Rapid Intravenous Glyceryl Trinitrate in Ischemic Damage (RIGID): A potential neuroprotection strategy for acute ischemic stroke (AIS) patients.

Despite advances in intravenous thrombolysis and endovascular thrombectomy, numerous acute ischemic stroke survivors continue to experience various disability levels. The nitric oxide (NO) donor, Glyceryl Trinitrate (GTN), has been identified as a potential neuroprotective agent against ischemic damage. We evaluated the safety and feasibility of intravenous GTN in AIS patients. Subsequently, we conducted a secondary analysis to assess for possible efficacy of GTN as a neuroprotectant. We conducted a prospective, double-blind, randomized controlled trial in the Stroke Intervention & Translational Center (SITC) in Beijing Luhe Hospital, Capital Medical University (ChiCTR2100046271). AIS patients within 24 h of stroke onset were evenly divided into GTN or control groups (n = 20 each). The GTN group received intravenous GTN (5 mg in 50 ml saline at a rate of 0.4 mg/h for 12.5 h/day over 2 days), while controls were administered an equivalent volume of 0.9% saline. Both groups followed standard Stroke Guidelines for treatment. Safety measures focused on SBP<110 mmHg and headache occurrence. Efficacy was assessed via the 90-day modified rankin score (mRS) and the national institutes of health stroke score (NIHSS). Of the 40 AIS patients, baseline characteristics such as age, gender, risk factors, and pre-mRS scores showed no significant difference between the groups. Safety measures of SBP<110 mmHg and headache occurrence were comparable. Overall, 90-day mRS (1 vs. 1) and NIHSS (1 vs. 1) did not significantly differ between groups. However, the GTN-treated group had a benefit in enhancing NIHSS recovery (△NIHSS 4.5 vs. 3, p = 0.028), indicating that GTN may augment recovery. Subgroup analyses revealed a benefit in the GTN group at the 90-day NIHSS score and △NIHSS follow up for non-thrombolysis patients (1 vs. 2, p = 0.016; 5 vs. 2, p = 0.001). Moreover, the GTN group may benefit mild stroke patients in NIHSS score at 90 day and △NIHSS observed at 90 days (1 vs. 1, p = 0.025; 3 vs. 2 p = 0.002). Overall, while preliminary data suggest GTN might aid recovery in NIHSS improvement, the evidence is tempered due to sample size limitations. The RIGID study confirms the safety and feasibility of intravenous GTN administration for AIS patients. Preliminary data also suggest that the GTN group may provide improvement in NIHSS recovery compared to the control group. Furthermore, a potential benefit for non-thrombolysis patients and those with mild stroke symptoms was identified, suggesting a possible potential role as a tailored intervention in specific AIS subgroups. Due to the limited sample size, further larger RCT will be necessary to replicate these results. TRIAL REGISTRATION: www.chictr.org.cn, identifier: ChiCTR2100046271.

Association of Early Longitudinal Changes in the Neutrophil-to-Lymphocyte Ratio With Adverse Clinical Outcomes in Acute Ischemic Stroke Patients After Endovascular Treatment.

BACKGROUND: We aim to elucidate the contribution of early dynamic changes in the neutrophil-to-lymphocyte ratio (NLR) to poor clinical outcomes in acute ischemic stroke patients after endovascular treatment (EVT). METHODS: Acute ischemic stroke patients who underwent EVT were consecutively recruited from January 2019 to July 2022. Blood cell counts were sampled at admission and at following 24 hours after EVT. Clinical outcome measures included 3-month functional dependence (modified Rankin scale of 3-6), symptomatic intracranial hemorrhage, and mortality at 7 days and 30 days. Multinomial logistic regressions were used to evaluate the association of changes in the NLR with unfavorable outcomes. RESULTS: A total of 590 patients were included in the final analysis. The multinomial logistic model indicated that the increasing changes in the NLR after EVT was an independent factor for poor outcomes; the adjusted odds ratio was 1.06 (95% confidence interval [CI] 1.03-1.10; P < 0.001) at poor 3-month functional outcomes, 1.07 (95% CI 1.04-1.10; P < 0.001) at symptomatic intracranial hemorrhage, 1.08 (95% CI 1.05-1.12; P < 0.001) at mortality at 7 days, and 1.04 (95% CI 1.02-1.07; P = 0.001) at mortality at 30 days. Areas under the curve of changes in NLR to discriminate adverse outcomes were 0.725, 0.687, 0.664, and 0.659, respectively. The optimal cutoff values were 5.77 (56.6% sensitivity, 81.0% specificity), 6.92 (60.0% sensitivity, 77.0% specificity), 8.64 (51.0% sensitivity, 82.0% specificity), and 8.64 (48.7% sensitivity, 83.0% specificity), respectively. CONCLUSIONS: The NLR in acute ischemic stroke patients increased remarkably independent of successful reperfusion. Elevated changes in the NLR might predict malignant hemorrhagic transformation, adverse functional outcomes, and short-term mortality.

Large vessel occlusion stroke outcomes in diabetic vs. non-diabetic patients with acute stress hyperglycemia.

Objective: This study assesses whether stress-induced hyperglycemia is a predictor of poor outcome at 3 months for patients with acute ischemic stroke (AIS) treated by endovascular treatment (EVT) and impacted by their previous blood glucose status. Methods: This retrospective study collected data from 576 patients with AIS due to large vessel occlusion (LVO) treated by EVT from March 2019 to June 2022. The sample was composed of 230 and 346 patients with and without diabetes mellitus (DM), respectively, based on their premorbid diabetic status. Prognosis was assessed with modified Rankin Scale (mRS) at 3-month after AIS. Poor prognosis was defined as mRS>2. Stress-induced hyperglycemia was assessed by fasting glucose-to-glycated hemoglobin ratio (GAR). Each group was stratified into four groups by quartiles of GAR (Q1-Q4). Binary logistic regression analysis was used to identify relationship between different GAR quartiles and clinical outcome after EVT. Results: In DM group, a poor prognosis was seen in 122 (53%) patients and GAR level was 1.27 ± 0.44. These variables were higher than non-DM group and the differences were statistically significant (p < 0.05, respectively). Patients with severe stress-induced hyperglycemia demonstrated greater incidence of 3-month poor prognosis (DM: Q1, 39.7%; Q2, 45.6%; Q3, 58.6%; Q4, 68.4%; p = 0.009. Non-DM: Q1, 31%; Q2, 32.6%; Q3, 42.5%; Q4, 64%; p < 0.001). However, the highest quartile of GAR was independently associated with poor prognosis at 3 months (OR 3.39, 95% CI 1.66-6.96, p = 0.001), compared to the lowest quartile in non-DM patients after logistic regression. This association was not observed from DM patients. Conclusion: The outcome of patients with acute LVO stroke treated with EVT appears to be influenced by premorbid diabetes status. However, the poor prognosis at 3-month in patients with DM is not independently correlated with stress-induced hyperglycemia. This could be due to the long-term damage of persistent hyperglycemia and diabetic patients' adaptive response to stress following acute ischemic damage to the brain.

Serum Bilirubin Associated with Stroke Severity and Prognosis: Preliminary Findings on Liver Function after Acute Ischemic Stroke.

OBJECTIVE: This study investigates relationships between serum bilirubin, stroke severity, and prognosis of patients with acute ischemic stroke (AIS) to elucidate the roles of the liver in AIS. METHODS: This retrospective study collected data from 527 patients diagnosed with AIS within 24 hours after their symptom onset. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Mild stroke was defined as NIHSS≤5. Prognosis was assessed with modified Rankin Scale (mRS) on 90 days after AIS and good prognosis was defined as mRS≤2. The patients were divided based on their total bilirubin (Tbil) and direct bilirubin (Dbil) levels to study these serum markers' association with the severity of stroke. Tbil levels were measured and compared with mRS on 90 days to analyze prognosis of mild stroke patients. RESULTS: Both Tbil abnormal (NIHSS = 6.8 ± 5.3) and Dbil abnormal groups (NIHSS = 7.3 ± 5.7) had higher NIHSS scores on admission than the normal groups (p< 0.05 or p< 0.01, respectively). Severity of stroke at discharge was similar between these groups (p = 0.025 and 0.019, respectively). Serum bilirubin levels were independently associated with stroke severity on admission and discharge after risk factors were adjusted (p< 0.001 and p< 0.05, respectively; ß (95%CI) were 0.116 (0.064-0.167) and 0.058 (0.012-0.103), respectively). The average Tbil levels of mild stroke with good prognosis was 15.1 ± 6.4umol/l versus 11.8 ± 3.1umol/l with poor prognosis; this difference was statistically significant (p = 0.003). The same difference was observed with Dtil levels but it did not reach a significant level. CONCLUSION: High Tbil and Dbil level within 48 hours of symptom onset could be an independent marker of severity of stroke on admission and discharge for all AIS patients. For patient with mild stroke, elevation of bilirubin after AIS suggests a good prognosis. These findings imply that the liver play the key roles in the mechanism of AIS.

Optimal rehabilitation strategies for early postacute stroke recovery: An ongoing inquiry.

Early rehabilitation is crucial in reducing stroke-related disability, but the optimal training model remains unclear. We conducted a trial comparing different initiation timings and intensities of mobilization strategies after stroke. Results showed that early intensive mobilization had favorable outcomes at 3 months post-stroke, while very early intensive mobilization had poorer chances of favorable outcomes. Our investigation into brain injury mechanisms induced by very early exercise within 24 hours of stroke onset aligned with guidelines advising against high-dose very early mobilization. Additionally, we are studying the effects of various exercise intensities and frequencies on early stroke rehabilitation. Integrated rehabilitation models, such as combining remote ischemic conditioning (RIC) with exercise (RICE), hold promise. Our study found RICE to be safe and feasible for early rehabilitation of acute ischemic stroke patients, and further research is underway to determine its efficacy in a larger sample size. Despite extensive research, identifying the most effective early recovery strategies remains a complex challenge, necessitating ongoing work in the field of early rehabilitation after stroke.

Remote ischemic conditioning (RIC) with exercise (RICE) is safe and feasible for acute ischemic stroke (AIS) patients.

Objective: Rehabilitation is essential in reducing stroke disability and should be performed as early as possible. Exercise is an established and effective rehabilitation method; however, its implementation has been limited as its very early use exacerbates cerebral injury and is restricted by patients' unstable conditions and disabilities. Remote ischemic conditioning (RIC) is a passive and accessible therapy in acute phases of stroke and appears to have similar neuroprotective effects as exercise. This study assessed the safety and feasibility of the novel rehabilitation strategy-early RIC followed by exercise (RICE) in acute ischemic stroke (AIS). Methods: We conducted a single-center, double-blinded, randomized controlled trial with AIS patients within 24 h of stroke onset or symptom exacerbation. All enrolled patients were randomly assigned, at a ratio of 1:1, to either the RICE group or the sham-RICE group (sham RIC with exercise). Each group received either RIC or sham RIC within 24 h after stroke onset or symptom exacerbation, once a day, for 14 days. Both groups started the exercise routine on day 4, twice daily, for 11 total days. The safety endpoints included clinical deterioration, recurrence of stroke, hemorrhagic transformation, complications, and adverse events resulting from RICE during hospitalization. The efficacy endpoints [Modified Rankin Scale (mRS) score, National Institutes of Health Stroke Scale (NIHSS) score, Barthel Index, and walking ability] were evaluated at admission and 90 days after stroke onset. Results: Forty AIS patients were recruited and completed the study. No significant differences in baseline characteristics were found between the two groups, which included risk factors, stroke severity at admission, pre-morbid disability, and other special treatments. No significant differences were found in the safety endpoints between two groups. Excellent recovery (mRS 0-2) at 3 months was obtained in 55% of the patients with RICE as compared 40% in sham group, but it did not reach a significant level. Conclusions: RICE was safe and feasible for AIS patients, and seems to be a promising early stroke rehabilitation. The results of this study suggest a need for a future randomized and controlled multicenter trial with a larger sample size to determine the efficacy of RICE.

Effects of remote ischemic conditioning on sleep complaints in Parkinson's disease-rationale, design, and protocol for a randomized controlled study.

Objective: Sleep disturbances are common non-motor symptoms of Parkinson's disease. The symptoms affect the quality of patients' life by impeding normal sleep cycles and causing excessive daytime sleepiness. Remote Ischemic Conditioning (RIC) is a therapy often used for ischemic stroke patients to minimize infarct size and maximize post-stroke neurological function. Animal experiments have shown that RIC plays a protective role for retinal ganglion cells and other critical areas of the brain of Parkinson's disease. However, whether RIC improves excessive daytime sleepiness (EDS) for patients with Parkinson's disease remains to be determined. Methods: This is a single-center, double-blind, and randomized controlled trial, which includes patients with Parkinson's disease with EDS. All recruited patients will be randomly assigned either to the RIC or the control group (i.e., sham-RIC) with 20 patients in each group. Both groups receive RIC or sham-RIC treatment once a day for 28 days within 24 h of enrollment. Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Parkinson Disease Sleep Scale-2 (PDSS-2), Parkinson's Disease Questionnaire39 (PDQ39) score scales, and adverse events, such as inability to tolerate the treatment leading to suspension of the study or objective signs of tissue or neurovascular injury caused by RIC and/or sham-RIC are evaluated at 7, 14, 28, and 90 days after enrollment. Results: The primary goal of this study is to assess the feasibility of the treatments in patients with Parkinson's disease by measuring serious RIC-related adverse events and any reduced incidence of adverse events during the trial and to study potential efficacy, improvement of patients' excessive daytime sleepiness, quality of life-based on ESS, PSQI, PDSS-2, and PDQ39 scores. The secondary goal is to confirm the safety of the treatments. Conclusion: This study is a prospective randomized controlled trial to determine the safety, feasibility, and potential efficacy of RIC for patients with Parkinson's disease associated with EDS.

Clinical Characteristics and Outcomes of Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder With Brainstem Lesions as Heralding Prodrome.

Objective: The present study sought to differentiate multiple sclerosis and neuromyelitis optica spectrum disorder patients at their first attack by describing and distinguishing their clinical features, radiographic characteristics, and immunologic characteristics of serum and cerebrospinal fluid. Methods: We retrospectively studied 58 patients with multiple sclerosis (MS) and 52 patients with neuromyelitis optica spectrum disorder (NMOSD) by referencing brainstem lesions as the prodromal events. Their demographics and presentation at the time of the first attack was evaluated including their gender, age, clinical features of the first attack, the expanded disability status scale (EDSS), brainstem lesion(s) by head MRI, and immunological indices of serum and cerebrospinal fluid. Results: The NMOSD group had more female patients (4.8 vs. 1.9, p < 0.05), and was older than the MS group (37.81 ± 16.60 vs. 27.57 ± 11.17, p <0.001). NMOSD patients also had a significantly higher association with autoimmune diseases or positive autoimmune antibodies (p < 0.01). There was no significant difference in the EDSS scores between the two groups (p = 0.420). Central hiccups, vomiting, and pyramidal tract signs were more common in the NMOSD group than the MS group (p < 0.001, p < 0.001, p < 0.01), while eye movement abnormalities were more common with MS (p < 0.01). There were no significant differences in other clinical manifestations such as vertigo, diplopia, limb weakness, numbness, and eating difficulty. MS patients were more likely to have midbrain and pons imaging lesions (p < 0.001, p < 0.001), while NMOSD patients had more lesions in the medulla oblongata (p < 0.001). The lesions in the MS group were mostly located in the periphery, while those in the NMOSD group were centrally located (p < 0.001, p < 0.001). Patchy lesions were more common in MS patients (p < 0.001), while large lesions were more common in the NMOSD group (p < 0.001). Finally, serum AQP4 Ab was found only in the NMOSD group (p < 0.001). Conclusion: Patients with MS and NMOSD have differentiating clinical manifestations at the time of their first brainstem lesions which include central hiccups, vomiting, pyramidal tract signs, and abnormal eye movements. Additionally, distinct imaging manifestations such as lesion location(s) and morphology may also aid in the development of pathognomonic criteria leading to timely initial diagnosis of MS and NMOSD.

Early mobilisation post-stroke: a systematic review and meta-analysis of individual participant data.

PURPOSE: To investigate the safety and efficacy of early mobilisation (EM) compared to usual care by meta-analysing individual participant data (IPD). MATERIALS AND METHODS: IPD were sought from randomised controlled trials comparing out-of-bed mobilisation starting within 48 h from stroke onset to usual care for acute stroke patients. Six trials were sourced from a recent Cochrane review. Favourable outcome (modified Rankin Scale 0-2) and death at 3 months post-stroke were compared between both groups using mixed-effect logistic regression modelling. Adjusted odds ratios (aORs) with respective 95% confidence intervals (95%CI) were reported. RESULTS: Out of 2630 participants, 1437 (54.6%) were assigned to EM and 1193 (45.4%) to usual care. Intervention protocols varied considerably between trials. The median (interquartile range) delay to starting mobilisation post-stroke onset was 20 h (14.5-23.8) for EM and 23 h (16.7-34.3) for usual care group. Fewer EM participants had a favourable outcome at 3 months post-stroke compared to the usual care group (678 [48%] vs. 611 [52%]; aOR = 0.75, 95%CI: 0.62-0.92, p = 0.005). No difference in death at 3 months post-stroke between EM and usual care was observed (102 [7%] vs. 84 [7%]; aOR = 1.46, 95%CI: 0.92-2.31, p = 0.108). CONCLUSION: The commencement of mobilisation should only be considered after 24 h post-stroke. Further research is required to identify safe, optimal dose, and timing of EM post-stroke.IMPLICATIONS FOR REHABILITATIONPatients who commenced mobilisation early after stroke had worse outcome than usual care.Insufficient detail about mobilisation interventions or usual care in many studies limits any further interpretation.The commencement of mobilisation should only be considered after 24-h post-stroke.

Remote Ischemic Conditioning With Exercise (RICE)-Rehabilitative Strategy in Patients With Acute Ischemic Stroke: Rationale, Design, and Protocol for a Randomized Controlled Study.

Objective: Exercise rehabilitation is an effective therapy in reducing the disability rate after stroke and should be carried out as early as possible. However, very early rehabilitation exercise exacerbates brain injury and is difficult to conduct in stroke patients due to their weakened and potentially disabled state. It is valuable to explore additional early rehabilitation strategies. Remote Ischemic Conditioning (RIC) is a novel therapy designed to protect vital organs from severe lethal ischemic injury by transient sublethal blood flow to non-vital organs, including the distal limbs, in order to induce endogenous protection. RIC has previously been conducted post-stroke for neuroprotection. However, whether combined early RIC and exercise (RICE) therapy enhances stroke rehabilitation remains to be determined. Methods: This is a single-center, double-blinded, randomized controlled trial that will enroll acute ischemic stroke patients within 24 h of symptom onset or symptom exacerbation. All enrolled patients will be randomly assigned to either the RICE group (exercise with RIC) or the control group (exercise with sham RIC) at a ratio of 1:1, with 20 patients in each group. Both groups will receive RIC or sham RIC within 24 h after stroke onset or symptom exacerbation, once a day, for 14 days. All patients will begin exercise training on the fourth day, twice a day, for 11 days. Their neurological function [Modified Rankin Scale (mRS) score, National Institutes of Health Stroke Scale (NIHSS) score, Barthel Index, and walking ability], infarct volume (nuclear magnetic resonance, MRI), and adverse events will be evaluated at different time points in their post-stroke care. Results: The primary outcome is safety, measured by the incidence of any serious RICE-related adverse events and decreased adverse events during hospitalization. The secondary outcome is a favorable prognosis within 90 days (mRS score < 2), determined by improvements in the mRS score, NIHSS score, Barthel Index, walking ability after 90 days, and infarct volume after 12 ± 2 days. Conclusion: This study is a prospective randomized controlled trial to determine the rehabilitative effect of early RIC followed by exercise on patients with acute ischemic stroke. Trial Registration: www.chictr.org.cn, identifier: ChiCTR2000041042.

Adjuvant High-Flow Normobaric Oxygen After Mechanical Thrombectomy for Anterior Circulation Stroke: a Randomized Clinical Trial.

Adjuvant neuroprotective therapies for acute ischemic stroke (AIS) have demonstrated benefit in animal studies, albeit without human translation. We investigated the safety and efficacy of high-flow normobaric oxygen (NBO) after endovascular recanalization in anterior circulation stroke. This is a prospective randomized controlled study. Eligible patients were randomized to receive high-flow NBO by a Venturi mask (FiO2 50%, flow 15 L/min) or routine low-flow oxygen supplementation by nasal cannula (flow 3 L/min) after vessel recanalization for 6 h. Patient demographics, procedural metrics, complications, functional outcomes, symptomatic intracranial hemorrhage (sICH), and infarct volume were assessed. A total of 91 patients were treated with high-flow NBO. NBO treatment revealed a common odds ratio of 2.2 (95% CI, 1.26 to 3.87) favoring the distribution of global disability scores on the mRS at 90 days. The mortality at 90 days was significantly lower in the NBO group than in the control group, with an absolute difference of 13.86% (rate ratio, 0.35; 95% CI, 0.13-0.93). A significant reduction of infarct volume as determined by MRI was noted in the NBO group. The median infarct volume was 9.4 ml versus 20.5 ml in the control group (beta coefficient, - 20.24; 95% CI, - 35.93 to - 4.55). No significant differences were seen in the rate of sICH, pneumonia, urinary infection, and seizures between the 2 groups. This study suggests that high-flow NBO therapy after endovascular recanalization is safe and effective in improving functional outcomes, decreasing mortality, and reducing infarct volumes in anterior circulation stroke patients within 6 h from stroke onset.

Acute Anterior Choroidal Artery Territory Infarction: A Retrospective Study.

OBJECTIVES: To explore the clinical features, risk factors, etiopathogenesis, mechanism of progression, effect of intravenous thrombolysis therapy (IVT) and prognosis of acute ischemic stroke (AIS) in the anterior choroidal artery (AChA) territory. PATIENTS AND METHODS: A total of 113 AChA infarction patients were enrolled in the current study retrospectively. The demographic and clinical characteristics were collected and analyzed in all patients. The clinical characteristics were compared between clinical progression and no clinical progression groups, good and poor outcome groups, as well as with and without intravenous rt-PA groups. RESULTS: Hemiparesis was the most common clinical manifestation (92.9%), followed by dyslexia (54.9%), hemianesthesia (43.4%) and other syndromes. Forty-nine patients (43.4%) suffered from clinical progression and showed a higher rate with multiple risk factors together than patients without clinical progression (30.6% vs.14.1%, P = 0.039). Moreover, more patients with progression were found with carotid plaques (73.5% vs. 51.6%, P = 0.018) or carotid artery stenosis (18.4% vs. 6.3%, P = 0.045) than patients without progression. 69.9% of patients got good prognosis at 6-months. In good prognosis group, the proportion of patients with atrial fibrillation, clinical progression and large infarct size were significantly lower than in poor prognosis group (1.3% vs. 11.8%, P = 0.047; 23.9% vs. 67.6%, P = 0.001; 15.2% vs. 38.2%, P = 0.007). No significant difference was found on rate of clinical progression and good prognosis between patients with and without IVT. CONCLUSION: Motor deficits are the most frequent and typical symptoms in AChA infarcts. Although small artery disease was considered to be the important etiopathogenesis of the AChA infarcts, large vascular disease may be associated with clinical progression in AChA infarcts. Additionally, prognosis of AChA infarcts is correlated with clinical progression, infarct size and atrial fibrillation. IVT does not seem to prevent the clinical progression and improve prognosis of AChA infarcts.

Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway.

Phenothiazine treatment has been shown to reduce post-stroke ischemic injury, though the underlying mechanism remains unclear. This study sought to confirm the neuroprotective effects of phenothiazines and to explore the role of the NOX (nicotinamide adenine dinucleotide phosphate oxidase)/Akt/PKC (protein kinase C) pathway in cerebral apoptosis. Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) for 2 h and were randomly divided into 3 different cohorts: (1) saline, (2) 8 mg/kg chlorpromazine and promethazine (C+P), and (3) 8 mg/kg C+P as well as apocynin (NOX inhibitor). Brain infarct volumes were examined, and cell death/NOX activity was determined by assays. Western blotting was used to assess protein expression of kinase C-δ (PKC-δ), phosphorylated Akt (p-Akt), Bax, Bcl-XL, and uncleaved/cleaved caspase-3. Both C+P and C+P/NOX inhibitor administration yielded a significant reduction in infarct volumes and cell death, while the C+P/NOX inhibitor did not confer further reduction. In both treatment groups, anti-apoptotic Bcl-XL protein expression generally increased, while pro-apoptotic Bax and caspase-3 proteins generally decreased. PKC protein expression was decreased in both treatment groups, demonstrating a further decrease by C+P/NOX inhibitor at 6 and 24 h of reperfusion. The present study confirms C+P-mediated neuroprotection and suggests that the NOX/Akt/PKC pathway is a potential target for efficacious therapy following ischemic stroke.

Low dose concomitant treatment with chlorpromazine and promethazine is safe in acute ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is associated with significant morbidity and mortality and has a very narrow window of treatment with fibrinolytics. We investigated the safety and efficacy of combined chlorpromazine and promethazine (C+P) treatment in AIS. METHODS: A total of 64 consecutive patients diagnosed with AIS were selected and were randomly (double-blind) assigned into either the control group (standard of care [SOC] treatment) or the treatment group (SOC+C+P [12.5+12.5 mg BID or 25+25 mg BID]) which were treated for 2 weeks. The National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) were computed prior to and after treatment to evaluate neurological deficits and daily functional status. RESULTS: In our study, 64 patients (males=81.3%) were divided into either the control (34 patients, 83.3% males, mean age=58.8±11.7 years) or the study group (30 patients, 79.4% males, mean age=62.3±9.1 years). While the NIHSS scores were not different between the control and treatment group at admission (P>0.05), a greater proportion of the cohort in both the groups (control group low NIHSS=79.4%, high NIHSS=20.6%, P<0.01) had a lower NIHSS at admission and (treatment group low NIHSS=83.3%, high NIHSS=16.7%, P<0.01). Interestingly, while both the control and treatment group had lower NIHSS and mRS scores at 90d post treatment compared to those at baseline, there were no significant differences in those scores between the two group (P>0.05) suggesting no improved benefit with C+P. Moreover, using C+P did not lead to any serious adverse effects when compared to the treatment group. CONCLUSIONS: While the addition of low dose chlorpromazine and promethazine to standard of care for acute ischemic stroke did not have any significant improvement in functional outcomes, there were no serious adverse effects. Thus, the use of chlorpromazine and promethazine in the acute ischemic stroke setting and future studies using higher doses of C+P are justified.

High Intensity Physical Rehabilitation Later Than 24 h Post Stroke Is Beneficial in Patients: A Pilot Randomized Controlled Trial (RCT) Study in Mild to Moderate Ischemic Stroke.

Objective: Very early mobilization was thought to contribute to beneficial outcomes in stroke-unit care, but the optimal intervention strategy including initiation time and intensity of mobilization are unclear. In this study, we sought to confirm the rehabilitative effects of different initiation times (24 vs. 48 h) with different mobilization intensities (routine or intensive) in ischemic stroke patients within three groups. Materials and Methods: We conducted a randomized and controlled trial with a blinded follow-up assessment. Patients with ischemic stroke, first or recurrent, admitted to stroke unit within 24 h after stroke onset were recruited. Eligible subjects were randomly assigned (1:1:1) to 3 groups: Early Routine Mobilization in which patients received < 1.5 h/d out-of-bed mobilization within 24-48 h after stroke onset, Early Intensive Mobilization in which patients initiated ≥3 h/d mobilization at 24-48 h after the stroke onset, and Very Early Intensive Mobilization in which patients received≥3 h/d mobilization within 24 h. The modified Rankin Scale score of 0-2 was used as the primary favorable outcome. Results: We analyzed 248 of the 300 patients (80 in Early Routine Mobilization, 82 in Very Early Intensive Mobilization and 86 in Early Intensive Mobilization), with 52 dropping out (20 in Early Routine Mobilization, 18 in Very Early Intensive Mobilization and 14 in Early Intensive Mobilization). Among the three groups, the Early Intensive Mobilization group had the most favorable outcomes at 3-month follow-up, followed by patients in the Early Routine Mobilization group. Patients in Very Early Intensive Mobilization received the least odds of favorable outcomes. At 3 month follow up, 53.5%, (n = 46) of patients with Early Intensive Mobilization showed a favorable outcome (modified Rankin Scale 0-2) (p = 0.041) as compared to 37.8% (n = 31) of patients in the Very Early Intensive Mobilization. Conclusions: Post-stroke rehabilitation with high intensity physical exercise at 48 h may be beneficial. Very Early Intensive Mobilization did not lead to a favorable outcome at 3 months. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR-ICR-15005992.

MicroRNA-323 suppresses nerve cell toxicity in cerebral infarction via the transforming growth factor-ß1/SMAD3 signaling pathway.

In the present study, the aim was to investigate the function of microRNA­323 (miR­323) in cerebral infarction and its underlying mechanism. A rat model of cerebral infarction was established and hippocampal tissues were analyzed. In addition, to further understand the role of miR­323, PC12 cells were transfected with miR­323 mimics or inhibitors and subjected to hypoxia to model cerebral infarction. Reverse transcription­quantitative polymerase chain reaction was used to measure the expression of miR­323. A luciferase reporter assay was conducted to analyze miR­323 target sites the partial sequence of the 3'­untranslated region of SMAD3 mRNA in vitro. Western blot analysis was also used to analyze transforming growth factor­ß1 (TGF­ß1) and SMAD3 protein expression levels. It was observed that miR­323 expression was significantly upregulated in rats with cerebral infarction compared with rats in the sham­control group. In addition, overexpression of miR­323 induced nerve cell toxicity and reduced nerve cell growth in an in vitro model of cerebral infarction, whereas downregulation of miR­323 caused the opposite effects on nerve cell toxicity and growth in this model. In addition, overexpression of miR­323 directly targeted and suppressed SMAD3 expression in the in vitro model of cerebral infarction, while inhibition of miR­323 induced SMAD3 expression. The use of a SMAD3 inhibitor suppressed the effect of anti­miR­323 on nerve cell toxicity in the in vitro model of cerebral infarction. Collectively, these findings suggested that miR­323 suppresses nerve cell apoptosis in cerebral infarction via the TGF­ß1/SMAD3 signaling pathway.

MicroRNA-132 modifies angiogenesis in patients with ischemic cerebrovascular disease by suppressing the NF­κB and VEGF pathway.

In the present study, the expression of microRNA (miR)­132 and the mechanism by which it modifies angiogenesis in patients with ischemic cerebrovascular disease (ICD) was investigated. RNA isolation and reverse transcription­quantitative polymerase chain reaction were used to measure miR­132 expression in patients with ICD. Inflammatory factors were measured using ELISA kits and western blotting measured B­cell lymphoma­2 (Bcl­2)­associated X/Bcl­2 ratio (Bax/Bcl­2 ratio), nuclear factor (NF)­κB p65, matrix metalloproteinase­9 (MMP­9), vascular cell adhesion molecule­1 (VCAM­1) and protein expression of inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) protein expression. miR­132 expression in patients with ICD was lower compared with healthy volunteers. PC12 cells were used to create an oxygen glucose deprivation (OGD) model. miR­132 overexpression in an in vitro model was able to reduce tumor necrosis factor­a, interleukin (IL)­1ß, IL­6, IL­8, cyclooxygenase­2, caspase­3 and caspase­9 levels, suppress Bax/Bcl­2 ratio, NF­κB p65, MMP­9, VCAM­1, iNOS, VEGF protein expression. The results suggested that miR­132 may modify angiogenesis in patients with ICD by suppressing the NF­κB pathway and promoting the VEGF pathway, and may develop into a therapy for ICD in future research.

Motor Imagery-Based Rehabilitation: Potential Neural Correlates and Clinical Application for Functional Recovery of Motor Deficits after Stroke.

Motor imagery (MI), defined as the mental implementation of an action in the absence of movement or muscle activation, is a rehabilitation technique that offers a means to replace or restore lost motor function in stroke patients when used in conjunction with conventional physiotherapy procedures. This article briefly reviews the concepts and neural correlates of MI in order to promote improved understanding, as well as to enhance the clinical utility of MI-based rehabilitation regimens. We specifically highlight the role of the cerebellum and basal ganglia, premotor, supplementary motor, and prefrontal areas, primary motor cortex, and parietal cortex. Additionally, we examine the recent literature related to MI and its potential as a therapeutic technique in both upper and lower limb stroke rehabilitation.

Music-supported therapy (MST) in improving post-stroke patients' upper-limb motor function: a randomised controlled pilot study.

OBJECTIVE: Music-supported therapy (MST) is a new approach for motor rehabilitation of stroke patients. Recently, many studies have demonstrated that MST improved the motor functions of post-stroke patients. However, the underlying mechanism for this effect is still unclear. It may result from repeated practice or repeated practice combined with musical stimulation. Currently, few studies have been designed to clarify this discrepancy. In this study, the application of "mute" musical instruments allowed for the study of music as an independent factor. METHODS: Thirty-three post-stroke patients with no substantial previous musical training were included. Participants were assigned to either audible music group (MG) or mute music group (CG), permitting observation of music's independent effect. All subjects received the conventional rehabilitation treatments. Patients in MG (n = 15) received 20 extra sessions of audible musical instrument training over 4 weeks. Patients in CG (n = 18) received "mute" musical instrument training of the same protocol as that of MG. Wolf motor function test (WMFT) and Fugl-Meyer assessment (FMA) for upper limbs were utilised to evaluate motor functions of patients in both groups before and after the treatment. Three patients in CG dropped out. RESULTS: All participants in both groups showed significant improvements in motor functions of upper limbs after 4  weeks' treatment. However, significant differences in the WMFT were found between the two groups (WMFT-quality: P = 0.025; WMFT-time: P = 0.037), but not in the FMA (P = 0.448). In short, all participants showed significant improvement after 4 weeks' treatment, but subjects in MG demonstrated greater improvement than those in CG. DISCUSSION: This study supports that MST, when combined with conventional treatment, is effective for the recovery of motor skills in post-stroke patients. Additionally, it suggests that apart from the repetitive practices of MST, music may play a unique role in improving upper-limb motor function for post-stroke patients.