ObjectiveThe objective of this study was to investigate the safety and efficacy of remote ischemic conditioning (RIC) combined with intravenous thrombolysis (IVT) in the treatment of acute ischemic stroke (AIS).MethodsPatients with AIS who underwent IVT were enrolled and 1:1 randomized to the RIC group and sham‐RIC group in this study. RIC (or sham‐RIC) was performed twice within 6–24 h of IVT. The subjects in the two groups were followed up for 90 days. The safety outcome included the ratio of hemorrhagic transformation (HT), adverse events during the follow‐up, blood pressure within the first 24 h after IVT, and laboratory tests 24 h after IVT. The efficacy outcome included the modified Rankin Scale (mRS) score, National Institute of Health Stroke Scale (NIHSS) score during the follow‐up, and level of high‐sensitivity C‐reactive protein (hs‐CRP) tested 24 h after IVT.ResultsForty‐nine patients (24 in the RIC group and 25 in the sham‐RIC group) were recruited. No significant difference was observed in the ratio of HT, adverse events, blood pressure, coagulation function or liver function between groups. In addition, there was no significant difference in mRS score and NIHSS score during the follow‐up between groups. However, patients in the RIC group exhibited a significant lower level of hs‐CRP compared with the control group (P = 0.048).InterpretationRIC combined with IVT is safe in the treatment of AIS. The neuroprotective and anti‐inflammatory effects of this therapy warrant further study on a larger scale.

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Rationale: Remote ischemic conditioning (RIC) combined with intravenous thrombolysis (IVT) may improve functional outcomes in patients with acute ischemic stroke (AIS). Aim: To assess the efficacy and safety of RIC combined with IVT for AIS. Methods and design: SERIC-IVT is a multicenter, randomized, parallel-controlled, blinded endpoint clinical trial. A total of 558 patients with AIS who underwent IVT therapy will be randomly assigned 1:1 to receive RIC or sham-RIC plus standard medical therapy. The cuff pressures of the RIC group and the sham-RIC group will be 200 mmHg and 60 mmHg, respectively, performed twice a day for 7 consecutive days. Study outcomes: The primary efficacy outcome is the proportion of patients with a favorable functional outcome as defined as a modified Rankin Scale ≤ 1 at 90 days. Safety outcomes include mortality and adverse events within 90 days. Sample size estimates: A sample size of 558 patients with AIS (279 in each group) will allow detection of a shift of 13.14% toward favorable functional outcome at 90 days (modified Rankin Scale ≤1) with 5% significance and 80% power. Discussion: RIC is a promising adjuvant treatment for AIS. SERIC-IVT will inform on whether RIC treatment combined with IVT improves functional outcomes in AIS patients and identify any safety issues.

Introduction: Preclinical studies have indicated insulin-like growth factor 1 (IGF1) as a novel therapeutic target in the treatment of migraines. We aimed to investigate the causal effect of circulating IGF1 levels on migraine risk using the two-sample Mendelian randomization method.Methods: A total of 431 independent variants from 363,228 unrelated individuals in the UK Biobank were used as genetic instruments for circulating IGF1 levels. Summary-level data for migraines were obtained from two independent studies with 10,536 and 28,852 migraine cases, respectively. Results: Mendelian randomization using inverse-variance weighting showed that increased IGF1 levels were significantly associated with decreased risk of migraines in both outcome datasets (odds ratio 0.905, 95% confidence interval 0.842-0.972, p = 0.006; odds ratio 0.929, 95% confidence interval 0.882-0.979, p = 0.006). Although some other robust Mendelian randomization methods did not demonstrate a significant association, no unbalanced horizontal pleiotropy was found by Mendelian randomization-Egger regression (p values for horizontal pleiotropy 0.232 and 0.435). The effect was confirmed in additional analyses including multivariable Mendelian randomization analyses. Conclusion: This two-sample Mendelian randomization study showed that genetically determined increased IGF1 levels are causally associated with decreased migraine risk. Future randomized controlled trials are warranted to confirm the benefits of IGF1 administration on migraines.Reziya Abuduxukuer and Peng-Peng Niu contributed equally.

Background: Ischemic stroke is a major cause of death and disability worldwide and results from inadequate cerebrovascular blood supply; mitochondrial dysfunction plays an essential role in its pathogenesis. DL-3-n-butylphthalide (NBP) is an effective medicine for ischemic stroke that reduces cell apoptosis and improves long-term prognosis. Objective: Whether and how NBP regulates mitochondria-associated apoptosis in cerebral ischemia-reperfusion injury remains unclear. Methods: Male Sprague Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) stroke and treated with low (20 mg/kg) or high (80 mg/kg) concentrations of NBP. The Omi/HtrA2 inhibitor UCF-101 was used as a positive control. Cerebral infarction, neuron injury and neuronal apoptosis were assessed to determine the efficacy of NBP compared to UCF-101. We assessed the expression of the Omi/HtrA2 signaling pathway by western blotting and tested the mRNA expression of mitochondrial metabolism-related genes by PCR. Results: Compared to the MCAO group, both low and high concentrations of NBP substantially improved cerebral infarction, neuron injury, and neuronal apoptosis; high concentrations of NBP were more potent than low concentrations. The expression of proteins of the mitochondrial Omi/HtrA2 signaling pathway, including Omi/HtrA2, XIAP, PARL, OPA1, CHOP, and ClpP, was inhibited in the NBP group. Conclusion: Overall, early application of NBP attenuated cerebral ischemia-reperfusion injury by inhibiting mitochondrial Omi/HtrA2-mediated apoptosis in rats. Our study supports a novel neuroprotective mechanism of NBP, making it a promising therapeutic agent for ischemic stroke.