Blood vessels in the central nervous system (CNS) form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells to peripheral endothelial cells. We also assessed the regulation of CNS Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Gut microbiota modulates metabolic and immunoregulatory axes and contributes to the pathophysiology of diseases with inflammatory components, such as atherosclerosis, diabetes, and ischemic stroke. Inflammation is emerging as a critical player in the pathophysiology of intracranial aneurysm. Therefore, we hypothesized that the gut microbiota affects aneurysm formation by modulating inflammation. We induced intracranial aneurysms in mice by combining systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Depletion of the gut microbiota was achieved via an oral antibiotic cocktail of vancomycin, metronidazole, ampicillin, and neomycin. Antibiotics were given three weeks before aneurysm induction and either continued until the end of the experiment or stopped one day before aneurysm induction. We also assessed the effects of the gut microbiota depletion on macrophage infiltration and mRNA levels of inflammatory cytokines. Gut microbiota depletion by antibiotics reduced the incidence when antibiotics were started three weeks before aneurysm induction and continued until the end of the experiment (83% vs. 6%, P < 0.001). Even when antibiotics were stopped one day before aneurysm induction, the gut microbiota depletion significantly reduced the incidence of aneurysms (86% vs. 28%, P < 0.05). Both macrophage infiltration and mRNA levels of inflammatory cytokines were reduced with gut microbiota depletion. These findings suggest that the gut microbiota contributes to the pathophysiology of aneurysms by modulating inflammation. Human studies are needed to determine the exact contribution of the gut microbiota to the pathophysiology of aneurysm formation and disease course in humans.

Keywords:High-flow nasal therapy Pathogen transmission Droplet infection S U M M A R YHigh-flow nasal therapy is increasingly used in hospitals because of its effectiveness and patient comfort. However, pathogens in the patient's nasal and oral cavities may be dispersed by forced air. This study aimed to investigate the risk of pathogen dispersal during high-flow nasal therapy. Liquid and bacterial dispersal were assessed via in-vitro experimental set-ups using a manikin. Thickened water or fresh yeast solution mimicked saliva and nasal mucus secretions. Dispersal was limited to the proximal area of the face and nasal cannula, suggesting that high-flow nasal therapy does not increase the risk of droplet and contact infection.

Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release.

These data suggest that the lack of myeloid cell autophagy aggravates secondary injury by augmenting and prolonging inflammation after ischemic stroke without affecting the initial injury.

The lack of sensitive and robust behavioral assessments of pain in preclinical models has been a major limitation for both pain research and the development of novel analgesics. Here, we demonstrate a novel data acquisition and analysis platform that provides automated, quantitative, and objective measures of naturalistic rodent behavior in an observer-independent and unbiased fashion. The technology records freely behaving mice, in the dark, over extended periods for continuous acquisition of 2 parallel video data streams: (1) near-infrared frustrated total internal reflection for detecting the degree, force, and timing of surface contact and (2) simultaneous ongoing video graphing of whole-body pose. Using machine vision and machine learning, we automatically extract and quantify behavioral features from these data to reveal moment-by-moment changes that capture the internal pain state of rodents in multiple pain models. We show that these voluntary pain-related behaviors are reversible by analgesics and that analgesia can be automatically and objectively differentiated from sedation. Finally, we used this approach to generate a paw luminance ratio measure that is sensitive in capturing dynamic mechanical hypersensitivity over a period and scalable for highthroughput preclinical analgesic efficacy assessment.

Background We evaluated the change of cerebral regional tissue oxygen saturation (rSO 2 ) along with the pneumoperitoneum and the Trendelenburg position. We also assessed the relationship between the change of rSO 2 and the changes of mean arterial blood pressure (MAP), heart rate (HR), arterial carbon dioxide tension (PaCO 2 ), arterial oxygen tension (PaO 2 ), or arterial oxygen saturation (SaO 2 ). Methods Forty-one adult patients who underwent a robotic assisted endoscopic prostatic surgery under propofol and remifentanil anesthesia were involved in this study. During the surgery, a pneumoperitoneum was established using carbon dioxide. Measurements of rSO 2 , MAP, HR, PaCO 2 , PaO 2 , and SaO 2 were performed before the pneumoperitoneum (baseline), every 5 min after the onset of pneumoperitoneum, before the Trendelenburg position. After the onset of the Trendelenburg position, rSO 2 , MAP, HR were recorded at 5, 10, 20, 30, 45, and 60 min, and PaCO 2 , PaO 2 , and SaO 2 were measured at 10, 30, and 60 min. Results Before the pneumoperitoneum, left and right rSO 2 were 67.9 ± 6.3% and 68.5 ± 7.0%. Ten minutes after the onset of pneumoperitoneum, significant increase in the rSO 2 was observed (left: 69.6 ± 5.9%, right: 70.6 ± 7.4%). During the Trendelenburg position, the rSO 2 increased initially and peaked at 5 min (left: 72.2 ± 6.5%, right: 73.1 ± 7.6%), then decreased. Multiple regression analysis showed that change of rSO 2 correlated with MAP and PaCO 2 . Conclusions Pneumoperitoneum and the Trendelenburg position in robotic-assisted endoscopic prostatic surgery did not worsen cerebral oxygenation. Arterial blood pressure is the critical factor in cerebral oxygenation. Trial registration Japan Primary Registries Network (JPRN); UMIN-CTR ID; UMIN000026227 (retrospectively registered).

BackgroundIon channels play a crucial role in the development of ischemic brain injury. Recent studies have reported that the blockade of various types of ion channels improves outcomes in experimental stroke models. Amiodarone, one of the most effective drugs for life-threatening arrhythmia, works as a multiple channel blocker and its characteristics cover all four Vaughan-Williams classes. Although it is known that amiodarone indirectly contributes to preventing ischemic stroke by maintaining sinus rhythm in patients with atrial fibrillation, the direct neuroprotective effect of amiodarone has not been clarified. The purpose of this study was to investigate the direct effect of amiodarone on ischemic stroke in mice.MethodsFocal cerebral ischemia was induced via distal permanent middle cerebral artery occlusion (MCAO) in adult male mice. The amiodarone pre-treatment group received 50 mg/kg of amiodarone 1 h before MCAO; the amiodarone post-treatment groups received 50 mg/kg of amiodarone immediately after MCAO; the control group received vehicle only. In addition, the sodium channel opener veratrine and selective beta-adrenergic agonist isoprotelenol were used to elucidate the targeted pathway. Heart rate and blood pressure were monitored perioperatively. Infarct volume analysis was conducted 48 h after MCAO. The body asymmetry test and the corner test were used for neurological evaluation.ResultsAmiodarone pre-treatment and post-treatment reduced the heart rate but did not affect the blood pressure. No mice showed arrhythmia. Compared with the control group, the amiodarone pre-treatment group had smaller infarct volumes (8.9 ± 2.1% hemisphere [mean ± SD] vs. 11.2 ± 1.4%; P < 0.05) and improved functional outcomes: lower asymmetric body swing rates (52 ± 17% vs. 65 ± 18%; P < 0.05) and fewer left turns (7.1 ± 1.2 vs. 8.3 ± 1.2; P < 0.05). In contrast, amiodarone post-treatment did not improve the outcomes after MCAO. The neuroprotective effect of amiodarone pre-treatment was abolished by co-administration of veratrine but not by isoproterenol.ConclusionsAmiodarone pre-treatment attenuated ischemic brain injury and improved functional outcomes without affecting heart rhythm and blood pressure. The present results showed that amiodarone pre-treatment has neuroprotective effects, at least in part, via blocking the sodium channels.