Effect of N-Acetylcysteine on Sleep: Impacts of Sex and Time of Day.

Non-rapid eye movement sleep (NREMS) is accompanied by a decrease in cerebral metabolism, which reduces the consumption of glucose as a fuel source and decreases the overall accumulation of oxidative stress in neural and peripheral tissues. Enabling this metabolic shift towards a reductive redox environment may be a central function of sleep. Therefore, biochemical manipulations that potentiate cellular antioxidant pathways may facilitate this function of sleep. N-acetylcysteine increases cellular antioxidant capacity by serving as a precursor to glutathione. In mice, we observed that intraperitoneal administration of N-acetylcysteine at a time of day when sleep drive is naturally high accelerated the onset of sleep and reduced NREMS delta power. Additionally, N-acetylcysteine administration suppressed slow and beta electroencephalographic (EEG) activities during quiet wake, further demonstrating the fatigue-inducing properties of antioxidants and the impact of redox balance on cortical circuit properties related to sleep drive. These results implicate redox reactions in the homeostatic dynamics of cortical network events across sleep/wake cycles, illustrating the value of timing antioxidant administration relative to sleep/wake cycles. A systematic review of the relevant literature, summarized herein, indicates that this "chronotherapeutic hypothesis" is unaddressed within the clinical literature on antioxidant therapy for brain disorders such as schizophrenia. We, therefore, advocate for studies that systematically address the relationship between the time of day at which an antioxidant therapy is administered relative to sleep/wake cycles and the therapeutic benefit of that antioxidant treatment in brain disorders.

Propofol infusion syndrome & COVID-19 in a victim of multiple gunshot wounds: Diagnostic and therapeutic dilemmas.

Background: COVID-19 has become a global pandemic. It has affected patients the world over, and when minimally symptomatic, it can be an incidental finding in trauma patients. It may also make the diagnosis of other rare conditions more difficult due to clinical finding superimposition. Case presentation: A 23-year-old male was transferred to our Trauma Center in hemorrhagic shock after sustaining multiple gunshot wounds in the upper back. Imaging showed a retained projectile in the right pharyngeal area, a right upper lobe contusion, and a right hemopneumothorax; with additional infiltrates on both lungs suggestive of atelectasis. After intubation, a propofol infusion was started for sedation. Shortly thereafter worsening acidosis, refractory hypoxia, and hypotension with additional laboratory anomalies ensued, as the PCR screening for SARS-CoV-2 returned positive. The clinical findings suggested COVID-19 pneumonia with possible superimposed Propofol Infusion Syndrome. The drug was stopped, and the symptoms improved. Conclusion: A high index of suspicion is necessary to manage unusual pathologies and difficult differential diagnoses, and this is especially true during the ongoing pandemic.

Hybrid Steered Molecular Dynamics-Docking: An Efficient Solution to the Problem of Ranking Inhibitor Affinities Against a Flexible Drug Target.

Existing techniques which attempt to predict the affinity of protein-ligand interactions have demonstrated a direct relationship between computational cost and prediction accuracy. We present here the first application of a hybrid ensemble docking and steered molecular dynamics scheme (with a minimized computational cost), which achieves a binding affinity rank-ordering of ligands with a Spearman correlation coefficient of 0.79 and an RMS error of 0.7 kcal/mol. The scheme, termed Flexible Enzyme Receptor Method by Steered Molecular Dynamics (FERM-SMD), is applied to an in-house collection of 17 validated ligands of glutamate racemase. The resulting improved accuracy in affinity prediction allows elucidation of the key structural components of a heretofore unreported glutamate racemase inhibitor (K(i) = 9 µM), a promising new lead in the development of antibacterial therapeutics.