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Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods for post-hypoxia/anoxia injuries are limited and still have deficiencies in terms of safety and efficacy. Recently, clinical studies of stroke have reported the use of drugs containing riboflavin for post-injury clinical rehabilitation, however, the effects of vitamin B2 on exposure to cerebral oxygen deprivation are not completely elucidated. This review aimed to investigate the potential antioxidant, anti-inflammatory and neuroprotective effects of riboflavin in cerebral hypoxia/anoxia. After a systematic search, 21 articles were selected, 8 preclinical and 12 clinical studies, and 1 translational study. Most preclinical studies used B2 alone in models of hypoxia in rodents, with doses of 1–20 mg/kg (in vivo) and 0.5–5 µM (in vitro). Together, these works suggested greater regulation of lipid peroxidation and apoptosis and an increase in neurotrophins, locomotion, and cognition after treatment. In contrast, several human studies have administered riboflavin (5 mg) in combination with other Krebs cycle metabolites, except one study, which used only B2 (20 mg). A reduction in lactic acidosis and recovery of sensorimotor functions was observed in children after treatment with B2, while adults and the elderly showed a reduction in infarct volume and cognitive rehabilitation. Based on findings from preclinical and clinical studies, we conclude that the use of riboflavin alone or in combination acts beneficially in correcting the underlying brain damage caused by hypoxia/anoxia and its inflammatory, oxidative, and behavioral impairments. [ABSTRACT FROM AUTHOR]

Intracranial atherosclerotic disease (ICAD) is a common cause of ischaemic stroke and transient ischaemic attack (TIA) with a high recurrence rate. It is often referred to as intracranial atherosclerotic stenosis (ICAS), when the plaque has caused significant narrowing of the vessel lumen. The lesion is usually considered symptomatic ICAD/ICAS (sICAD/sICAS) when it has caused an ischaemic stroke or TIA. The severity of luminal stenosis has long been established as a prognostic factor for stroke relapse in sICAS. Yet, accumulating studies have also reported the important roles of plaque vulnerability, cerebral haemodynamics, collateral circulation, cerebral autoregulation and other factors in altering the stroke risks across patients with sICAS. In this review article, we focus on cerebral haemodynamics in sICAS. We reviewed imaging modalities/methods in assessing cerebral haemodynamics, the haemodynamic metrics provided by these methods and application of these methods in research and clinical practice. More importantly, we reviewed the significance of these haemodynamic features in governing the risk of stroke recurrence in sICAS. We also discussed other clinical implications of these haemodynamic features in sICAS, such as the associations with collateral recruitment and evolution of the lesion under medical treatment, and indications for more individualised blood pressure management for secondary stroke prevention. We then put forward some knowledge gaps and future directions on these topics.

BACKGROUND: Secondary prevention of ischemic stroke (IS) requires adequate diagnostic evaluation to identify the likely etiologic subtype. We describe hospital-level variability in diagnostic testing and IS subtyping in a large nationwide registry. METHODS AND RESULTS: We used the GWTG-Stroke (Get With The Guidelines-Stroke) registry to identify patients hospitalized with a diagnosis of acute IS at 1906 hospitals between January 1, 2016, and September 30, 2017. We compared the documentation rates and presence of risk factors, diagnostic testing, achievement/quality measures, and outcomes between patients with and without reported IS subtype. Recording of diagnostic evaluation was optional in all IS subtypes except cryptogenic, where it was required. Of 607 563 patients with IS, etiologic IS subtype was documented in 57.4% and missing in 42.6%. Both the rate of missing stroke pathogenesis and the proportion of cryptogenic strokes were highly variable across hospitals. Patients missing stroke pathogenesis less frequently had documentation of risk factors, evidence-based interventions, or discharge to home. The reported rates of major diagnostic testing, including echocardiography, carotid and intracranial vascular imaging, and short-term cardiac monitoring were 40% of patients. Long-term cardiac rhythm monitoring was rarely reported, even in cryptogenic stroke. CONCLUSIONS: Reporting of IS etiologic subtype and supporting diagnostic testing was low overall, with high rates of missing optional data. Improvement in the capture of these data elements is needed to identify opportunities for quality improvement in the diagnostic evaluation and secondary prevention of stroke.

BACKGROUND AND PURPOSE: Perfusion-based collateral indices such as the perfusion collateral index and the hypoperfusion intensity ratio have shown promise in the assessment of collaterals in patients with acute ischemic stroke. We aimed to compare the diagnostic performance of the perfusion collateral index and the hypoperfusion intensity ratio in collateral assessment compared with angiographic collaterals and outcome measures, including final infarct volume, infarct growth, and functional independence. MATERIALS AND METHODS: Consecutive patients with acute ischemic stroke with anterior circulation proximal arterial occlusion who underwent endovascular thrombectomy and had pre- and posttreatment MRI were included. Using pretreatment MR perfusion, we calculated the perfusion collateral index and the hypoperfusion intensity ratio for each patient. The angiographic collaterals obtained from DSA were dichotomized to sufficient (American Society of Interventional and Therapeutic Neuroradiology [ASITN] scale 3-4) versus insufficient (ASITN scale 0-2). The association of collateral status determined by the perfusion collateral index and the hypoperfusion intensity ratio was assessed against angiographic collaterals and outcome measures. RESULTS: A total of 98 patients met the inclusion criteria. Perfusion collateral index values were significantly higher in patients with sufficient angiographic collaterals (P < .001), while there was no significant (P = .46) difference in hypoperfusion intensity ratio values. Among patients with good (mRS 0-2) versus poor (mRS 3-6) functional outcome, the perfusion collateral index of ≥ 62 was present in 72% versus 31% (P = .003), while the hypoperfusion intensity ratio of ≤0.4 was present in 69% versus 56% (P = .52). The perfusion collateral index and the hypoperfusion intensity ratio were both significantly predictive of final infarct volume, but only the perfusion collateral index was significantly (P = .03) associated with infarct growth. CONCLUSIONS: Results show that the perfusion collateral index outperforms the hypoperfusion intensity ratio in the assessment of collateral status, infarct growth, and determination of functional outcomes.

Metabolites are reliable biomarkers for many diseases. However, their role in acute ischemic stroke (AIS) pathogenesis is not well understood. In this systematic review we aim to evaluate the current literature on the presence of metabolites in thrombi retrieved by mechanical thrombectomy from AIS patients. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines, we searched OVID Medline, PubMed, OVID Embase, Scopus, and Web of Science until July 13, 2022. Metabolites lists were extracted, and pathway analysis was performed in MetaboAnalyst database. Four articles listing metabolites were included in this systematic review. D-Glucose, diacylglycerol, phytosphingosine, galabiosylceramide, glucosylceramide and 4-hydroxynonenal were reported to be associated with clots. Metabolomics data analysis showed that glycolysis, lactose, and sphingolipid metabolism pathways were enriched. In conclusion, results of the present study show that the thrombi niche has a glycolytic phenotype. Future studies should work to better understand the metabolic properties of AIS thrombi.

OBJECTIVE: This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients with intracranial atherosclerotic stroke. METHODS: Patients with intracranial large artery atherosclerotic (LAA) stroke and an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3 from the Effect of Intravenous Tirofiban versus Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke (RESCUE BT) trial were included. The primary outcome was the difference in proportion of independent functional outcome (modified Rankin score of 0-2 at 90 days). Safety outcomes included the rates of symptomatic intracranial hemorrhage (sICH) and 90-day mortality. RESULTS: Among the 382 patients with intracranial LAA stroke and successful reperfusion, 175 patients (45.8%) were treated with intravenous tirofiban and 207 (54.2%) with placebo. The proportion of patients with independent functional outcome at 90 days was 54.3% (95 out of 175) with tirofiban and 44.0% (91 out of 207) with placebo (adjusted odds ratio [aOR], 1.58; 95% CI, 1.02-2.44; p = 0.04). Intravenous tirofiban was not significantly associated with an increased risk of sICH (12/175 [6.9%] vs. 11/207 [5.3%]; aOR, 1.41; 95% CI, 0.59-3.34; p = 0.44) or 90-day mortality (21/175 [12.0%] vs. 34/207 [16.4%]; aOR, 0.71; 95% CI, 0.38-1.31; p = 0.27). INTERPRETATION: Among patients with acute intracranial LAA stroke and successful reperfusion following endovascular thrombectomy, adjunct intravenous tirofiban was associated with a higher rate of independent functional outcome, without higher rates of sICH or mortality. Confirmatory randomized trials in these patients are desirable.

High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N-tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins' interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood-brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an "informed" selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.

AIMS: The clinical correlates and outcomes of asymptomatic atrial fibrillation (AF) in hospitalized patients are largely unknown. We aimed to investigate the clinical correlates and in-hospital outcomes of asymptomatic AF in hospitalized Chinese patients. METHODS AND RESULTS: We conducted a cross-sectional registry study of inpatients with AF enrolled in the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation Project between February 2015 and December 2019. We investigated the clinical characteristics of asymptomatic AF and the association between the clinical correlates and the in-hospital outcomes of asymptomatic AF. Asymptomatic and symptomatic AF were defined according to the European Heart Rhythm Association score. Asymptomatic patients were more commonly males (56.3%) and had more comorbidities such as hypertension (57.4%), diabetes mellitus (18.6%), peripheral artery disease (PAD; 2.3%), coronary artery disease (55.5%), previous history of stroke/transient ischaemic attack (TIA; 17.9%), and myocardial infarction (MI; 5.4%); however, they had less prevalent heart failure (9.6%) or left ventricular ejection fractions ≤40% (7.3%). Asymptomatic patients were more often hospitalized with a non-AF diagnosis as the main diagnosis and were more commonly first diagnosed with AF (23.9%) and long-standing persistent/permanent AF (17.0%). The independent determinants of asymptomatic presentation were male sex, long-standing persistent AF/permanent AF, previous history of stroke/TIA, MI, PAD, and previous treatment with anti-platelet drugs. The incidence of in-hospital clinical events such as all-cause death, ischaemic stroke/TIA, and acute coronary syndrome (ACS) was higher in asymptomatic patients than in symptomatic patients, and asymptomatic clinical status was an independent risk factor for in-hospital all-cause death, ischaemic stroke/TIA, and ACS. CONCLUSION: Asymptomatic AF is common among hospitalized patients with AF. Asymptomatic clinical status is associated with male sex, comorbidities, and a higher risk of in-hospital outcomes. The adoption of effective management strategies for patients with AF should not be solely based on clinical symptoms.

BACKGROUND: Recent advances in endovascular devices have allowed access and targeting of perivascular tissues of the peripheral circulation. The perivascular tissues of the cervical and cranial circulations have many important structures of clinical significance, yet the feasibility and safety of such an approach has not been demonstrated. OBJECTIVE: To evaluate the safety of a novel endovascular transmural approach to target the perivascular tissues of the common carotid artery in swine. METHODS: A micro-infusion device was positioned in the carotid arteries of three Yorkshire pigs (six carotid arteries in total), and each carotid artery was punctured 10 times in the same location to gain access to the perivascular tissues. Digital subtraction angiography was used to evaluate vessel injury or contrast extravasation. MRI and MR angiography were used to evaluate evidence of cerebral ischemia or vessel injury. Post-mortem tissue analysis was performed to assess the level of extravascular hematoma and intravascular dissection. RESULTS: None of the tested carotid arteries showed evidence of vessel injury (dissection or perforation) or intravascular thrombosis. MRI performed after repeated puncture was negative for neck hematoma and brain ischemia. Post-mortem tissue analysis of the carotid arteries showed mild adventitial staining with blood, but without associated hematoma and without vessel dissection. CONCLUSION: Repeated puncture of the carotid artery to gain access to the perivascular tissues using a novel endovascular transmural approach is safe in a swine model. This represents a novel approach to various tissues in close proximity to the cervical and cranial vasculature.

Neuroprotection to attenuate or block the ischemic cascade and salvage neuronal damage has been extensively explored for treating ischemic stroke. However, despite increasing knowledge of the physiologic, mechanistic, and imaging characterizations of the ischemic penumbra, no effective neuroprotective therapy has been found. This study focuses on the neuroprotective bioactivity of docosanoid mediators: Neuroprotectin D1 (NPD1), Resolvin D1 (RvD1), and their combination in experimental stroke. Molecular targets of NPD1 and RvD1 are defined by following dose-response and therapeutic window. We demonstrated that treatment with NPD1, RvD1, and combination therapy provides high-grade neurobehavioral recovery and decreases ischemic core and penumbra volumes even when administered up to 6 h after stroke. The expression of the following genes was salient: (a) Cd163, an anti-inflammatory stroke-associated gene, was the most differentially expressed gene by NPD1+RvD1, displaying more than a 123-fold upregulation in the ipsilesional penumbra (Lisi et al., Neurosci Lett 645:106-112, 2017); (b) 100-fold upregulation takes place in astrocyte gene PTX3, a key regulator of neurogenesis and angiogenesis after cerebral ischemia (. Rodriguez-Grande et al., J Neuroinflammation 12:15, 2015); and (c) Tmem119 and P2y12, two markers of homeostatic microglia, were found to be enhanced by ten- and fivefold, respectively (Walker et al. Int J Mol Sci 21:678, 2020). Overall, we uncovered that protection after middle cerebral artery occlusion (MCAo) by the lipid mediators elicits expression of microglia and astrocyte-specific genes (Tmem119, Fcrls, Osmr, Msr1, Cd68, Cd163, Amigo2, Thbs1, and Tm4sf1) likely participating in enhancing homeostatic microglia, modulating neuroinflammation, promoting DAMP clearance, activating NPC differentiation and maturation, synapse integrity and contributing to cell survival.

BACKGROUND: We hypothesized that treatment delays might be an effect modifier regarding risks and benefits of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT). METHODS: We used the dataset of the SWIFT-DIRECT trial, which randomized 408 patients to IVT+MT or MT alone. Potential interactions between assignment to IVT+MT and expected time from onset-to-needle (OTN) as well as expected time from door-to-needle (DTN) were included in regression models. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes included mRS shift, mortality, recanalization rates, and (symptomatic) intracranial hemorrhage at 24 hours. RESULTS: We included 408 patients (IVT+MT 207, MT 201, median age 72 years (IQR 64-81), 209 (51.2%) female). The expected median OTN and DTN were 142 min and 54 min in the IVT+MT group and 129 min and 51 min in the MT alone group. Overall, there was no significant interaction between OTN and bridging IVT assignment regarding either the functional (adjusted OR (aOR) 0.76, 95% CI 0.45 to 1.30) and safety outcomes or the recanalization rates. Analysis of in-hospital delays showed no significant interaction between DTN and bridging IVT assignment regarding the dichotomized functional outcome (aOR 0.48, 95% CI 0.14 to 1.62), but the shift and mortality analyses suggested a greater benefit of IVT when in-hospital delays were short. CONCLUSIONS: We found no evidence that the effect of bridging IVT on functional independence is modified by overall or in-hospital treatment delays. Considering its low power, this subgroup analysis could have missed a clinically important effect, and exploratory analysis of secondary clinical outcomes indicated a potentially favorable effect of IVT with shorter in-hospital delays. Heterogeneity of the IVT effect size before MT should be further analyzed in individual patient meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03192332.

Objective(s): This study assessed the effects of electroacupuncture (EA) stimulation at different frequencies at the Dazhui and Baihui acupoints in the subacute phase after transient global cerebral ischemia (GCI). Materials and Methods: Rats were subjected to GCI for 25 min, followed by reperfusion for 7 days. EA at acupoints was performed at 10, 30, or 50 Hz, 1 day after reperfusion and then once daily for 6 consecutive days. Results: EA at acupoints at 10 and 50 Hz effectively down-regulated apoptosis in the hippocampal cornu ammonis 1(CA1) area and ameliorated memory deficits. Moreover, EA treatment at 10 and 50 Hz markedly increased phospho (p)-extracellular signal-regulated protein kinase 1/2 (ERK1/2), p-ERK1/2/neuronal nuclei (NeuN), p-cAMP response element-binding protein (CREB)/p-ERK1/2, B-cell lymphoma-2 (Bcl-2)/p-CREB, and X-linked inhibitor of apoptosis protein/NeuN expression levels and decreased Bcl-2 homologous antagonist/killer, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI, cytochrome c, cleaved caspase-3, and apoptosis-inducing factor expression levels. Furthermore, 10-Hz EA treatment effectively increased p-p38 mitogen-activated protein kinase (MAPK), p-p38 MAPK/NeuN, and p-CREB/p-p38 MAPK expression levels. Pretreatment with U0126 (ERK1/2 inhibitor) completely abrogated the effects of 10- and 50-Hz EA treatments on the aforementioned protein expression levels. Similarly, pretreatment with SB203580 (p38 MAPK inhibitor) completely abrogated the effects of 10-Hz treatment on the aforementioned protein expression levels. Conclusion: The effects of 10- and 50-Hz EA treatments on mitochondria-related apoptosis can be attributed to the activation of ERK1/2/p38 MAPK/CREB/Bcl-2- and ERK1/2/CREB/Bcl-2-mediated signaling, respectively, in the hippocampal CA1 area at 7 days after transient GCI.

Glutamate (Glu) is a major excitatory neurotransmitter in the brain, essential for synaptic plasticity, neuronal activity, and memory formation. However, its dysregulation leads to excitotoxicity, implicated in neurodegenerative diseases and brain ischemia. Vesicular glutamate transporters (VGLUTs) regulate Glu loading into synaptic vesicles, crucial for maintaining optimal extracellular Glu levels. This study investigates the neuroprotective effects of VGLUT1 inhibition in HT22 cells overexpressing VGLUT1 under oxygen glucose deprivation (OGD) conditions. HT22 cells, a hippocampal neuron model, were transduced with lentiviral vectors to overexpress VGLUT1. Cells were subjected to OGD, with pre-incubation of Chicago Sky Blue 6B (CSB6B), an unspecific VGLUT inhibitor. Cell viability, lactate dehydrogenase (LDH) release, mitochondrial membrane potential, and hypoxia-related protein markers (PARP1, AIF, NLRP3) were assessed. Results indicated that VGLUT1 overexpression increased vulnerability to OGD, evidenced by higher LDH release and reduced cell viability. CSB6B treatment improved cell viability and reduced LDH release in OGD conditions, particularly at 0.1 μM and 1.0 μM concentrations. Moreover, CSB6B preserved mitochondrial membrane potential and decreased levels of PARP1, AIF, and NLRP3 proteins, suggesting neuroprotective effects through mitigating excitotoxicity. This study demonstrates that VGLUT1 inhibition could be a promising therapeutic strategy for ischemic brain injury, warranting further investigation into selective VGLUT1 inhibitors. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to monitor blood-brain barrier permeability within 24 h and during the delayed cerebral ischemia (DCI) time window (DCITW) spanning 4–14 days after aneurysmal subarachnoid hemorrhage (aSAH) and to investigate its correlation with both DCI occurrence and outcomes at three months. Methods: A total of 128 patients were stratified based on the DCI occurrence and three-month modified Rankin scale scores. Comparison of Ktrans at admission (admission Ktrans) and during DCITW (DCITW Ktrans) was conducted between DCI and non-DCI groups, as well as between groups with good and poor outcomes. Changes in Ktrans were also analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of DCI and poor outcomes. Results: Admission Ktrans (0.58 ± 0.18 vs 0.47 ± 0.12, p = 0.002) and DCITW Ktrans (0.54 ± 0.19 vs 0.41 ± 0.14, p < 0.001) were significantly higher in the DCI group compared with the non-DCI group. Although both were higher in the poor outcome group than the good outcome group, the difference was not statistically significant at admission (0.53 ± 0.18 vs 0.49 ± 0.14, p = 0.198). Ktrans in the non-DCI group (0.47 ± 0.12 vs 0.41 ± 0.14, p = 0.004) and good outcome group (0.49 ± 0.14 vs 0.41 ± 0.14, p < 0.001) decreased significantly from the admission to DCITW. Multivariate analysis identified DCITW Ktrans and admission Ktrans as independent predictors of poor outcomes (OR = 1.73, 95%CI: 1.24–2.43, p = 0.001) and DCI (OR = 1.75, 95%CI: 1.25–2.44, p = 0.001), respectively. Conclusion: Elevated Ktrans at admission is associated with the occurrence of DCI. Continuous monitoring of Ktrans from admission to DCITW can accurately identify reversible and irreversible changes and can predict outcomes at 3 months. Clinical relevance statement: Ktrans measured with CT perfusion is a valuable tool for predicting both delayed cerebral ischemia and three-month outcomes following aneurysmal subarachnoid hemorrhage. Monitoring changes in Ktrans from admission to time window of delayed cerebral ischemia can guide treatment and management decisions for aneurysmal subarachnoid hemorrhage patients. Key Points: • Ktrans measured at admission and during the delayed cerebral ischemia time window (4–14 days) holds distinct clinical significance following aneurysmal subarachnoid hemorrhage. • Admission Ktrans serves as a predictor for delayed cerebral ischemia, while continuous assessment of Ktrans from admission to the delayed cerebral ischemia time window can predict three-month outcomes. • Monitoring Ktrans at different stages improves instrumental in enhancing decision-making and treatment planning for patients with aneurysmal subarachnoid hemorrhage. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and brain ischemia/reperfusion cause neurodegenerative processes that can continue after the acute stage with the development of severe brain atrophy with dementia. In this case, the long-term neurodegeneration of the brain is similar to the neurodegeneration characteristic of Alzheimer's disease (AD) and is associated with the accumulation of beta amyloid and tau protein. In the pathogenesis of AD as well as in the pathogenesis of cerebral ischemia and TBI oxidative stress, progressive inflammation, glial activation, blood–brain barrier dysfunction, and excessive activation of autophagy are involved, which implies the presence of many targets that can be affected by neuroprotectors. That is, multivariate cascades of nerve tissue damage represent many potential targets for therapeutic interventions. One of such substances that can be used in multi-purpose therapeutic strategies is methylene blue (MB). This drug can have an antiapoptotic and anti-inflammatory effect, activate autophagy, inhibit the aggregation of proteins with an irregular shape, inhibit NO synthase, and bypass impaired electron transfer in the respiratory chain of mitochondria. MB is a well-described treatment for methemoglobinemia, malaria, and encephalopathy caused by ifosfamide. In recent years, this drug has attracted great interest as a potential treatment for a number of neurodegenerative disorders, including the effects of TBI, ischemia, and AD. [ABSTRACT FROM AUTHOR]

Background: Currently, no evidence exists on the expression of apoptosis (CASP3), autophagy (BECN1), and mitophagy (BNIP3) genes in the CA3 area after ischemia with long-term survival. Objective: The goal of the paper was to study changes in above genes expression in CA3 area after ischemia in the period of 6–24 months. Methods: In this study, using quantitative RT-PCR, we present the expression of genes associated with neuronal death in a rat ischemic model of Alzheimer's disease. Results: First time, we demonstrated overexpression of the CASP3 gene in CA3 area after ischemia with survival ranging from 0.5 to 2 years. Overexpression of the CASP3 gene was accompanied by a decrease in the activity level of the BECN1 and BNIP3 genes over a period of 0.5 year. Then, during 1-2 years, BNIP3 gene expression increased significantly and coincided with an increase in CASP3 gene expression. However, BECN1 gene expression was variable, increased significantly at 1 and 2 years and was below control values 1.5 years post-ischemia. Conclusions: Our observations suggest that ischemia with long-term survival induces neuronal death in CA3 through activation of caspase 3 in cooperation with the pro-apoptotic gene BNIP3. This study also suggests that the BNIP3 gene regulates caspase-independent pyramidal neuronal death post-ischemia. Thus, caspase-dependent and -independent death of neuronal cells occur post-ischemia in the CA3 area. Our data suggest new role of the BNIP3 gene in the regulation of post-ischemic neuronal death in CA3. This suggests the involvement of the BNIP3 together with the CASP3 in the CA3 in neuronal death post-ischemia. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect and potential mechanism of early exercise intervention on cerebral myelin in cerebral ischemia rats. Methods A total of 18 SD rats were randomly divided into the sham group, the middle cerebral artery occlusion resting group (MCAO-SED) and the middle cerebral artery occlusion exercise group (MCAO-EX), with 6 rats in each group. Except the sham group, the middle cerebral artery occlusion model was prepared by modified Longa line embolization method in other groups. After modeling, rats in the MCAO-EX group were placed on a treadmill for exercise intervention for 28 days. Neurological function was assessed by modified neural function deficit score (mNSS). Infarct volume was detected by MRI scanning (T2), myelin basic protein (MBP) expression was detected by immunofluorescence. Myelin sheath structure was detected by transmission electron microscopy. Western blot assay was used to detect endoplasmic reticulum stress-related protein expression. Apoptosis was detected by TUNEL staining. Results After 28 days of intervention, compared with the MCAO-SED group, the nerve function recovered well in the MCAO-EX group, infarct volume decreased, myelin integrity increased, MBP fluorescence intensity expression increased and MBP expression level increased. The expression levels of ATF6, p-IRE1, p-PERK and cleaved caspase 3 were significantly decreased, and apoptosis was reduced. Conclusion Early exercise can inhibit endoplasmic reticulum stress-induced apoptosis, promote cerebral myelin repair, reduce infarct size and improve nerve function. [ABSTRACT FROM AUTHOR]

Background: Neuromonitoring during carotid endarterectomy (CEA) under general anesthesia is desirable and may be useful for preventing brain ischemia, but the selection of the most appropriate method remains controversial. Purpose: To determine the effectiveness of near infrared spectroscopy (NIRS) compared to multimodality intraoperative neuromonitoring (IONM) in indicating elective shunts and predicting postoperative neurological status. Methods: This is a retrospective observational study including 86 consecutive patients with CEA under general anesthesia. NIRS and multimodality IONM were performed during the procedure. IONM included electroencephalography (EEG), somatosensory evoked potentials (SSEPs) and transcranial motor-evoked potentials (TcMEPs). Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated for each neuromonitoring modality. Results: NIRS presented a sensitivity and a specificity for detecting brain ischemia of 77.7% and 89.6%, respectively (PPV = 46.6% and NPV = 97.2%). In contrast, a 100% sensitivity and specificity for multimodality IONM was determined (PPV and NPV = 100%). No significant difference (in demographical or clinical data) between "true positive" and "false-positive" patients was identified. Among the methods included in multimodality IONM, EEG showed the best results for predicting postoperative outcome after CEA (PPV and NPV=100%). Conclusion: NIRS is inferior to multimodality IONM in detecting brain ischemia and predicting postoperative neurological status during CEA under general anesthesia. [ABSTRACT FROM AUTHOR]

How brain functions in the distorted ischemic state before and after reperfusion is unclear. It is also uncertain whether there are any indicators within ischemic brain that could predict surgical outcomes. To alleviate these issues, we applied individual brain connectome in chronic steno‐occlusive vasculopathy (CSOV) to map both ischemic symptoms and their postbypass changes. A total of 499 bypasses in 455 CSOV patients were collected and followed up for 47.8 ± 20.5 months. Using multimodal parcellation with connectivity‐based and pathological distortion‐independent approach, areal MR features of brain connectome were generated with three measurements of functional connectivity (FC), structural connectivity, and PageRank centrality at the single‐subject level. Thirty‐three machine‐learning models were then trained with clinical and areal MR features to obtain acceptable classifiers for both ischemic symptoms and their postbypass changes, among which, 11 were deemed acceptable (AUC > 0.7). Notably, the FC feature‐based model for long‐term neurological outcomes performed very well (AUC > 0.8). Finally, a Shapley additive explanations plot was adopted to extract important individual features in acceptable models to generate "fingerprints" of brain connectome. This study not only establishes brain connectomic fingerprint databases for brain ischemia with distortion, but also provides informative insights for how brain functions before and after reperfusion. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: There is growing evidence for endovascular thrombectomy (EVT) in patients with large ischemic core infarct and large vessel occlusion (LVO). The objective of this study was to compare the efficacy and safety of EVT vs medical management (MM) using a systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs). METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases to obtain articles related to mechanical thrombectomy for large ischemic core from inception until February 10, 2023. The primary outcome was independent ambulation (modified Rankin Scale [mRS] 0-3). Effect sizes were computed as risk ratio (RR) with random-effect or fixed-effect models. The quality of articles was evaluated through the Cochrane risk assessment tool and the Newcastle-Ottawa Scale. This study was registered in PROSPERO (CRD42023396232). RESULTS: A total of 5,395 articles were obtained through the search and articles that did not meet the inclusion criteria were excluded by review of the title, abstract, and full text. Finally, 3 RCTs and 10 cohort studies met the inclusion criteria. The RCT analysis showed that EVT improved the 90-day functional outcomes of patients with large ischemic core with high-quality evidence, including independent ambulation (mRS 0-3: RR 1.78, 95% CI 1.28-2.48, p < 0.001) and functional independence (mRS 0-2: RR 2.59, 95% CI 1.89-3.57, p < 0.001), but without significantly increasing the risk of symptomatic intracranial hemorrhage (sICH: RR 1.83, 95% CI 0.95-3.55, p = 0.07) or early mortality (RR 0.95, 95% CI 0.78-1.16, p = 0.61). Analysis of the cohort studies showed that EVT improved functional outcomes of patients without an increase in the incidence in sICH. DISCUSSION: This systematic review and meta-analysis indicates that in patients with LVO stroke with a large ischemic core, EVT was associated with improved functional outcomes over MM without increasing sICH risk. The results of ongoing RCTs may provide further insight in this patient population.

OBJECTIVES: COMMANDER-HF was a randomised trial comparing rivaroxaban 2.5 mg two times a day to placebo, in addition to antiplatelet therapy, in patients hospitalised for worsening heart failure with coronary artery disease and sinus rhythm. Patients with diabetes are at increased risk of cardiovascular events and therefore have more to gain. METHODS AND RESULTS: In this post-hoc analysis, we evaluated the efficacy and safety of rivaroxaban in patients with (n=2052) and without diabetes (n=2970). The primary outcome was the composite of cardiovascular death, myocardial infarction (MI) or ischaemic stroke. HRs and 95% CIs with interaction analyses were used to describe event-rates and treatment effects. Patients with diabetes had a higher prevalence of cardiovascular comorbidities (eg, hypertension, obesity) and increased incidence of cardiovascular events. Adjusted HRs for events in people with versus without diabetes were 1.34 (95% CI 1.19 to 1.50) for the primary outcome, 1.21 (95% CI 0.84 to 1.75) for stroke, 1.51 (95% CI 1.14 to 1.99) for MI, 1.17 (95% CI 1.05 to 1.31) for heart failure hospitalisation and 1.06 (95% CI 0.56 to 2.01) for major bleeding. Rivaroxaban had no significant effect on event-rates in patients with and without diabetes (all interaction p values >0.05). Low-dose rivaroxaban was associated with an overall reduction in ischaemic stroke (HR 0.66; 95% CI 0.47 to 0.95), with no apparent subgroup interaction according to diabetes status (p-int=0.93). CONCLUSIONS: In COMMANDER-HF a diagnosis of diabetes conferred higher rates of cardiovascular events that, with exception of ischaemic stroke, was not substantially reduced by rivaroxaban. Rivaroxaban was associated with reduced risk of ischaemic stroke for patients with and without diabetes. TRIAL REGISTRATION NUMBER: NCT01877915; Post-results.

We have previously demonstrated protection from impending cortical ischemic stroke is achievable by sensory stimulation of the ischemic area in an adult rat model of permanent middle cerebral artery occlusion (pMCAo). We have further demonstrated that a major underpinning mechanism that is necessary for such protection is the system of collaterals among cerebral arteries that results in reperfusion of the MCA ischemic territory. However, since such collateral flow is weak, it may be necessary but not sufficient for protection and therefore we sought other complementary mechanisms that contribute to sensory-based protection. We hypothesized that astrocytes-neuron lactate shuttle (ANLS) activation could be another potential underpinning mechanism that complements collateral flow in the protection process. Supporting our hypothesis, using functional imaging, pharmacological treatments, and postmortem histology, we showed that ANLS played a pivotal role in sensory stimulation-based protection of cortex and therefore serves as the other supporting mechanism underpinning the protection process.

AIMS: The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known. METHODS AND RESULTS: Array genotyping and imputation for common genetic variants were performed. Polygenic risk scores (PRS) were calculated for AF (PRS-AF) and ischaemic stroke risk (PRS-stroke). The effects of PRS-AF and PRS-stroke on the primary outcome (composite of cardiovascular death, stroke, and hospitalization for acute coronary syndrome or worsening heart failure), its components, and recurrent AF were determined.A total of 1567 of the 2789 trial patients were analysed [793 randomized to early rhythm control; 774 to usual care, median age 71 years (65-75), 704 (44%) women]. Baseline characteristics were similar between randomized groups. Early rhythm control reduced the primary outcome compared with usual care [HR 0.67, 95% CI: (0.53, 0.84), P < 0.001]. The randomized intervention, early rhythm control, did not interact with PRS-AF (interaction P = 0.806) or PRS-stroke (interaction P = 0.765). PRS-AF was associated with recurrent AF [HR 1.08 (01.0, 1.16), P = 0.047]. PRS-stroke showed an association with the primary outcome [HR 1.13 (1.0, 1.27), P = 0.048], driven by more heart failure events [HR 1.23 (1.05-1.43), P = 0.010] without differences in stroke [HR 1.0 (0.75, 1.34), P = 0.973] in this well-anticoagulated cohort. In a replication analysis, PRS-stroke was associated with incident AF [HR 1.16 (1.14, 1.67), P < 0.001] and with incident heart failure in the UK Biobank [HR 1.08 (1.06, 1.10), P < 0.001]. The association with heart failure was weakened when excluding AF patients [HR 1.03 (1.01, 1.05), P = 0.001]. CONCLUSIONS: Early rhythm control is effective across the spectrum of genetic AF and stroke risk. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risk and treatment. REGISTRATION: ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

BACKGROUND: Existing data and clinical trials could not determine whether faster intravenous thrombolytic therapy (IVT) translates into better long-term functional outcomes after acute ischemic stroke among those treated with endovascular thrombectomy (EVT). Patient-level national data can provide the required large population to study the associations between earlier IVT, versus later, with longitudinal functional outcomes and mortality in patients receiving IVT+EVT combined treatment. METHODS: This cohort study included older US patients (age ≥65 years) who received IVT within 4.5 hours or EVT within 7 hours after acute ischemic stroke using the linked 2015 to 2018 Get With The Guidelines-Stroke and Medicare database (38 913 treated with IVT only and 3946 with IVT+EVT). Primary outcome was home time, a patient-prioritized functional outcome. Secondary outcomes included all-cause mortality in 1 year. Multivariate logistic regression and Cox proportional hazards models were used to evaluate the associations between door-to-needle (DTN) times and outcomes. RESULTS: Among patients treated with IVT+EVT, after adjusting for patient and hospital factors, including onset-to-EVT times, each 15-minute increase in DTN times for IVT was associated with significantly higher odds of zero home time in a year (never discharged to home) (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]), less home time among those discharged to home (adjusted odds ratio, 0.93 per 1% of 365 days [95% CI, 0.89-0.98]), and higher all-cause mortality (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.11]). These associations were also statistically significant among patients treated with IVT but at a modest degree (adjusted odds ratio, 1.04 for zero home time, 0.96 per 1% home time for those discharged to home, and adjusted hazard ratio 1.03 for mortality). In the secondary analysis where the IVT+EVT group was compared with 3704 patients treated with EVT only, shorter DTN times (≤60, 45, and 30 minutes) achieved incrementally more home time in a year, and more modified Rankin Scale 0 to 2 at discharge (22.3%, 23.4%, and 25.0%, respectively) versus EVT only (16.4%, P60 minutes. CONCLUSIONS: Among older patients with stroke treated with either IVT only or IVT+EVT, shorter DTN times are associated with better long-term functional outcomes and lower mortality. These findings support further efforts to accelerate thrombolytic administration in all eligible patients, including EVT candidates.

BackgroundMany stroke recovery interventions are most beneficial when started 2-14d post-stroke, a time when patients become eligible for inpatient rehabilitation facilities (IRF) and neuroplasticity is often at its peak. Clinical trials focused on recovery need to expand the time from this plasticity to later outcome timepoints.MethodsThe disability course of patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) enrolled in Field Administration of Stroke Therapy Magnesium (FAST-MAG) Trial with moderate-severe disability (modified Rankin Scale [mRS] 3-5) on post-stroke day4 who were discharged to IRF 2-14d post-stroke were analyzed.ResultsAmong 1422 patients, 446 (31.4%) were discharged to IRFs, including 23.6% within 2-14d and 7.8% beyond 14d. Patients with mRS 3-5 on day4 discharged to IRFs between 2-14d accounted for 21.7% (226/1041) of AIS patients and 28.9% (110/381) of ICH patients, (p

Whether endovascular thrombectomy (EVT) improves functional outcome in patients with large-vessel occlusion (LVO) stroke that do not comply with inclusion criteria of randomized controlled trials (RCTs) but that are considered for EVT in clinical practice is uncertain. We aimed to systematically identify patients with LVO stroke underrepresented in RCTs who might benefit from EVT. Following the premises that (i) patients without reperfusion after EVT represent a non-treated control group and (ii) the level of reperfusion affects outcome in patients with benefit from EVT but not in patients without treatment benefit, we systematically assessed the importance of reperfusion level on functional outcome prediction using machine learning in patients with LVO stroke treated with EVT in clinical practice (N = 5235, German-Stroke-Registry) and in patients treated with EVT or best medical management from RCTs (N = 1488, Virtual-International-Stroke-Trials-Archive). The importance of reperfusion level on outcome prediction in an RCT-like real-world cohort equaled the importance of EVT treatment allocation for outcome prediction in RCT data and was higher compared to an unselected real-world population. The importance of reperfusion level was magnified in patient groups underrepresented in RCTs, including patients with lower NIHSS scores (0-10), M2 occlusions, and lower ASPECTS (0-5 and 6-8). Reperfusion level was equally important in patients with vertebrobasilar as with anterior LVO stroke. The importance of reperfusion level for outcome prediction identifies patient target groups who likely benefit from EVT, including vertebrobasilar stroke patients and among patients underrepresented in RCT patients with low NIHSS scores, low ASPECTS, and M2 occlusions.