Glymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke.

BACKGROUND: Blood-brain barrier damage has traditionally been considered to determine the occurrence and development of poststroke brain edema, a devastating and life-threatening complication. However, no treatment strategy targeting blood-brain barrier damage has been proven clinically effective in ameliorating brain edema. METHODS: In mice with stroke models induced by transient middle cerebral artery occlusion (MCAO), the changes in glymphatic system (GS) function impairment were detected by ex vivo fluorescence imaging, 2-photon in vivo imaging, and magnetic resonance imaging within 1 week after MCAO, and the effects of GS impairment and recovery on the formation and resolution of brain edema were evaluated. In addition, in patients with ischemic stroke within 1 week after onset, changes in GS function and brain edema were also observed by magnetic resonance imaging. RESULTS: We found that the extravasation of protein-rich fluids into the brain was not temporally correlated with edema formation after MCAO in mice, as brain edema reabsorption preceded blood-brain barrier closure. Strikingly, the time course of edema progression matched well with the GS dysfunction after MCAO. Pharmacological enhancement of the GS function significantly alleviated brain edema developed on day 2 after MCAO, accompanied by less deposition of Aß (amyloid-ß) and better cognitive function. Conversely, functional suppression of the GS delayed the absorption of brain edema on day 7 after MCAO. Moreover, patients with ischemic stroke revealed a consistent trend of GS dysfunction after reperfusion as MCAO mice, which was correlated with the severity of brain edema and functional outcomes. CONCLUSIONS: GS is a key contributor to the formation of brain edema after ischemic stroke, and targeting the GS may be a promising strategy for treating brain edema in ischemic stroke. REGISTRATION: URL: https://www.chictr.org.cn/showproj.html?proj=162857; Unique identifier: NFEC-2019-189.

Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): a randomized, double-blind, placebo-controlled trial.

Background: Glibenclamide alleviates brain edema and improves neurological outcomes in experimental models of stroke. We aimed to assess whether glibenclamide improves functional outcomes in patients with acute ischemic stroke treated with recombinant tissue plasminogen activator (rtPA). Methods: In this randomized, double-blind, placebo-controlled trial, patients with acute ischemic stroke were recruited to eight academic hospitals in China. Patients were eligible if they were aged 18-74 years, presented with a symptomatic anterior circulation occlusion with a deficit on the NIHSS of 4-25, and had been treated with rtPA within 4.5 h of symptom onset. We used web-based randomization (1:1) to allocate eligible participants to the glibenclamide or placebo group, stratified according to endovascular treatment and baseline stroke severity. Glibenclamide or placebo was taken orally or via tube feeding at a loading dose of 1.25 mg within 10 h after symptom onset, followed by 0.625 mg every 8 h for 5 days. The primary outcome was the proportion of patients with good outcomes (modified Rankin Scale of 0-2) at 90 days, assessed in all randomly assigned patients who had been correctly diagnosed and had begun study medication. The study is registered with ClinicalTrials.gov, NCT03284463, and is closed to new participants. Findings: Between January 1, 2018, and May 28, 2022, 305 patients were randomly assigned, of whom 272 (142 received glibenclamide and 130 received placebo) were included in the primary efficacy analysis. 103 (73%) patients in the glibenclamide group and 94 (72%) in the placebo group had a good outcome (adjusted risk difference 0.002, 95% CI -0.098 to 0.103; p = 0.96). 12 (8%) patients allocated to glibenclamide and seven (5%) patients allocated to placebo died from any cause at 90 days (p = 0.35). The number and type of adverse events were similar between the two groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: The addition of glibenclamide to thrombolytic therapy did not increase the proportion of patients who achieved good outcomes after stroke compared with placebo, but it did not lead to any safety concerns. Funding: Southern Medical University and Nanfang Hospital.

Magnetically empowered bone marrow cells as a micro-living motor can improve early hematopoietic reconstitution.

BACKGROUND AIMS: Bone marrow-derived hematopoietic stem cell transplantation/hematopoietic progenitor cell transplantation (HSCT/HPCT) is widely used and one of the most useful treatments in clinical practice. However, the homing rate of hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) by routine cell transfusion is quite low, influencing hematopoietic reconstitution after HSCT/HPCT. METHODS: The authors developed a micro-living motor (MLM) strategy to increase the number of magnetically empowered bone marrow cells (ME-BMCs) homing to the bone marrow of recipient mice. RESULTS: In the in vitro study, migration and retention of ME-BMCs were greatly improved in comparison with non-magnetized bone marrow cells, and the biological characteristics of ME-BMCs were well maintained. Differentially expressed gene analysis indicated that ME-BMCs might function through gene regulation. In the in vivo study, faster hematopoietic reconstitution was observed in ME-BMC mice, which demonstrated a better survival rate and milder symptoms of acute graft-versus-host disease after transplantation of allogeneic ME-BMCs. CONCLUSIONS: This study demonstrated that ME-BMCs serving as MLMs facilitated the homing of HSCs/HPCs and eventually contributed to earlier hematopoietic reconstitution in recipients. These data might provide useful information for other kinds of cell therapies.

The Performances of SNAQ, GLIM, mNICE, and ASPEN for Identification of Neurocritically Ill Patients at High Risk of Developing Refeeding Syndrome.

We previously found that neurocritically ill patients are prone to refeeding syndrome (RFS), a potentially life-threatening complication. However, there is no unified or validated consensus on the screening tool for RFS so far. We aimed to validate and compare the performance of four screening tools for RFS in neurocritically ill patients. We conducted a single-center, observational, retrospective cohort study among neurocritically ill adult patients who were admitted to the neurocritical care unit (NCU), and who received enteral nutrition for 72 h or longer. They were scored on the Short Nutritional Assessment Questionnaire (SNAQ), the Global Leadership Initiative on Malnutrition (GLIM), the modified criteria of the Britain's National Institute for Health and Care Excellence (mNICE), and ASPEN Consensus Recommendations for Refeeding Syndrome (ASPEN) scales to predict RFS risk via admission data. The performance of each scale in predicting RFS was evaluated. Logistic regression analysis was used to identify the independent risk factors for RFS, and they were added to the above scales to strengthen the identification of RFS. Of the 478 patients included, 84 (17.57%) developed RFS. The sensitivity of the SNAQ and GLIM was only 20.2% (12.6-30.7%), although they had excellent specificities of 84.8% (80.8-88.1%) and 86.0% (82.1-89.2%), respectively; mNICE predicted RFS with a sensitivity of 48.8% (37.8-59.9%) and a specificity of 65.0% (60.0-69.9%); ASPEN had the highest Youden index, with a sensitivity and specificity of 53.6% (42.4-64.4%) and 64.7% (59.8-69.4%), respectively. The Area Under the receiver operating characteristic Curves (AUC) of SNAQ, GLIM, mNICE, and ASPEN to predict RFS were 0.516 (0.470-0.561), 0.533 (0.487-0.579), 0.568 (0.522-0.613), and 0.597 (0.551-0.641), respectively. We identified age, Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Glasgow Coma Scale (GCS) score as independent risk factors of RFS, and the combination of GCS and age can improve the AUC of ASPEN to 0.664 (0.620-0.706) for predicting RFS. SNAQ, GLIM, mNICE, and ASPEN do not perform well in identifying neurocritically ill patients at high risk of RFS, although ASPEN appears to have relatively a good validity among them. Combining GCS and age with ASPEN slightly improves RFS recognition, but it still leaves a lot of room for improvement.

Interparental Conflict and Delinquency Among Chinese Adolescents: Parental Knowledge as a Mediator and Deviant Peer Affiliation as a Moderator.

Interparental conflict has been found to positively affect adolescent delinquency; however, the underlying mechanism that explains this association remains unclear. This study investigated whether parental knowledge mediates the association between interparental conflict and adolescent delinquency, and whether this mediating process is moderated by deviant peer affiliation. To examine this, a total of 3,129 Chinese adolescents (47.27% boys, Mean age = 14.94 years) completed a survey. Structural equation modeling indicated that the positive association between interparental conflict and adolescent delinquency is mediated by parental knowledge. Moreover, for adolescents with high deviant peer affiliation, interparental conflict was found to positively predict delinquency via parental knowledge; however, this indirect link was non-significant for adolescents with low deviant peer affiliation. These findings highlight the influence of parental knowledge and deviant peer affiliation on the association between interparental conflict and adolescent delinquency. This can provide guidance for the development of effective interventions that address the adverse effects of interparental conflict.

Exposure to Community Violence, Affiliations With Risk-Taking Peer Groups, and Internet Gaming Disorder Among Chinese Adolescents: The Moderating Role of Parental Monitoring.

Among adolescents, exposure to community violence (ECV) has been consistently linked to problem behaviors such as Internet gaming disorder (IGD). However, the associated risk and protective factors have not been adequately explored in past studies. Therefore, in accordance with the risk-buffering model and social development model, this study aimed to test whether parental monitoring moderated the relationship between ECV and IGD among adolescents, and whether this moderating effect was mediated by affiliations with risk-taking peer groups. A sample of 2,423 Chinese middle-school students anonymously responded to questionnaires that assessed ECV, IGD, affiliations with risk-taking peer groups, and parental monitoring. The results of structural equation modeling revealed that the interaction between ECV and parental monitoring negatively related to IGD among adolescents. Specifically, the positive relationship between ECV and IGD was stronger for adolescents, who reported low levels of parental monitoring than for those who reported high levels of parental monitoring. Moreover, this moderating effect was mediated by affiliations with risk-taking peer groups. These results suggest that parental monitoring is an important protective factor that can mitigate the risk of IGD among adolescents who have been exposed to community violence. Accordingly, these findings serve as an empirical base upon which prevention and intervention strategies that are aimed at mitigating the risk of IGD among adolescents can be developed.