The Modulatory Role of Hypothermia in Post-Stroke Brain Inflammation: Mechanisms and Clinical Implications.

BACKGROUND: Acute ischemic stroke remains a major contributor to mortality and disability worldwide. The use of hypothermia has emerged as a promising neuroprotective strategy, with proven effectiveness in cardiac arrest and neonatal hypoxic-ischemic injury. SUMMARY: This review explores the therapeutic potential of hypothermia in ischemic stroke by examining its impact on post-stroke inflammatory responses. We synthesized evidence from basic and clinical studies to illustrate the inhibitory effects of hypothermia on post-stroke brain inflammation. The underlying mechanisms include modulation of microglial activation and polarization, downregulation of key inflammatory pathways such as MAPKs, NF-KB, and JAK/STAT, protection of the blood-brain barrier integrity, and reduction of immune cell infiltration into the brain. We also discuss the current limitations of hypothermia treatment in clinical practice and highlight future research directions for optimizing protocols and evaluating its clinical efficacy in stroke patients. KEY MESSAGES: Therapeutic hypothermia (TH) has evolved significantly with advancements in medical technologies, especially with the introduction of automated cooling devices, both intravascular and surface based. However, a refined, highly individualized and effective hypothermia protocol may stand robust against the devastating consequences of ischemic stroke, and we think it should become the future development goal.

Hypoxia-Preconditioned Bone Marrow Mesenchymal Stem Cells Improved Cerebral Collateral Circulation and Stroke Outcome in Mice.

BACKGROUND: Adequate collateral circulation can remarkably improve patient prognoses for patients experiencing ischemic stroke. Hypoxic preconditioning enhances the regenerative properties of bone marrow mesenchymal stem cells (BMSCs). Rabep2 (RAB GTPase binding effector protein 2) is a key protein in collateral remodeling. We investigated whether BMSCs and hypoxia-preconditioned BMSCs (H-BMSCs) augment collateral circulation poststroke, particularly through Rabep2 regulation. METHODS: BMSCs or H-BMSCs (1×106) were delivered intranasally in ischemic mice with distal middle cerebral artery occlusion at 6 hours poststroke. Two-photon microscopic imaging and vessel painting methods were used to analyze collateral remodeling. Blood flow, vascular density, infarct volume, and gait analysis were assessed to evaluate poststroke outcomes. Expressions of proangiogenic marker VEGF (vascular endothelial growth factor) and Rabep2 were determined by Western blotting. Western blot, EdU (5-ethynyl-2'-deoxyuridine) incorporation, and tube formation assays were conducted on cultured endothelial cells treated with BMSCs. RESULTS: BMSCs were more effectively transplanted in the ischemic brain after hypoxic preconditioning. The ipsilateral collateral diameter was increased by BMSCs and strengthened by H-BMSCs (P<0.05). BMSCs increased peri-infarct blood flow and vascular density and reduced infarct volume, gait deficits (P<0.05), and furthermore by H-BMSCs (P<0.05). VEGF and Rabep2 protein expression was increased by BMSCs (P<0.05), which was enhanced by preconditioning (P<0.01). Additionally, BMSCs increased Rabep2 expression, proliferation, and tube formation of endothelial cells in vitro (P<0.05). H-BMSCs enhanced these effects (P<0.05), which were annulled by Rabep2 knockdown. CONCLUSIONS: BMSCs increased collateral circulation and improved poststroke outcomes, through the upregulation of Rabep2. These effects were enhanced by hypoxic preconditioning.

Investigation on acceptor-donor co-doped SnO2 nanoparticles enriched with oxygen vacancies: a capacitive humidity sensor for respiration detection.

In this work, we develop a novel capacitive humidity sensor based on Al-Si acceptor-donor co-doped SnO2 for real-time monitoring of ambient humidity and human respiration. XRD measurements reveal that all samples exhibit a tetragonal rutile phase and the crystallite size of SnO2 decreases with increasing Al-Si content. The high intensity of the Raman peak at 762 cm-1 confirms the presence of bridging mode oxygen vacancies in (Al + Si)0.02Sn0.98O2. The EPR results show that the amount of singly ionized oxygen vacancies increases after the introduction of Al-Si. Both types and amounts of oxygen vacancy defects are particularly sensitive to the adsorption of water molecules. Moreover, according to DFT calculations, the contribution of the Si 3s orbital and Al 3s orbital to the band edge verifies the formation of acceptor-donor complexes in Al-Si co-doped SnO2. The humidity sensing results reveal that the (Al + Si)0.02Sn0.98O2 humidity sensor shows high sensitivity (S = 839), low hysteresis (1.94%) and fast response/recovery times (25 s/5 s). The respiratory intervals during shallow, medium and deep breathing states of (Al + Si)0.02Sn0.98O2 were measured at 2.8 s, 3.8 s and 4.5 s, respectively. The chemical mechanism for the enhancement of humidity sensing performance corresponding to the oxygen vacancy defects induced by Al-Si interplay is proposed.

New insights into the roles of oligodendrocytes regulation in ischemic stroke recovery.

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system, are integral to axonal integrity and function. Hypoxia-ischemia episodes can cause severe damage to these vulnerable cells through excitotoxicity, oxidative stress, inflammation, and mitochondrial dysfunction, leading to axonal dystrophy, neuronal dysfunction, and neurological impairments. OLs damage can result in demyelination and myelination disorders, severely impacting axonal function, structure, metabolism, and survival. Adult-onset stroke, periventricular leukomalacia, and post-stroke cognitive impairment primarily target OLs, making them a critical therapeutic target. Therapeutic strategies targeting OLs, myelin, and their receptors should be given more emphasis to attenuate ischemia injury and establish functional recovery after stroke. This review summarizes recent advances on the function of OLs in ischemic injury, as well as the present and emerging principles that serve as the foundation for protective strategies against OLs deaths.

Long-term follow-up of Janus-kinase inhibitor and novel active disease biomarker in juvenile dermatomyositis.

OBJECTIVE: To evaluate the use of Janus kinase inhibitor (JAKi) in treating JDM and develop cytokine biomarkers of active disease. METHODS: This study involved a retrospective cohort study that evaluated JAKi in 101 JDM patients as well as a cross-sectional study of cytokines in 128 JDM patients and 30 controls between November 2017 and December 2021 in the Affiliated Children's Hospital of Capital Institute of Pediatrics (China). RESULTS: During the median follow-up period of 19 months, 65.5% of the patients had improved rashes, and CAT-BM scores decreased. Overall, 39.6% of JDM patients eliminated glucocorticoids. Muscle strength was improved in all patients who had abnormal muscle strength before JAKi use. Patients and parents provided positive subjective reviews of JAKi, and no serious adverse events were reported. Potential side effects of JAKi included abnormal leukopoenia (14/95) and cough (16/83), which affected over 10% of the JDM patients. In the cytokine analysis, 12/34 cytokines were significantly elevated in active JDM patients. Compared with active JDM patients with multiple phenotypes, active JDM patients with only rashes demonstrated lower cytokine levels. Anti-NXP2-positive active patients had lower cytokine levels compared with those without positive anti-NXP2 antibodies. Among all increased cytokines, IL-1RA changed most dramatically, reaching over 793 times the mean of normal values. We developed a panel composed of six cytokines to differentiate active or stable status in our cohort (area under the curve = 0.8486, P < 0.05). CONCLUSION: The preliminary evidence suggested that JAKi is a relatively safe and effective alternative for JDM patients. Cytokine profiles could well reflect the inflammatory status of JDM patients.

Normobaric oxygen may attenuate the headache in patients with patent foramen povale and migraine.

BACKGROUND AND PURPOSES: There has been both great interest in and skepticism about the strategies for headache inhibition in patients with patent foramen ovale and migraines (PFO-migraine). Furthermore, many questions remain about the fundamental pathophysiology of PFO-migraines. Herein, the inhibiting effect of normobaric oxygenation (NBO) on PFO-migraine was analyzed. METHODS: This real-world self-control study consecutively enrolled patients during the ictal phase of migraines who had patent foramen ovale (PFO) confirmed by Trans esophageal Ultrasound(TEE). After comparing the baseline arterial oxygen partial pressure (PaO2) in their blood gas with that of healthy volunteers, all the patients with PFO-migraine underwent treatment with NBO (8 L/min. for 1 h/q8h) inhalation through a mask. Their clinical symptoms, blood gas, and electroencephalograph (EEG) prior to and post-NBO were compared. RESULTS: A total of 39 cases with PFO-migraine (in which 36% of participants only had a small-aperture of PFO) and 20 non-PFO volunteers entered the final analysis. Baseline blood gas analysis results showed that the PaO2 in patients with PFO-migraine were noticeably lower than PaO2 levels in non-PFO volunteers. After all patients with PFO-migraines underwent NBO treatment, 29(74.4%) of them demonstrated dramatic headache attenuation and a remarkable increase in their arterial PaO2 levels after one time treatment of NBO inhalation (p < 0.01). The arterial PaO2 levels in these patients gradually went down during the following 4 h after treatment. 5 patients finished their EEG scans prior to and post-NBO, and 4(80%) were found to have more abnormal slow waves in their baseline EEG maps. In the follow up EEG maps post-NBO treatment for these same 4 patients, the abnormal slow waves disappeared remarkably. CONCLUSIONS: Patients with PFO-migraine may derive benefit from NBO treatment. PFOs result in arterial hypoxemia due to mixing of venous blood, which ultimately results in brain hypoxia and migraines. This series of events may be the key pathologic link explaining how PFOs lead to migraines. NBO use may attenuate the headaches from migraines by correcting the hypoxemia.

Intermittent Hypoxia Conditioning: A Potential Multi-Organ Protective Therapeutic Strategy.

Severe hypoxia can induce a range of systemic disorders; however, surprising resilience can be obtained through sublethal adaptation to hypoxia, a process termed as hypoxic conditioning. A particular form of this strategy, known as intermittent hypoxia conditioning hormesis, alternates exposure to hypoxic and normoxic conditions, facilitating adaptation to reduced oxygen availability. This technique, originally employed in sports and high-altitude medicine, has shown promise in multiple pathologies when applied with calibrated mild to moderate hypoxia and appropriate hypoxic cycles. Recent studies have extensively investigated the protective role of intermittent hypoxia conditioning and its underlying mechanisms using animal models, demonstrating its potential in organ protection. This involves a range of processes such as reduction of oxidative stress, inflammation, and apoptosis, along with enhancement of hypoxic gene expression, among others. Given that intermittent hypoxia conditioning fosters beneficial physiological responses across multiple organs and systems, this review presents a comprehensive analysis of existing studies on intermittent hypoxia and its potential advantages in various organs. It aims to draw attention to the possibility of clinically applying intermittent hypoxia conditioning as a multi-organ protective strategy. This review comprehensively discusses the protective effects of intermittent hypoxia across multiple systems, outlines potential procedures for implementing intermittent hypoxia, and provides a brief overview of the potential protective mechanisms of intermittent hypoxia.

Induced Inflammatory and Oxidative Markers in Cerebral Microvasculature by Mentally Depressive Stress.

Background: Cerebrovascular disease (CVD) is recognized as the leading cause of permanent disability worldwide. Depressive disorders are associated with increased incidence of CVD. The goal of this study was to establish a chronic restraint stress (CRS) model for mice and examine the effect of stress on cerebrovascular inflammation and oxidative stress responses. Methods: A total of forty 6-week-old male C57BL/6J mice were randomly divided into the CRS and control groups. In the CRS group (n = 20), mice were placed in a well-ventilated Plexiglas tube for 6 hours per day for 28 consecutive days. On day 29, open field tests (OFT) and sucrose preference tests (SPT) were performed to assess depressive-like behaviors for the two groups (n = 10/group). Macrophage infiltration into the brain tissue upon stress was analyzed by measuring expression of macrophage marker (CD68) with immunofluorescence in both the CRS and control groups (n = 10/group). Cerebral microvasculature was isolated from the CRS and controls (n = 10/group). mRNA and protein expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), and macrophage chemoattractant protein-1 (MCP-1) in the brain vessels were measured by real-time PCR and Western blot (n = 10/group). Reactive oxygen species (ROS), hydrogen peroxide (H2O2), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activities were quantified by ELISA to study the oxidative profile of the brain vessels (n = 10/group). Additionally, mRNA and protein expressions of NOX subunits (gp91phox, p47phox, p67phox, and p22phox) in the cerebrovascular endothelium were analyzed by real-time PCR and Western blot (n = 10/group). Results: CRS decreased the total distances (p < 0.05) and the time spent in the center zone in OFT (p < 0.001) and sucrose preference test ratio in SPT (p < 0.01). Positive ratio of CD68+ was increased with CRS in the entire region of the brain (p < 0.001), reflecting increased macrophage infiltration. CRS increased the expression of inflammatory factors and oxidative stress in the cerebral microvasculature, including TNF-α (p < 0.001), IL-1ß (p < 0.05), IL-6 (p < 0.05), VCAM-1 (p < 0.01), MCP-1 (p < 0.01), ROS (p < 0.001), and H2O2 (p < 0.001). NADPH oxidase (NOX) was activated by CRS (p < 0.01), and mRNA and protein expressions of NOX subunits (gp91phox, p47phox, p67phox, and p22phox) in brain microvasculature were found to be increased. Conclusions: To our knowledge, this is the first study to demonstrate that CRS induces depressive stress and causes inflammatory and oxidative stress responses in the brain microvasculature.

Abdominal Aortic Occlusion and the Inflammatory Effects in Heart and Brain.

Background: Abdominal aortic occlusion (AAO) occurs frequently and causes ischemia/reperfusion (I/R) injury to distant organs. In this study, we aimed to investigate whether AAO induced I/R injury and subsequent damage in cardiac and neurologic tissue. We also aimed to investigate the how length of ischemic time in AAO influences reactive oxygen species (ROS) production and inflammatory marker levels in the heart, brain, and serum. Methods: Sixty male C57BL/6 mice were used in this study. The mice were randomly divided into either sham group or AAO group. The AAO group was further subdivided into 1-4 hr groups of aortic occlusion times. The infrarenal abdominal aorta was clamped for 1-4 hr depending on the AAO group and was then reperfused for 24 hr after clamp removal. Serum, hippocampus, and left ventricle tissue samples were then subjected to biochemical and histopathological analyses. Results: AAO-induced I/R injury had no effect on cell necrosis, cell apoptosis, or ROS production. However, serum and hippocampus levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH) increased in AAO groups when compared to sham group. Superoxide dismutase and total antioxidant capacity decreased in the serum, hippocampus, and left ventricle. In the serum, AAO increased the level of inducible nitric oxide synthase (iNOS) and decreased the levels of anti-inflammatory factors (such as arginase-1), transforming growth factor- ß1 (TGF-ß1), interleukin 4 (IL-4), and interleukin 10 (IL-10). In the hippocampus, AAO increased the levels of tumor necrosis factor (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6), IL-4, and IL-6, and decreased the level of TGF-ß1. In the left ventricle, AAO increased the level of iNOS and decreased the levels of TGF-ß1, IL-4, and IL-10. Conclusions: AAO did not induce cell necrosis or apoptosis in cardiac or neurologic tissue, but it can cause inflammation in the serum, brain, and heart.

Biphasic dose response in the anti-inflammation experiment of PBM.

Non-invasive laser irradiation can induce photobiomodulation (PBM) effects in cells and tissues, which can help reduce inflammation and pain in several clinical scenarios. The purpose of this study is to review the current literature to verify whether PBM can produce dose effects in anti-inflammatory experiments by summarizing the clinical and experimental effects of different laser parameters of several diseases. The so-called Arndt-Schulz curve is often used to describe two-phase dose reactions, assuming small doses of therapeutic stimulation, medium doses of inhibition, and large doses of killing. In the past decade, more and more attention has been paid to the clinical application of PBM, especially in the field of anti-inflammation, because it represents a non-invasive strategy with few contraindications. Although there are different types of lasers available, their use is adjusted by different parameters. In general, the parameters involved are wavelength, energy density, power output, and radiation time. However, due to the biphasic effect, the scientific and medical communities remain puzzled by the ways in which the application of PBM must be modified depending on its clinical application. This article will discuss these parameter adjustments and will then also briefly introduce two controversial theories of the molecular and cellular mechanisms of PBM. A better understanding of the extent of dualistic dose response in low-intensity laser therapy is necessary to optimize clinical treatment. It also allows us to explore the most dependable mechanism for PBM use and, ultimately, standardize treatment for patients with various diseases.

A novel score to estimate thrombus burden and predict intracranial hypertension in cerebral venous sinus thrombosis.

BACKGROUND: Current methods to evaluate the severity of cerebral venous sinus thrombosis (CVST) lack patient-specific indexes. Herein, a novel scoring method was investigated to estimate the thrombus burden and the intracranial pressure (ICP) of CVST. METHODS: In this retrospective study from January 2019 through December 2021, we consecutively enrolled patients with a first-time confirmed diagnosis of CVST by contrast-enhanced magnetic resonance venography (CE-MRV) or computed tomography venography (CTV). In these patients, a comprehensive CVST-Score was established using magnetic resonance black-blood thrombus imaging (MRBTI) to estimate the thrombus burden semi-quantitatively. The relationship between CVST-Score and ICP was explored to assess the potential of using the CVST-score to evaluate ICP noninvasively and dynamically. RESULTS: A total of 87 patients were included in the final analysis. The CVST-Scores in different ICP subgroups were as follows: 4.29±2.87 in ICP<250mmH2O subgroup, 11.36±3.86 in ICP =250-330mmH2O subgroup and 14.99±3.15 in ICP>330mmH2O subgroup, respectively (p<0.001). For patients with ICP ≤330mmH2O, the CVST-Score was linearly and positively correlated with ICP (R2=0.53). The receiver operating characteristic (ROC) curves showed the optimal CVST-Score cut-off values to predict ICP ≥250mmH2O and >330mmH2O were 7.15 and 11.62, respectively (P<0.001). Multivariate analysis indicated CVST-Score as an independent predictor of ICP ≥250mmH2O (odds ratio, 2.15; 95% confidence interval, 1.49-3.10; p<0.001). CONCLUSIONS: A simple and noninvasive CVST-Score can rapidly estimate the thrombus burden and predict the severity of intracranial hypertension in patients with CVST. The CVST-Score can aid in evaluating therapeutic responses and avoiding unnecessary invasive procedures at long-term follow-up.

Passing Extracranial Artery Occlusion by Intermediate Catheter With Expanding Microballoon (PEACE): A Novel Endovascular Therapy in Acute Tandem Occlusion Stroke.

PURPOSE: Endovascular treatment of atherosclerotic tandem occlusions in acute ischemic stroke (AIS) is a matter of debate. This article reports a single-center experience using an intermediate catheter with microballoon for treatment of tandem occlusions. METHODS: A total of 151 AIS patients with large vessel occlusion received endovascular therapy and a consecutive series of patients (n = 26) who suffered from tandem cervical intracranial occlusions were treated using the Passing Extracranial Artery Occlusion by Intermediate Catheter with Expanding Microballoon (PEACE) technique. Intracranial recanalization was achieved by aspiration or stent retriever and then emergency stenting was performed for extracranial internal carotid artery (ICA) lesion. Demographic, clinical characteristics, procedural details of endovascular therapy, and prognosis outcome were assessed. The outcomes of tandem occlusion group were compared with isolated intracranial occlusion group (n = 122) and previous studies. RESULTS: As compared to isolated intracranial occlusion groups, only a few patients suffered from atrial fibrillation (7.7% vs 38.5%, p<0.01) in tandem occlusions group. A larger proportion of patients (61.5% vs 29.5%) had tandem occlusions in which extracranial ICA occlusion was combined with intracranial terminus occlusion in ICA (p<0.01). 46.2% of tandem occlusions patients achieved intracranial recanalization by aspiration alone versus 15.6% in patients with isolated intracranial occlusion (p<0.01). In tandem occlusion patients treated with PEACE, 92.3% achieved successful reperfusion (thrombolysis in cerebral infarct [TICI] ≥2b). The median time from puncture to recanalization was 51 minutes (interquartile range [IQR], 41-66). 67.6% favorable functional prognosis (modified Rankin score [mRS], 0-2) was seen, with 11.5% mortality and 3.8% of symptomatic intracerebral hemorrhage (sICH) at 90 days. These outcomes are all consistent or better than previously reported studies performed for tandem occlusion. CONCLUSIONS: Endovascular therapy using the PEACE technique with intermediate catheter and lined expanding microballoon is safe, efficient, and fast in the treatment of atherosclerotic tandem occlusion patients.

Safety and efficacy comparison between OACs plus single antiplatelet and dual antiplatelet therapy in patients with cerebral venous sinus stenosis poststenting.

BACKGROUND AND PURPOSE: The present strategies regarding poststent management for cerebral venous sinus stenosis (CVSS) are inconsistent. Herein, we compared the safety and efficacy of oral anticoagulants (OACs) plus single antiplatelet therapy and dual antiplatelet therapy for CVSS poststenting. METHODS: A real-world observational study conducted from January 2009 through October 2019 enrolled patients who were diagnosed with CVSS and received stenting. Patients were divided into two groups according to the management they received poststenting. Group 1: OACs plus a single antiplatelet agent (clopidogrel 75 mg or aspirin 100 mg) and Group 2: dual antiplatelet therapy (clopidogrel 75 mg plus aspirin 100 mg). The safety (such as major or minor bleeding or venous thrombosis) and efficacy (the incidences of cerebral venous sinus restenosis, intrastent thrombosis, or stent displacement) of the two groups were compared. RESULTS: There were a total of 110 eligible patients in the final analysis, including 79 females and 31 males with a mean age of 43.42 ± 13.23 years. No major bleeding or venous thrombosis occurred in either of the two groups. Two minor bleeding events occurred in group 2 (one with subcutaneous bleeding points in both lower limbs, another with submucosal bleeding in the mouth), whereas no bleeding events occurred in Group 1. In addition, at the 1-year follow-up, one case of intraluminal restenosis and two cases of in-stent thrombi occurred in Group 2, while none occurred in Group 1. Neither stenosis at stent-adjacent segments nor stent migration was detected in either group during the 1-year following stent placement. CONCLUSION: OACs plus single antiplatelet therapy and dual antiplatelet therapy alone are both safe and efficacious management strategies after CVSS stent placement. The former may have more advantages than the latter for inhibiting intrastent thrombosis. However, further research by larger, multicenter clinical trials is needed.

Efficacy and safety of rivaroxaban in cerebral venous thrombosis: insights from a prospective cohort study.

Rivaroxaban, as a novel oral anticoagulant agent, emerged in thrombosis management. This study aimed to compare the efficacy and safety of once-daily rivaroxaban versus dose-adjusted warfarin for cerebral venous thrombosis treatment in a real-world clinical setting. This is a prospective cohort study based on the real-world clinical data analysis of the patients with imaging-confirmed CVT enrolled from August 2016 through January 2020 and their outcomes were followed up. Patients were grouped according to their treatment strategies: rivaroxaban (15-20 mg daily) or warfarin (dosage-adjusted according to international normalized ratio), which were matched 1:2 on the propensity score. The primary efficacy outcome was recanalization assessed by magnetic resonance venography. Thrombus burden, CVT recurrence and modified Rankin Scale (mRS) were also compared. The safety outcome was major bleeding. Baseline characteristics were well balanced between the 33 patients in rivaroxaban group and 49 in warfarin group after propensity score matching. During 6-month (median) follow-up, 29 patients (87.9%) in rivaroxaban group and 38 patients (77.6%) in warfarin group obtained recanalization (OR, 1.44; 95% CI 0.63-3.30). The thrombus reduction at the 6-month follow-up did not reach statistical difference (p = 0.118). No CVT recurrence was observed in both groups. All patients in rivaroxaban group obtained favorable functional outcomes (mRS = 0-2), whereas in warfarin group, 1 patient remained physically disable (mRS = 3) at the follow-up. No major bleeding events occurred in two groups. Rivaroxaban might have the same or stronger efficacy in facilitating CVT recanalization and preventing CVT recurrence with a lower incidence of bleeding than that of warfarin in Chinese population.

Different patterns of white matter lesions among patent foramen ovale, atherosclerotic cerebral small vessel disease and cerebral venous thrombosis.

None of studies are available on the predictive ability of white matter lesions (WMLs) among patent foramen ovale (PFO), atherosclerotic cerebral small vessel disease (aCSVD) and cerebral venous thrombosis (CVT). Herein, we aimed to uncover the difference of the WML patterns among the three disease entities in a real-world setting to provide clinical references for predicting probable WML etiologies. We retrospectively reviewed data from consecutive patients with imaging-confirmed PFO, aCSVD, or CVT enrolled from 2014 through 2020. WMLs presented on fluid-attenuated inversion recovery (FLAIR) maps were compared among the three groups based on visual evaluation, Fazekas and modified Scheltens scales. Propensity score matching (PSM) was implemented to correct age and hypertension differences among groups. A total of 401 patients were entered into final analysis, including PFO (n = 112, 46.5 ± 12.8 years), aCSVD (n = 177, 61.6 ± 11.8 years) and CVT (n = 112, 37.4 ± 11.4 years) groups. In this study, WMLs occurred in all of the involved patients in the three groups (100%), which were independent to age, symptom onset and disease durations. On visual evaluation, PFO-WMLs were multiple spots distributed asymmetrically around bilateral subcortex and peri-ventricles. aCSVD-WMLs were dots or sheets distributed symmetrically in subcortex and peri-ventricles, and often coexisted with lacunar infarctions. CVT-WMLs were cloud-like around bilateral peri-ventricles, and enabled to attenuate after recanalization. Fazekas and modified Scheltens scores of PFO-WML vs. aCSVD-WML were significantly different even after being matched by 1:2 PSM (all p < 0.05), meaning that the WML burden in aCSVD was considerably heavier than that in PFO. WML patterns induced by PFO, aCSVD and CVT were obviously different, and were therefore of great clinical significance to preliminarily predict and differentiate the three diseases entities.

Characteristics of cerebral ischemic stroke based on moyamoya disease and atherosclerosis-associated intracranial arterial stenosis.

PURPOSE: To analyze the characteristics of acute ischemic stroke (AIS) resulting from moyamoya disease (MMD) and intracranial large artery atherosclerotic stenosis (LAS). METHOD: This real-world case control study enrolled imaging-confirmed AIS patients owing to MMD or LAS hospitalized from January 2015 through September 2020 consecutively. The features of risk factors, peripheral blood, and imaging presentations were compared between the two cohorts. RESULTS: A total of 191 eligible patients entered into final analysis, including 70 cases with MMD stroke and 121 with LAS stroke. LAS stroke vs. MMD stroke, the ratios of hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia were higher in the former (65.3 vs.12.9%, 65.3% vs. 4.3%, 39.7% vs. 2.9%, and 43.8% vs.12.9%; all p < 0.01) as well as baseline plasma arachidonic acid (AA) and adenosine diphosphate (ADP)-stimulated maximum platelet aggregation rates (75.3% vs. 60.8% and 73.1% vs.64.9%, respectively, all p < 0.01), which were positively correlated with triglycerides and cholesterol levels, blood glucose, age, and platelet counts (all p < 0.01). Classical watershed infarction (WSI) accounted for 87.14% in MMD stroke and 40.49% in LAS stroke, respectively (p < 0.01). Almost all of the patients with LAS showed plaques in arterial walls on CTA maps and non-homogeneous thickening with irregular luminal narrowing on HRMRI, while plaques were seldom found in MMD besides homogeneous thickening with regular luminal narrowing. CONCLUSIONS: Differing from LAS stroke, MMD stroke mainly presents with WSI and does not feature with platelet hyper-aggregation and fragmentation of ulcer plaque. Whereby, focusing on perfusion improvement rather than antiplatelets and statins may be the predominant step in MMD-stroke correction.

Arterial Glyceryl Trinitrate in Acute Ischemic Stroke after Thrombectomy for Neuroprotection (AGAIN): Rationale, design and protocol for a prospective randomized controlled trial.

BACKGROUND: Although endovascular recanalization therapy demonstrates robust clinical efficacy in acute ischemic stroke (AIS), not all victims of these cerebrovascular accidents can benefit from it and achieve a favorable prognosis after successful reperfusion. Therefore, alternative neuroprotective strategies are urgently needed for AIS patients after vessel recanalization. Nitric oxide (NO) levels are low after AIS and NO donor drugs may be neuroprotective against cerebral ischemia-reperfusion injury. Glyceryl trinitrate (GTN), often used in the clinic as a NO donor, may provide a novel neuroprotective strategy. This rationale, design, and protocol for a prospective pilot study plans to explore the preliminary safety, feasibility, and neuroprotective benefits of Arterial Glyceryl Trinitrate in Acute Ischemic Stroke after Thrombectomy for Neuroprotection (AGAIN). METHODS: AGAIN, a prospective RCT, is proposed for AIS patients after mechanical thrombectomy. Subjects will be randomly assigned in a 1:1 fashion (n = 40) to either the control group or the intervention group. Participants assigned to the intervention group will be administered 800 µg GTN in the catheter immediately after recanalization, whereas those in the control group will be administered the same volume of normal saline. All participants from either group will be given concurrent treatment with standard of care therapies in accordance with the current guidelines for stroke management. The primary outcome is safety [symptomatic intracranial hemorrhage (ICH), hypotension, neurological deterioration, ICH, fatal ICH, as well as headache, tachycardia, emesis, and seizures], whereas secondary outcomes included changes in poststroke functional outcomes, infarction volumes, and blood nitrate index detection. DISCUSSIONS: This study is a prospective randomized controlled trial to test the safety and efficacy of intra-arterial GTN in AIS patients after endovascular therapy. The results from this study will give insight for future GTN studies and new neuroprotective strategies for future AIS treatment strategies. TRIAL REGISTRATION NUMBER: ChiCTR2100045254. Registered on March 21, 2021.

MicroRNA-29b Suppresses Inflammation and Protects Blood-Brain Barrier Integrity in Ischemic Stroke.

Objectives: Following cerebral ischemia, microRNA- (miR-) 29b in circulating blood is downregulated. This study investigates the underlying mechanism and implications of miR-29b in leukocyte induction. Methods: miR-29b from stroke patients and rats with middle cerebral artery occlusion (MCAO) were assessed using real-time polymerase chain reaction (PCR). miR-29b agomir was used to increase miR-29b expression in leukocytes via intravenous injection. C1q and tumor necrosis factor (C1QTNF) 6, interleukin- (IL-) 1ß, zonula occludens- (ZO-) 1, occludin, and ischemic outcomes were assessed in MCAO rats. Additionally, hCMEC/D3 cells were subjected to oxygen-glucose deprivation (OGD) and cocultured with HL-60 cells. Results: miR-29b levels in neutrophils were found to be significantly lower in stroke patients compared with healthy controls, which may indicate its high diagnostic sensitivity and specificity for stroke. Moreover, miR-29b levels in leukocytes showed a negative correlation with National Institute of Health Stroke Scale (NIHSS) scores and C1QTNF6 levels. In MCAO rats, miR-29b overexpression reduced brain infarct volume and brain edema, decreasing IL-1ß levels in leukocytes and in the brain 24 hours poststroke. miR-29b attenuated IL-1ß expression via C1QTNF6 inhibition, leading to decreased blood-brain barrier (BBB) disruption and leukocyte infiltration. Moreover, miR-29b overexpression in HL-60 cells downregulated OGD-induced hCMEC/D3 cell apoptosis and increased ZO-1 and occludin levels in vitro. Conclusion: Leukocytic miR-29b attenuates inflammatory response by augmenting BBB integrity through C1QTNF6, suggesting a novel miR-29b-based therapeutic therapy for ischemic stroke.

Chlorpromazine and Promethazine (C+P) Reduce Brain Injury after Ischemic Stroke through the PKC-δ/NOX/MnSOD Pathway.

Cerebral ischemia-reperfusion (I/R) incites neurologic damage through a myriad of complex pathophysiological mechanisms, most notably, inflammation and oxidative stress. In I/R injury, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) produces reactive oxygen species (ROS), which promote inflammatory and apoptotic pathways, augmenting ROS production and promoting cell death. Inhibiting ischemia-induced oxidative stress would be beneficial for reducing neuroinflammation and promoting neuronal cell survival. Studies have demonstrated that chlorpromazine and promethazine (C+P) induce neuroprotection. This study investigated how C+P minimizes oxidative stress triggered by ischemic injury. Adult male Sprague-Dawley rats were subject to middle cerebral artery occlusion (MCAO) and subsequent reperfusion. 8 mg/kg of C+P was injected into the rats when reperfusion was initiated. Neurologic damage was evaluated using infarct volumes, neurological deficit scoring, and TUNEL assays. NOX enzymatic activity, ROS production, protein expression of NOX subunits, manganese superoxide dismutase (MnSOD), and phosphorylation of PKC-δ were assessed. Neural SHSY5Y cells underwent oxygen-glucose deprivation (OGD) and subsequent reoxygenation and C+P treatment. We also evaluated ROS levels and NOX protein subunit expression, MnSOD, and p-PKC-δ/PKC-δ. Additionally, we measured PKC-δ membrane translocation and the level of interaction between NOX subunit (p47phox) and PKC-δ via coimmunoprecipitation. As hypothesized, treatment with C+P therapy decreased levels of neurologic damage. ROS production, NOX subunit expression, NOX activity, and p-PKC-δ/PKC-δ were all significantly decreased in subjects treated with C+P. C+P decreased membrane translocation of PKC-δ and lowered the level of interaction between p47phox and PKC-δ. This study suggests that C+P induces neuroprotective effects in ischemic stroke through inhibiting oxidative stress. Our findings also indicate that PKC-δ, NOX, and MnSOD are vital regulators of oxidative processes, suggesting that C+P may serve as an antioxidant.

The antiphospholipid syndrome may induce non-thrombotic internal jugular vein stenosis: two cases report.

BACKGROUND: Antiphospholipid syndrome (APS) is associated with a high incidence of thrombotic events, either arterial thrombosis or venous thrombosis. However, APS-related non-thrombotic venous stenosis is rarely reported. CASE PRESENTATION: This study described two cases of young women with APS-related internal jugular vein stenosis (IJVS) and reviewed current literature on this issue, including clinical features, diagnosis, and treatment. CONCLUSIONS: IJVS is a rather rare complication of APS. Two cases were reported for the first time that high titer of antiphospholipid antibodies (aPL) might mediate direct vessel wall damage and further induce venous stenosis despite long-term standardized anticoagulation to prevent thrombus formation. Therefore, dynamic monitoring of autoantibodies and concomitant use of anticoagulants and corticosteroids may be necessary to the management of APS and its complications.