Glymphatic fluid transport is suppressed by the aquaporin-4 inhibitor AER-271.

The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain.

Modulation of central synapse remodeling after remote peripheral injuries by the CCL2-CCR2 axis and microglia.

Microglia-mediated synaptic plasticity after CNS injury varies depending on injury severity, but the mechanisms that adjust synaptic plasticity according to injury differences are largely unknown. This study investigates differential actions of microglia on essential spinal motor synaptic circuits following different kinds of nerve injuries. Following nerve transection, microglia and C-C chemokine receptor type 2 signaling permanently remove Ia axons and synapses from the ventral horn, degrading proprioceptive feedback during motor actions and abolishing stretch reflexes. However, Ia synapses and reflexes recover after milder injuries (nerve crush). These different outcomes are related to the length of microglia activation, being longer after nerve cuts, with slower motor-axon regeneration and extended expression of colony-stimulating factor type 1 in injured motoneurons. Prolonged microglia activation induces CCL2 expression, and Ia synapses recover after ccl2 is deleted from microglia. Thus, microglia Ia synapse removal requires the induction of specific microglia phenotypes modulated by nerve regeneration efficiencies. However, synapse preservation was not sufficient to restore the stretch-reflex function.

A National Study of Expedited Partner Therapy Use in Emergency Departments: A Survey of Medical Director Knowledge, Attitudes, and Practices.

BACKGROUND: Emergency departments (EDs) are the primary source of health care for many patients diagnosed with sexually transmitted infections (STIs). Expedited partner therapy (EPT), treating the partner of patients with STIs, is an evidence-based practice for patients who might not otherwise seek care. Little is known about the use of EPT in the ED. In a national survey, we describe ED medical directors' knowledge, attitudes, and practices of EPT. METHODS: A cross-sectional survey of medical directors from academic EDs was conducted from July to September 2020 using the Academy of Academic Administrators of Emergency Medicine Benchmarking Group. Primary outcomes were EPT awareness, support, and use. The survey also examined barriers and facilitators. RESULTS: Forty-eight of 70 medical directors (69%) responded. Seventy-three percent were aware of EPT, but fewer knew how to prescribe it (38%), and only 19% of EDs had implemented EPT. Seventy-nine percent supported EPT and were more likely to if they were aware of EPT (89% vs. 54%; P = 0.01). Of nonimplementers, 41% thought EPT was feasible, and 56% thought departmental support would be likely. Emergency department directors were most concerned about legal liability, but a large proportion (44%) viewed preventing sequelae of untreated STIs as "extremely important." CONCLUSIONS: Emergency department medical directors expressed strong support for EPT and reasonable levels of feasibility for implementation but low utilization. Our findings highlight the need to identify mechanisms for EPT implementation in EDs.

Does vaginal estrogen use increase the risk for adverse cardiovascular outcomes?

NO. In general, nonoral estrogen use for menopausal symptoms is associated with a lower cardiovascular (CV) risk profile than oral estrogen use (strength of recommendation [SOR], B; meta-analysis of cohort studies). Vaginal estrogen use is associated with lower risk for coronary heart disease (CHD) and similar risk for myocardial infarction (MI), stroke, and deep vein thrombosis/pulmonary embolism (DVT/ PE) compared with nonuse (SOR, B; cohort studies). Vaginal estrogen therapy also is associated with lower CV-related mortality for 3 to 5 years compared withnonuse (SOR, B; cohort study). No high-quality randomized trials address this topic.