliated tertiary children’s hospital.Subjects and MethodsMother‐baby pairs diagnosed with fetal nuchal lymphatic anomalies in a prenatal ultrasound database. Anomalies were classified as nuchal thickening, dorsal lymphatic malformation, or ventral lymphatic malformation. Pregnancy outcomes, prevalence of chromosomal and anatomic abnormalities, and rates of spontaneous lesion resolution were determined for each group.ResultsThe study included 189 patients: 58 with nuchal thickening, 120 with dorsal lymphatic malformation, and 11 with ventral lymphatic malformation. In fetuses for whom chromosomal analysis was available, chromosomal abnormalities were strongly associated with dorsal lymphatic malformations (83%), less associated with nuchal thickening (29%), and not associated with ventral lymphatic malformations. Dorsal lymphatic malformation predicted high rates of elective (43%) and spontaneous (20%) termination of pregnancy and showed the strongest association with cardiac, renal, and skeletal anomalies. Nuchal thickening was more likely to resolve in utero than dorsal lymphatic malformations, while no ventral lymphatic malformation resolved spontaneously.ConclusionsFetal nuchal anomalies demonstrate significant and clinically important prognostic differences depending on their anatomic location. The simple classification system proposed here therefore provides useful information to clinicians involved in the pre‐ and postnatal management of children with these anomalies.

Abstract Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose–effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).