Search

Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43-mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies-related diseases., (© 2021 Ho et al.)

Background: In the current COVID-19 pandemic, aggressive Infection Prevention and Control (IPC) measures have been adopted to prevent health care-associated transmission of COVID-19. We evaluated the impact of a multimodal IPC strategy originally designed for the containment of COVID-19 on the rates of other hospital-acquired-infections (HAIs)., Methodology: From February-August 2020, a multimodal IPC strategy was implemented across a large health care campus in Singapore, comprising improved segregation of patients with respiratory symptoms, universal masking and heightened adherence to Standard Precautions. The following rates of HAI were compared pre- and postpandemic: health care-associated respiratory-viral-infection (HA-RVI), methicillin-resistant Staphylococcus aureus, and CP-CRE acquisition rates, health care-facility-associated C difficile infections and device-associated HAIs., Results: Enhanced IPC measures introduced to contain COVID-19 had the unintended positive consequence of containing HA-RVI. The cumulative incidence of HA-RVI decreased from 9.69 cases per 10,000 patient-days to 0.83 cases per 10,000 patient-days (incidence-rate-ratio = 0.08; 95% confidence interval [CI] = 0.05-0.13, P< .05). Hospital-wide MRSA acquisition rates declined significantly during the pandemic (incidence-rate-ratio = 0.54, 95% CI = 0.46-0.64, P< .05), together with central-line-associated-bloodstream infection rates (incidence-rate-ratio = 0.24, 95% CI = 0.07-0.57, P< .05); likely due to increased compliance with Standard Precautions. Despite the disruption caused by the pandemic, there was no increase in CP-CRE acquisition, and rates of other HAIs remained stable., Conclusions: Multimodal IPC strategies can be implemented at scale to successfully mitigate health care-associated transmission of RVIs. Good adherence to personal-protective-equipment and hand hygiene kept other HAI rates stable even during an ongoing pandemic where respiratory infections were prioritized for interventions., (Copyright © 2020 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Integration and modulation of primary afferent sensory information begins at the first terminating sites within the CNS, where central inhibitory circuits play an integral role. Viscerosensory information is conveyed to the nucleus of the solitary tract (NTS) where it initiates neuroendocrine, behavioral, and autonomic reflex responses that ensure optimal internal organ function. This excitatory input is modulated by diverse, local inhibitory interneurons, whose functions are not clearly understood. Here we show that, in male rats, 65% of somatostatin-expressing (SST) NTS neurons also express GAD67, supporting their likely role as inhibitory interneurons. Using whole-cell recordings of NTS neurons, from horizontal brainstem slices of male and female SST-yellow fluorescent protein (YFP) and SST-channelrhodopsin 2 (ChR2)-YFP mice, we quantified the impact of SST-NTS neurons on viscerosensory processing. Light-evoked excitatory photocurrents were reliably obtained from SST-ChR2-YFP neurons ( n = 16) and the stimulation-response characteristics determined. Most SST neurons (57%) received direct input from solitary tract (ST) afferents, indicating that they form part of a feedforward circuit. All recorded SST-negative NTS neurons ( n = 72) received SST-ChR2 input. ChR2-evoked PSCs were largely inhibitory and, in contrast to previous reports, were mediated by both GABA and glycine. When timed to coincide, the ChR2-activated SST input suppressed ST-evoked action potentials at second-order NTS neurons, demonstrating strong modulation of primary viscerosensory input. These data indicate that the SST inhibitory network innervates broadly within the NTS, with the potential to gate viscerosensory input to powerfully alter autonomic reflex function and other behaviors. SIGNIFICANCE STATEMENT Sensory afferent input is modulated according to state. For example the baroreflex is altered during a stress response or exercise, but the basic mechanisms underpinning this sensory modulation are not fully understood in any sensory system. Here we demonstrate that the neuronal processing of viscerosensory information begins with synaptic gating at the first central synapse with second-order neurons in the NTS. These data reveal that the somatostatin subclass of inhibitory interneurons are driven by visceral sensory input to play a major role in gating viscerosensory signals, placing them within a feedforward circuit within the NTS., (Copyright © 2019 the authors.)