Author Correction: Potential circadian effects on translational failure for neuroprotection.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Potential circadian effects on translational failure for neuroprotection.

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans1,2 may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.

Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

Normobaric Hyperoxia Combined With Endovascular Treatment Based on Temporal Gradient: A Dose-Escalation Study.

BACKGROUND: Normobaric hyperoxia (NBO) has neuroprotective effects in acute ischemic stroke. Thus, we aimed to identify the optimal NBO treatment duration combined with endovascular treatment. METHODS: This is a single-center, randomized controlled, open-label, blinded-end point dose-escalation clinical trial. Patients with acute ischemic stroke who had an indication for endovascular treatment at Tianjin Huanhu Hospital were randomly assigned to 4 groups (1:1 ratio) based on NBO therapy duration: (1) control group (1 L/min oxygen for 4 hours); (2) NBO-2h group (10 L/min for 2 hours); (3) NBO-4h group (10 L/min for 4 hours); and (4) NBO-6h group (10 L/min for 6 hours). The primary outcome was cerebral infarction volume at 72 hours after randomization using an intention-to-treat analysis model. The primary safety outcome was the 90-day mortality rate. RESULTS: Between June 2022 and September 2023, 100 patients were randomly assigned to the following groups: control group (n=25), NBO-2h group (n=25), NBO-4h group (n=25), and NBO-6h group (n=25). The 72-hour cerebral infarct volumes were 39.4±34.3 mL, 30.6±30.1 mL, 19.7±15.4 mL, and 22.6±22.4 mL, respectively (P=0.013). The NBO-4h and NBO-6h groups both showed statistically significant differences (adjusted P values: 0.011 and 0.027, respectively) compared with the control group. Compared with the control group, both the NBO-4h and NBO-6h groups showed significant differences (P<0.05) in the National Institutes of Health Stroke Scale scores at 24 hours, 72 hours, and 7 days, as well as in the change of the National Institutes of Health Stroke Scale scores from baseline to 24 hours. Additionally, there were no significant differences among the 4 groups in terms of 90-day mortality rate, symptomatic intracranial hemorrhage, early neurological deterioration, or severe adverse events. CONCLUSIONS: The effectiveness of NBO therapy was associated with oxygen administration duration. Among patients with acute ischemic stroke who underwent endovascular treatment, NBO therapy for 4 and 6 hours was found to be more effective. Larger-scale multicenter studies are needed to validate these findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05404373.

ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke. METHODS: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro. RESULTS: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes. CONCLUSIONS: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.

SLC22A17 as a Cell Death-Linked Regulator of Tight Junctions in Cerebral Ischemia.

BACKGROUND: Beyond neuronal injury, cell death pathways may also contribute to vascular injury after stroke. We examined protein networks linked to major cell death pathways and identified SLC22A17 (solute carrier family 22 member 17) as a novel mediator that regulates endothelial tight junctions after ischemia and inflammatory stress. METHODS: Protein-protein interactions and brain enrichment analyses were performed using STRING, Cytoscape, and a human tissue-specific expression RNA-seq database. In vivo experiments were performed using mouse models of transient focal cerebral ischemia. Human stroke brain tissues were used to detect SLC22A17 by immunostaining. In vitro experiments were performed using human brain endothelial cultures subjected to inflammatory stress. Immunostaining and Western blot were used to assess responses in SLC22A17 and endothelial tight junctional proteins. Water content, dextran permeability, and electrical resistance assays were used to assess edema and blood-brain barrier (BBB) integrity. Gain and loss-of-function studies were performed using lentiviral overexpression of SLC22A17 or short interfering RNA against SLC22A17, respectively. RESULTS: Protein-protein interaction analysis showed that core proteins from apoptosis, necroptosis, ferroptosis, and autophagy cell death pathways were closely linked. Among the 20 proteins identified in the network, the iron-handling solute carrier SLC22A17 emerged as the mediator enriched in the brain. After cerebral ischemia in vivo, endothelial expression of SLC22A17 increases in both human and mouse brains along with BBB leakage. In human brain endothelial cultures, short interfering RNA against SLC22A17 prevents TNF-α (tumor necrosis factor alpha)-induced ferroptosis and downregulation in tight junction proteins and disruption in transcellular permeability. Notably, SLC22A17 could repress the transcription of tight junctional genes. Finally, short interfering RNA against SLC22A17 ameliorates BBB leakage in a mouse model of focal cerebral ischemia. CONCLUSIONS: Using a combination of cell culture, human stroke samples, and mouse models, our data suggest that SLC22A17 may play a role in the control of BBB function after cerebral ischemia. These findings may offer a novel mechanism and target for ameliorating BBB injury and edema after stroke.

Effects of acetazolamide combined with remote ischemic preconditioning on risk of acute mountain sickness: a randomized clinical trial.

BACKGROUND: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). METHODS: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. RESULTS: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07-0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3- 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. CONCLUSIONS: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05023941.

Remote ischemic conditioning improves cerebral hemodynamics in symptomatic intracranial atherosclerosis: A PET/CT-guided randomized controlled study.

Patients with symptomatic intracranial arterial stenosis (sICAS) suffer embarrassed hemodynamic status and acute ischemic stroke (AIS) recurrence. We aimed to assess the efficacy of remote ischemic conditioning (RIC) on improving this status by evaluating cerebral blood flow (CBF) and cerebral glucose metabolism (CGM) via PET/CT. Adult patients with unilateral sICAS in middle cerebral artery and/or intracranial segment of internal carotid artery-related AIS or transient ischemic attack within 6 months prior to randomization were enrolled. Individuals who received intravenous thrombolysis or endovascular treatment, or sICAS caused by cardiac embolism, small vessel occlusion, or other determined causes were excluded. Twenty-three eligible patients were randomly assigned to standard medical treatment (SMT) (n = 10) or RIC group (n = 13). The RIC protocol consisted of 5 cycles, each for 5-min bilateral upper limb ischemia and 5-min reperfusion period, twice a day, with a total duration of 3 months. Ten healthy volunteers were enrolled as healthy control group. We tested CBF and CGM at the rest stage and the methazolamide-induced stress stage. All patients received PET/CT at baseline and three-month followup. Both CBF and CGM in ipsilateral hemisphere of sICAS patients were significantly decreased at the rest stage and the stress stage (p < .05), which were improved by three-month RIC (p < .05). The lesions decreased notably in RIC group compared to SMT group (p < .05). RIC ameliorated the hemodynamic status and glucose metabolism in regions at high risk of infarction, which might improve the resistance capacity towards ischemic load in sICAS patients.

A case report: new-onset nummular headache after stenting of the middle cerebral artery.

BACKGROUND: Nummular headache (NH) is categorized as a primary headache in the International Classification of Headache Disorders, Third edition (ICHD-3) diagnostic criteria, but there are secondary etiologies as well. We present a case of secondary NH that associated with vascular lesion. CASE PRESENTATION: We report on a 40-year-old man with a medical history of symptomatic intracranial arterial stenosis who developed a headache after percutaneous transluminal angioplasty and stenting because of Intracranial atherosclerotic stenosis(ICAS). This new-onset headache was a pinprick headache confined to the parietal part of the head and 5 cm in size. This headache most closely resembled the phenotype of a NH. And other causes of secondary headache were excluded. Thus, the diagnosis of NH was highly speculated. This patient represents a rare headache phenomenon after intracranial arterial stent placement. CONCLUSION: This is the first report of NH after stent placement treatment in a patient with ICAS.

Vascular endothelial cells: a fundamental approach for brain waste clearance.

Accumulation of neurotoxic protein aggregates is the pathological hallmark of neurodegenerative disease. Proper clearance of these waste metabolites is an essential process for maintaining brain microenvironment homeostasis and may delay or even halt the onset and progression of neurodegeneration. Vascular endothelial cells regulate the molecular exchange between the circulation and brain parenchyma, thereby protecting the brain against the entry of xenobiotics and decreasing the accumulation of neurotoxic proteins. In this review, we provide an overview of cerebrovascular endothelial cell characteristics and their impact on waste metabolite clearance. Lastly, we speculate that molecular changes in cerebrovascular endothelial cells are the drivers of neurodegenerative diseases.

Remote ischemic conditioning reduces adverse events in patients with acute ischemic stroke complicating acute myocardial infarction: a randomized controlled trial.

BACKGROUND: Acute ischemic stroke (AIS) complicating an acute myocardial infarction (AMI) is not uncommon, but can severely worsen the clinical prognosis. This study aimed to investigate whether remote ischemic conditioning (RIC) could provide clinical benefits to patients with AIS complicating AMI. METHODS: Subjects with AIS complicating AMI were recruited in this double-blind, randomized, controlled trial; assigned to the RIC and sham groups; and respectively underwent twice daily RIC and sham RIC for 2 weeks. All subjects received standard medical therapy. The primary endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCEs) within 3 months after enrollment. MACCEs comprise of death from all causes, unstable anginas, AMI, acute ischemic strokes, and transient ischemic attacks. RESULTS: Eighty subjects were randomly assigned; 37 patients in the RIC group and 40 patients in the sham-RIC group completed the 3-month follow-up and were included in the final analysis. Both RIC and sham RIC procedures were well tolerated. At 3-month follow-up, 11 subjects (29.7%) in the RIC group experienced MACCEs compared to 21 (52.5%) in the sham group (hazard ratio [HR], 0.396; 95% confidence interval, 0.187-0.838; adjusted p < 0.05). Six subjects (16.2%) in the RIC group had died at the 3-month follow up, significantly lower than the 15 (37.5%) deaths in the sham group (adjusted HR 0.333; 95% CI 0.126-0.881; p = 0.027). Seventeen subjects (45.9%) in the RIC group and 6 subjects (15.0%) in the sham group achieved functional independence (mRS score ≤ 2) at 3-month follow-up (adjusted OR 12.75; 95% CI 2.104-77.21; p = 0.006). CONCLUSIONS: Among patients with acute ischemic stroke complicating acute myocardial infarction, treatment with remote ischemic conditioning decreased the major adverse cardiac and cerebrovascular events and improved functional outcomes at 90 days. TRIAL REGISTRATION: URL: www. CLINICALTRIALS: gov . Unique identifier: NCT03868007. Registered 8 March 2019.

Remote Ischemic Conditioning: Challenges and Opportunities.

Remote ischemic conditioning (RIC) has been investigated as a promising, safe, and well-tolerated nonpharmacological therapy for cardio-cerebrovascular disease over the past 3 decades; variable results have been found when it is used in cerebrovascular versus cardiovascular disease. For patients with cardiovascular disease, milestone studies suggest that the roles of RIC may be limited. Recently, however, 2 large trials investigating RIC in patients with cerebrovascular disease found promising results, which may reignite the field's research prospects after its setbacks in the cardiovascular field. This perspectives article highlights several important clinical trials of RIC in the cardio-cerebrovascular disease and describes the many challenges of RIC in clinical translation. Finally, based on the available evidence, several promising research directions such as chronic RIC, early initiation in target population, improvement of compliance, better understanding of dosing, and identification of specific biomarkers are proposed and should be investigated before RIC can become applied into clinical practice for patient benefit.

Safety and Tolerability of Direct Ischemic Postconditioning Following Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Experimental studies have demonstrated the neuroprotection of ischemic postconditioning (IPostC) in acute ischemic stroke by attenuating ischemia-reperfusion injury. This study aimed to investigate the safety and tolerability of direct IPostC in both a dog model and patients with acute ischemic stroke treated with thrombectomy. METHODS: The study involved 2 parts. First, IPostC was induced by repeated balloon inflation and deflation in dogs, where a low-pressure balloon was navigated to the anterior spinal artery, and 4 cycles of 5-minute ischemia followed by 5-minute reperfusion were performed. Vascular injuries were assessed using angiography and vascular tissue specimens. Then, a 3+3 dose-escalation trial was conducted in patients with acute ischemic stroke following successful thrombectomy recanalization. Patients received direct IPostC with ischemia and reperfusion durations in progressive increments of 0, 1, 2, 3, 4, and 5 minutes ×4 cycles. Major adverse responses were defined as vessel perforation, rupture, dissection, reocclusion, severe vasospasm, thrombotic events, and rupture of the balloon. RESULTS: IPostC was investigated in 4 dogs. No vessel perforation or rupture, dissection, or vasospasm was observed under the angiography. Only 1 vessel experienced mild injury between the intima and the internal elastic membrane detected on a histopathologic slide. Then, 18 patients were recruited. The duration of IPostC was progressively escalated with no major response happened. No patient experienced agitation, discomfort, or other tolerability issues. Five patients (27.8%) experienced any intracranial hemorrhage after thrombectomy, and 1 (5.6%) was symptomatic. At 3-month follow-up, no patient died, and 9 patients (50%) achieved functional independence. CONCLUSIONS: Direct IPostC inducing by 4 cycles of 5-minute ischemia followed by 5-minute reperfusion is safe, feasible, and tolerable in patients with acute ischemic stroke treated with thrombectomy. Further investigations are needed to determine the safety and preliminary efficacy of direct IPostC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05153655.

Deep Learning Algorithm Enables Cerebral Venous Thrombosis Detection With Routine Brain Magnetic Resonance Imaging.

BACKGROUND: Cerebral venous thrombosis (CVT) is a rare cerebrovascular disease. Routine brain magnetic resonance imaging is commonly used to diagnose CVT. This study aimed to develop and evaluate a novel deep learning (DL) algorithm for detecting CVT using routine brain magnetic resonance imaging. METHODS: Routine brain magnetic resonance imaging, including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images of patients suspected of CVT from April 2014 through December 2019 who were enrolled from a CVT registry, were collected. The images were divided into 2 data sets: a development set and a test set. Different DL algorithms were constructed in the development set using 5-fold cross-validation. Four radiologists with various levels of expertise independently read the images and performed diagnosis within the test set. The diagnostic performance on per-patient and per-segment diagnosis levels of the DL algorithms and radiologist's assessment were evaluated and compared. RESULTS: A total of 392 patients, including 294 patients with CVT (37±14 years, 151 women) and 98 patients without CVT (42±15 years, 65 women), were enrolled. Of these, 100 patients (50 CVT and 50 non-CVT) were randomly assigned to the test set, and the other 292 patients comprised the development set. In the test set, the optimal DL algorithm (multisequence multitask deep learning algorithm) achieved an area under the curve of 0.96, with a sensitivity of 96% (48/50) and a specificity of 88% (44/50) on per-patient diagnosis level, as well as a sensitivity of 88% (129/146) and a specificity of 80% (521/654) on per-segment diagnosis level. Compared with 4 radiologists, multisequence multitask deep learning algorithm showed higher sensitivity both on per-patient (all P<0.05) and per-segment diagnosis levels (all P<0.001). CONCLUSIONS: The CVT-detected DL algorithm herein improved diagnostic performance of routine brain magnetic resonance imaging, with high sensitivity and specificity, which provides a promising approach for detecting CVT.

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.

Protocol of a Multicenter Cohort Observational Study of Cerebral Venous Thrombosis in China Mainland.

Epidemiological data on cerebral venous thrombosis in China are still lacking at present on the aspects of incidence, recurrence, risk factors, and so on. Herein, we aimed to fill the gap, based on the result of this multicenter prospective cohort study. A total of 26 top tertiary hospitals distributed in China Mainland will take part in this study. For the first time, a dataset of cerebral venous thrombosis cohort (including multiethnic patients of all ages in almost all regions of Mainland China, regardless of gender) will be built. Inclusion criteria were as follows: (1) aged ≥14 years, (2) neuroimaging-confirmed cerebral venous thrombosis, (3) symptom onset was within 30 days prior to enrollment, (4) signed the informed consent form. Demographic data, risk factors, clinical and neuroimaging features, ophthalmologic and aural results, blood tests, cerebrospinal fluid examination, therapeutic strategies, and adverse events were analyzed. Two milliliters of fasting venous blood and 2 mL of cerebrospinal fluid will be collected and stored. Furthermore, patients will be followed up at months 1, 3, 6, and 12 after baseline assessment. Primary outcome will be all-cause mortality. Secondary outcomes: (1) cerebrospinal fluid pressure and Frisen grade; (2) recanalization rate on imaging; (3) rating scales such as GCS, NIHSS, mRS, Mini-Mental State Examination, Montreal Cognitive Assessment, Patient Health Questionnaire 9-item, HIT-6, and Tinnitus Handicap Index. This study will for the first time provide strong evidence on the incidence rate, recurrence rate, and demographic data, as well as special risk factors, clinical outcomes, symptomatic and imaging features of cerebral venous thrombosis in Chinese population. The results of this study will also provide an important reference on prevention, early diagnosis, and customized treatment of cerebral venous thrombosis in Chinese patients.

Causal effect of lipoprotein-associated phospholipase A2 activity on ischemic stroke : a Mendelian randomization study.

Background The relationship between ischemic stroke (IS) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is still unclear, and there is a dearth of stratified research on the relationship between Lp-PLA2 activity and different IS subtypes. Therefore, Mendelian randomization was used in this study to examine the relationship between genetically proxied Lp-PLA2 activity and the risks of IS and its subtypes. Methods Based on information from a meta-analysis of GWAS, which included 13,664 European people, five single-nucleotide polymorphisms related to Lp-PLA2 activity were chosen as instrumental variables. Summary statistics information about MEGESTROKE consortium with the European group (40,585 cases and 406,111 controls) include any ischemic stroke (AIS) (n = 34,217); large-artery stroke (LAS, n=4,373), cardioembolic stroke (CES, n=7,193) and small vessel stroke (SVS, n=5,386). In order to determine the causal relationships between Lp-PLA2 activity and IS as well as its subtypes, the inverse variance weighted (IVW) approach was chosen as the primary analysis. Significant estimates were then tested by sensitivity analysis to rule out heterogeneity and pleiotropy. Results IVW showed Lp-PLA2 activity was causally associated with LAS (OR=3.25, 95% CI=1.65-6.41, p=0.0007), but not with other subtypes of stroke. Sensitivity analysis for causal estimates between Lp-PLA2 activity and LAS showed no significant heterogeneity or pleiotropy. Conclusions These MR analyses support a causal effect of Lp-PLA2 activity on LAS but not on AIS, CES or SVS, which suggests that serum Lp-PLA2 activity might be a biomarker for prediction of LAS.

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.

Cortical vein involvement and its influence in a cohort of adolescents with cerebral venous thrombosis.

BACKGROUND AND PURPOSE: Cortical vein thrombosis (CVT) is a rare form of cerebral venous sinus thrombosis (CVST) in adolescent patients that has received little attention. We aimed to analyze the clinical and radiological features of adolescents with CVST and investigate the effects of CVT involvement. METHODS: Patients aged ≥ 10 to ≤ 18 years and diagnosed with CVST were identified at Xuanwu Hospital, Capital Medical University between January 2015 and August 2022 and divided into two groups according to the presence or absence of cortical vein involvement. Additionally, the patients were also categorized based on their sex. Clinical features, radiological characteristics, and 12-month follow-up outcomes were compared between the two groups. RESULTS: Fifty-three adolescents, including 21 with CVT, were included (mean age: 15.2 ± 1.8 years; females, 54.7%). The CVT group was more likely to experience seizures (P = 0.028) and deterioration (28.6% vs. 6.2%, P = 0.047) during hospitalization than the non-CVT group. Poor short-term outcomes, based on the modified Rankin Scale (mRS) score at discharge, were more common in adolescents with CVT (P = 0.007). The proportions of patients showing edema (42.9% vs. 6.2%, P = 0.004) and mass effect (P = 0.015) were significantly higher in the CVT group. Recanalization was observed in 61.9% and 82.1% of the patients in the CVT and non-CVT groups, respectively, during the first imaging review (median, 22 days). After a 12-month follow-up, female adolescents had more frequent resident secondary headaches than male adolescents (52.9% vs. 12.5%; P = 0.014). CONCLUSIONS: Cortical vein involvement in adolescents with CVST was associated with a higher risk of epilepsy at presentation, deterioration during hospitalization, edema, and mass effect on acute imaging. Moreover, cortical vein involvement may lead to worse short-term outcomes. Sex differences require consideration in etiological analyses and prolonged follow-ups.

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.