A Novel Na+-K+-Cl- Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke.

Background and Purpose- Inhibition of brain NKCC1 (Na+-K+-Cl- cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.

Neural Stem Cells in Adult Mammals are not Astrocytes.

At the turn of the 21st century studies of the cells that resided in the adult mammalian subventricular zone (SVZ) characterized the neural stem cells (NSCs) as a subtype of astrocyte. Over the ensuing years, numerous studies have further characterized the properties of these NSCs and compared them to parenchymal astrocytes. Here we have evaluated the evidence collected to date to establish whether classifying the NSCs as astrocytes is appropriate and useful. We also performed a meta-analysis with 4 previously published datasets that used cell sorting and unbiased single-cell RNAseq to highlight the distinct gene expression profiles of adult murine NSCs and niche astrocytes. On the basis of our understanding of the properties and functions of astrocytes versus the properties and functions of NSCs, and from our comparative transcriptomic analyses we conclude that classifying the adult mammalian NSC as an astrocyte is potentially misleading. From our vantage point, it is more appropriate to refer to the cells in the adult mammalian SVZ that retain the capacity to produce new neurons and macroglia as NSCs without attaching the term "astrocyte-like."

Development and Evaluation of a Sound-Swapped Video Database for Misophonia.

Misophonia has been characterized as intense negative reactions to specific trigger sounds (often orofacial sounds like chewing, sniffling, or slurping). However, recent research suggests high-level, contextual, and multisensory factors are also involved. We recently demonstrated that neurotypicals' negative reactions to aversive sounds (e.g., nails scratching a chalkboard) are attenuated when the sounds are synced with positive attributable video sources (PAVS; e.g., tearing a piece of paper). To assess whether this effect generalizes to misophonic triggers, we developed a Sound-Swapped Video (SSV) database for use in misophonia research. In Study 1, we created a set of 39 video clips depicting common trigger sounds (original video sources, OVS) and a corresponding set of 39 PAVS temporally synchronized with the OVS videos. In Study 2, participants (N = 34) rated the 39 PAVS videos for their audiovisual match and pleasantness. We selected the 20 PAVS videos with best match scores for use in Study 3. In Study 3, a new group of participants (n = 102) observed the 20 selected PAVS and 20 corresponding OVS and judged the pleasantness or unpleasantness of each sound in the two contexts accompanying each video. Afterward, participants completed the Misophonia Questionnaire (MQ). The results of Study 3 show a robust attenuating effect of PAVS videos on the reported unpleasantness of trigger sounds: trigger sounds were rated as significantly less unpleasant when paired with PAVS with than OVS. Moreover, this attenuating effect was present in nearly every participant (99 out of 102) regardless of their score on the MQ. In fact, we found a moderate positive correlation between the PAVS-OVS difference and misophonia severity scores. Overall our results provide validation that the SSV database is a useful stimulus database to study how misophonic responses can be modulated by visual contexts. Here, we release the SSV database with the best 18 PAVS and 18 OVS videos used in Study 3 along with aggregate ratings of audio-video match and pleasantness (https://osf.io/3ysfh/). We also provide detailed instructions on how to produce these videos, with the hope that this database grows and improves through collaborations with the community of misophonia researchers.

Diagnostic Value of Circulating MicroRNAs for Endometriosis: a Meta-analysis.

Endometriosis is a common reproductive system disease worldwide that mainly causes chronic pelvic pain and infertility. Despite its high prevalence, the diagnosis of some patients with endometriosis is delayed for several years, which may be because the gold standard for diagnosis is an expensive and invasive surgical assessment by laparoscopy or laparotomy. Circulating microRNAs (miRNAs) play an important role in a wide range of diseases, including endometriosis, and have been discovered to be potential diagnostic markers. This meta-analysis, which was designed to investigate the diagnostic value of circulating miRNAs for endometriosis, summarizes miRNA articles that met a set of inclusion criteria. Using a bivariate model, we calculated the sensitivities, specificities, and area under the curve (AUC) values of individual miRNAs and miRNA panels. The pooled diagnostic sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic (AUROC) curve were 0.86 (95% CI 0.79-0.90), 0.88 (95% CI 0.80-0.93), 7.05 (95% CI 4.20-11.84), 0.16 (95% CI 11-0.24), and 0.93, respectively. Taken together, these findings indicate that circulating microRNAs may serve as potential noninvasive biomarkers of endometriosis.

Efficacy and safety of sonothombolysis versus non-sonothombolysis in patients with acute ischemic stroke: A meta-analysis of randomized controlled trials.

Recent studies have shown that inconsistent results of safety and efficacy between sonothombolysis vs. non-sonothombolysis in acute ischemic stroke (AIS). We implemented a meta-analysis to explore the value of sonothrombolysis in AIS treatment. The MEDLINE, EMBASE, and Cochrane Library databases were searched for randomized controlled trials (RCTs) which had evaluated sonothrombolysis or ultrasound thrombolysis in AIS. One hundred five studies were retrieved and analyzed, among them, 7 RCTs were included in the current meta-analysis. In comparison with the non-sonothombolysis, sonothrombolysis significantly improved complete recanalization (RR 2.16, 95% CI 1.51 to 3.08, P < 0.001), complete or partial recanalization (RR 1.90, 95% CI 1.26 to 2.88, P = 0.002), there is also a tendency to improvement of ≥ 4 points in NIHSS score (RR 1.43, 95% CI 0.99 to 2.07, P = 0.057). However, sonothrombolysis and non-sonothrombolysis had insignificant differences in neurological recovery and adverse events. In subgroup analysis, we found that "With t-PA", "NIHSS > 15", "Treatment time ≤ 150min", and "Age ≤ 65 years" are potential favorable factors for efficacy outcomes of sonothombolysis. Sonothrombolysis can significantly increase the rate of recanalization in patients with AIS compared with non-sonothrombolysis, but there is no significant effect on improving neurological functional recovery and avoiding complications.

Interleukin-33 reduces neuronal damage and white matter injury via selective microglia M2 polarization after intracerebral hemorrhage in rats.

Interleukin-33 (IL-33) is closely related to the regulation of immunological cells, and its receptor ST2 is a member of the interleukin-1 (IL-1) receptor family. Inflammatory responses play critical roles in neuronal damage and white matter injury (WMI) post intracerebral hemorrhage (ICH). In this study, we tried to explore the role of IL-33 in neuronal damage and WMI after ICH and the underlying mechanisms. The in vivo ICH model was performed by autologous whole blood injection into the right basal ganglia in rats. Immunoblotting, immunofluorescence, brain water content measurement, FJB staining, and TUNEL staining were applied in this study. IL-33 expression was increased in whole brain tissues post-ICH, mainly rapidly increased in ipsilateral astrocyte and microglia, but stayed at a low level in neurons. Intracerebroventricular infusion of IL-33 after ICH attenuated short-term and long-term neurological deficits, WMI, neuronal degeneration, cell death and promoted the transformation of microglia phenotype from M1 to M2 in brain tissues after ICH. These results suggest that IL-33 reduces neuronal damage and WMI by promoting microglia M2 polarization after ICH, thereby improving the outcomes of neurological function.