Improve Stroke Outcomes Research Articles

Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats.

Previous studies reported that Tat-NR2B9c, a peptide disrupting the N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction, reduced ischemic damage in the acute phase after stroke. However, its effect in the subacute phase is unknown. The aim of this study is to determine whether disrupting the N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction in the subacute phase promotes recovery after stroke. Studies were performed on Sprague-Dawley rats or nNOS(-/-) mice, and experimental ischemic stroke was induced by middle cerebral artery occlusion. Animals were treated with drugs starting at day 4 after ischemia. Sensorimotor functions and spatial learning and memory ability were assessed after drug treatment. Then, rats were euthanized for morphological observation and biochemical tests. Disrupting the N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction with Tat-HA-NR2B9c significantly ameliorated the ischemia-induced impairments of spatial memory and sensorimotor functions in rats during subacute stage but did not improve stroke outcome in nNOS(-/-) mice. Consistent with the functional recovery, Tat-HA-NR2B9c substantially increased neurogenesis in the dentate gyrus and dendritic spine density of mature neurons in the motor cortex of rats, meanwhile, reversed the ischemia-induced formation of S-nitrosylation-cyclin-dependent kinase 5 and increased cyclin-dependent kinase 5 activity in ipsilateral hippocampus. However, directly blocking N-methyl-d-aspartate receptors with MK-801 or Ro 25-6981 did not show the beneficial effects above. Dissociating N-methyl-d-aspartate receptor-postsynaptic density protein-95 coupling by Tat-HA-NR2B9c in the subacute phase after stroke promotes functional recovery, probably because of that it increases neurogenesis and dendritic spine density of mature neurons via regulating cyclin-dependent kinase 5 in the ischemic brain.

Time is Brain: A Quality Improvement Project to Improve Stroke Outcomes by Educating EMS. (P4.308)

Time is Brain: A Quality Improvement Project to Improve Stroke Outcomes by Educating EMS. (P4.308)

Mechanical Thrombectomy Improves Stroke Outcomes

Although thrombectomy devices became available years ago to treat acute ischemic stroke, whether this therapy actually improves outcomes was unclear.

Abstract T P96: Controlled Brain Glucose Uptake and Metabolism by Ethanol: An Alternative Approach in Improving Stroke Outcome

Introduction: Post-stroke oxygen deficit impairs oxidative phosphorylation of glucose. Surviving brain cells increase anaerobic glycolysis (hyperglycolysis) promoting reactive oxygen species (ROS) synthesis via lactic acidosis and NADPH oxidase (NOX) activation. Hyperglycemia present in 40% of stroke patients with or without diabetes perpetuates hyperglycolysis. Insulin, the only treatment to attenuate hyperglycemia-induced hyperglycolysis, is linked to increased risk of hypoglycemia and mortality. We showed that EtOH reduced ROS-mediated brain damage. Here, we studied whether hyperglycemia/hyperglycolysis-enhanced brain injury are ameliorated by reducing brain glucose uptake and metabolism rather than affecting blood glucose levels. Methods: Sprague-Dawley rats underwent a 2 h right middle cerebral artery occlusion (MCAO). EtOH (1.5 g/kg) or saline was injected IP upon reperfusion, then sacrificed 3 and 24 h later. Energy stores, hyperglycolysis-associated glucose uptake and metabolism, lactic acidosis, and oxidative stress were assessed via ADP/ATP ratio, NAD+/NADH ratio, Na+/K+ ATPase activity, levels of brain and blood glucose, glucose transporter GLUT 1 and 3, lactate, lactate dehydrogenase (LDH), ROS, phosphofructokinase-1 (PFK-1), NOX, and PFK-1 and NOX activity. Results: Ischemic rats showed significant (p<0.01) increase in ADP/ATP and NAD+/NADH ratios, and decrease in Na+/K+ ATPase activity indicating impaired metabolic and neural activity. Increased blood glucose and decreased brain glucose indicate hyperglycemic condition with hyperglycolysis. High levels of GLUT 1 and 3, lactate, LDH , PFK-1, NOX, and ROS support ROS associated hyperglycolysis. EtOH normalized these metabolic parameters to control levels, but only blood glucose remained higher. In sum, EtOH attenuates hyperglycemia-enhance brain injury by reducing glucose uptake and its hyperglycolytic-mediated metabolism under hyperglycemic condition. Conclusion: EtOH administered upon reperfusion is neuroprotective against ROS-mediated brain damage in acute ischemic stroke. It attenuates hyperglycemia-enhanced hyperglycolysis at the level of glucose uptake, utilization, and metabolism rather than reducing serum glucose levels.

Abstract T P296: Race/Ethnicity Disparities in Access to Inpatient Physical and Occupational Therapy Exist

Introduction: African-Americans and Hispanics have worse functional outcomes after stroke, although the reasons for these disparities are not known. As more intense rehabilitation therapy after stroke is associated with improved outcomes, we hypothesized that decreased access to therapy during stroke hospitalization may contribute to outcome disparities. Methods: The 2008 State Inpatient Databases (SID) for seven states, which include data on all inpatient discharges within a state were used to identify all primary ischemic stroke (ICD-9-CM 433.x1, 434.x1, 436) and intracerebral hemorrhage discharges (435). Receipt of physical (PT) and occupational (OT) therapy was determined using HCUP definitions. Logistic regression was used to compare receipt of therapy by race/ethnicity adjusting for demographics, insurance, comorbidities, stroke type, and presumptive severity markers (length of stay, ICU use, presentation via ED, receipt of IV tPA, use of life-sustaining treatments). Hospital effects were then accounted for by including all risk adjustors in a multi-level model with a random hospital-level intercept. Results: A total of 472, 210 discharges in 702 hospitals were identified, 59% in whites, 13% in African Americans and 4% in Hispanics; 71% received PT and 47% OT. Before accounting for hospital effects, African-Americans (OR 0.82 for PT, 0.84 for OT) and Hispanics (OR 0.79 for PT, 0.64 for OT) were less likely to receive therapy (p < 0.001 for all comparisons). Hospital was an important predictor of receipt of therapy, intra-class correlation coefficient (ICC) 0.14 for PT and 0.56 for OT. After accounting for the hospital where they were admitted, African-Americans were more likely to receive PT (OR 1.11) and OT (OR 1.08, p < 0.05) and therapy use was the same in Hispanics and whites (OR 1.05 for PT, p = 0.3 and 1.10 for OT, p = 0.09). Conclusions: In this large sample, African-Americans and Hispanics were less likely to receive inpatient PT and OT than whites. This disparity is explained by the fact that minorities receive care at hospitals that use less PT and OT. Optimizing therapy use in these hospitals may improve stroke outcomes and reduce outcome disparities.

Abstract W P287: Collaborative Cryptogenic Stroke Clinic Improves Secondary Stroke Prevention While Helping Achieve Stroke Metrics

Introduction: Stroke centers are faced with the challenges of achieving stroke metrics to meet certification requirements. Recent trials have demonstrated the efficacy of the implantable cardiac monitor (ICM) in detecting atrial fibrillation (AF) in cryptogenic stroke patients. We have created a Comprehensive Cryptogenic Stroke Clinic (CCSC), a collaborative effort between electrophysiology (EP) and stroke neurology, which improves patient care and provides a venue for successfully addressing stroke metrics. Methods: All acute ischemic stroke patients (n= 2100) in the ProMedica Stroke Network were screened and evaluated by an EP and vascular stroke neurologist. Appropriate cryptogenic patients are offered an ICM for AF detection, ideally during their stroke admission. Patients are evaluated periodically, both for their rhythm status and their stroke recovery, and important stroke metric follow-up data such as medication compliance, obtaining Modified Rankin scores at 90 days and prevention of stroke readmission through availability of resources. Results: We have enrolled 135 patients in our CCS clinic and implanted 92 loop monitors for AF detection. Through follow-up in CCSC, we have: detected AF in 11 patients; identified 27 patients with additional therapy needs; and modified medical management for 38 patients to decrease their secondary stroke risk. 90-day Modified Rankin score compliance improved from 27% to 67%. The collaboration and efficiency has improved stroke outcomes and helped reduce readmission rates by 22% since the CCSC’s inception. Conclusions: Our CCSC has improved compliance with multiple stroke metrics, while ensuring patients are cognizant of their real risk for another stroke. Our collaborative team approach has been instrumental in reducing stroke readmission rates, changing medical therapies, and offering additional resources are streamlined through medical collaboration. The CCSC has proven to be a critical venue for accomplishing successful stroke outcomes.

Abstract W P240: S1177-eNOS Phosphorylation Protects Against Stroke Injury in Akt1 Deficient Mice

Background: Phosphorylation of eNOS at serine 1177 (S1177) by Akt1 increases NO production and vascular reactivity. The goal of this study is to test the hypothesis that Akt1 deficiency increases susceptibility to stroke because of insufficient eNOS phosphorylation. Thus, constitutively phosphorylated eNOS will overcome Akt1 deficiency and protect against stroke. We generated knock-in mice (S1177D) carrying phosphomimetic mutation (serine to aspartate substitutions) in the eNOS gene. We bred S1177D mice with Akt1 knockout (Akt1KO) mice to test whether constitutively active eNOS could improve stroke outcome in Akt1KO mice. Methods: Adult male mice were anesthetized by 30% oxygen, 70% nitrous oxide, and 1.5% isoflurane. Body temperature was maintained at 36-37°C. The common carotid artery was catheterized to measure systemic blood pressure using a blood pressure transducer. For stroke studies we used the middle cerebral artery occlusion (MCAO) by filament with subsequent reperfusion with Laser Doppler cortical blood flow monitoring. Mice were examined for neurologic deficits by 5 point scale 24 hours after stroke. Infarct sizes were determined by the indirect method by 2,3,5-triphenyltetrazolium chloride staining. Results: Mean blood pressure was higher in Akt1KO (95±7 mmHg, Mean±SD, n=9) and WT mice (93±3 mmHg, n=8) than in S1177D/Akt1KO mice (80±11 mmHg, n=6, P<0.05). One hour of MCAO with 23 hours of reperfusion produced increased cerebral infarct volume in Akt1KO mice (106±21 mm3, n=9) as compared with WT (70±33, n=9, p< 0.05) mice. S1177D phosphomimetic mutation decreased cerebral infarct volume in Akt1KO mice (64±20 mm3, n=9, P<0.05). This was associated with a functional impairment in the neurologic deficit, as quantities by neurologic scoring (2.7 point deficit for Akt1KO; 1.9 for WT and 1.3 for S1177D/Akt1KO mice). Conclusion: Stroke injury was more pronounced in Akt1KO mice than in WT mice. Introducing S1177D mutation in Akt1KO mice resulted in decreased infarct volume, neurological deficit and blood pressure. These results demonstrated that S1177D eNOS-derived NO is able to protect against stroke in the absence of Akt1.

Abstract W MP57: Effects of Wearable Robotic Training of Ankle and Mobility Rehabilitation in Acute Stroke

Background and Purpose: Stroke is the fourth leading cause of death in the US and is a leading cause of adult disability. It was reported that the first few months post stroke is critical in neural plasticity and motor recovery. Presently, effective treatment options for ankle impairment and mobility are limited, especially for in-bed acute stroke rehabilitation. In this study, wearable robotic training involving passive stretching and active movement training was investigated to determine its efficacy in improving stroke outcome. Methods: Eleven patients with acute stroke participated. This was completed in a clinical in-patient setting (45 min/session, 3~5х/week, total 18 session). Participants were aged 53.7±17.4 (mean±SD); robotic treatment was given averaged 40.5 days of stroke onset. They continued receiving standard inpatient physical therapy during the study. One way repeated measures ANOVA was used to compare clinical and biomechanical outcome measures across the repeated measures. Results: Preliminary results showed an improvement after the multiple sessions of training with F-M in LE increased from 14.8 ± 8.8 and 19.4 ± 8.2 (p<.01), STREAM score in LE from 32.1±21.4 to 47.9±30.1 (p=.02), the BBS increased from 35.2±17.8 to 38.0±18.2. Ankle active range of motion (AROM) in dorsiflexion increased from -5.7 ± 7.2° to 2.3 ± 8.1°(p=.004), ankle passive ROM in dorsiflexion from 14.0 ± 7.1° to 19.9 ± 5.3° (p=.002). Dorsiflexor strength increased from 0 ± 2.2 N m before training to 2.4 ±3.5 N m after training (p=.003). Plantarflexor strength increased from 6.7±9.9 Nm, to 12.6 ± 11.4 Nm (p=.004). Other measures showed no significant improvements, such as 6MWT increased from 302.0 ± 416.4 and 540.6 ± 563.4 feet, the MAS of ankle was 2.2 ± 1.1 to 1.6 ± 1.2. Conclusions: The use of robotic device demonstrated improvements in selected outcome measures in hospital settings, and it was efficiently administer in the clinic. The results suggest that impaired lower limbs of acute stroke can respond to controlled stretching and movement training in terms of muscle biomechanical properties and improve lower extremity functional activities in acute rehabilitation.The limitation of this study was its small sample size and lack of a control group.

Abstract W P300: Ethnic Differences in Post-Stroke Quality of Life in the Brain Attack Surveillance in Corpus Christi (BASIC) Project

Background: Mexican Americans (MAs) have worse stroke outcomes than non-Hispanic whites (NHWs), which could translate into worse quality of life (QOL). Our objective was to investigate ethnic differences in post-stroke QOL across multiple domains in a bi-ethnic community. Methods: Ischemic stroke survivors, identified through the population-based Brain Attack Surveillance in Corpus Christi (BASIC) Project in Nueces County, Texas, participated in in-person interviews 90 days post-stroke from May 2010 - June 2012. The validated short form stroke-specific QOL (SSQOL) was used to assess overall, physical, and psychosocial QOL; scores range from 1-5 with higher scores representing greater QOL. Tobit regression was used to model unadjusted associations between ethnicity and the 3 QOL domains. Models were then adjusted for the following demographic and clinical factors obtained from the medical record and patient interview: age, sex, education, insurance status, marital status, nursing home residence before stroke, prestroke modified Rankin scale, prestroke Informant Questionnaire on Cognitive Decline in the Elderly, initial NIH stroke scale, risk factors, BMI, and a comorbidity index. Results: A total of 335 ischemic strokes with complete data were identified (66% MA, 34% NHW). QOL was lower among MAs compared to NHWs, both overall (mean difference=-0.3, p=0.02) and in the physical domain (mean difference=-0.4, p=0.008); however, there was no difference in the psychosocial domain (p=0.22). After adjustment for demographic and clinical factors, MAs continued to experience poorer QOL compared to NHWs overall (mean difference=-0.5,p=0.049) and in the physical domain (mean difference=-0.3, p=0.006). Conclusions: Ethnic disparities in stroke outcome extend to QOL, with MAs experiencing substantially worse post-stroke QOL than NHWs. Interventions are urgently needed to improve stroke outcomes among the rapidly growing MA stroke population.

Abstract W P93: MiR-122 Improves Stroke Outcomes after Middle Cerebral Artery Occlusion in Rats

MicroRNA (miRNA) are recently discovered small (~22 nucleotides), non-coding RNA that regulate translation of messenger RNA (mRNA) to protein. Though there are only hundreds of miRNAs, each of them can potentially regulate hundreds of target genes, via base-pairing with complementary sequences in mRNA. This provides one approach that targets a single miRNA to have effects on multiple genes. Our previous genomic studies have demonstrated that miR-122 decreased significantly in blood of experimental strokes produced by middle cerebral artery (MCA) occlusion in rats as well as in blood of patients with ischemic strokes. Therefore, we hypothesized that elevating blood miR-122 has the potential for treating stroke. Using the newly developed in vivo polyethylene glycol-liposome based miRNA transfection system and rat suture MCAO occlusion model, we show that injection of chemically modified mimic miR-122 (600ug/rat, i.v.) through tail vein immediately after MCAO occlusion significantly decreases the neurological impairment and significantly attenuates brain infarct volumes. Ongoing studies are identifying the target genes that are associated with the neuroprotective effects of miR-122 following stroke. Acknowledgements: This study was supported by NIH grant R01NS066845 (FRS). There were no conflicts of interest.

Abstract T P79: Rapamycin Improves Outcome Post Stroke Injury by Enhancing Autophagy in Neuronal Cells

Background and Purpose: Previous literature and studies from our laboratory indicate that pharmacological inhibition and enhancement of autophagy are both effective in reducing infarct volume after stroke injury. Methods: Mice were treated with rapamycin to enhance, and chloroquine to suppress autophagy in mice immediately after stroke injury and again 24 hours post stroke injury in a murine stroke model. Survival data and neurological score were taken before sacrifice at 48 hours and lesion size was determined by TTC. HT22 neuronal mouse hippocampal cells were treated for one hour with H2O2 to mimic an oxidative stress injury and treated concurrently with rapamycin to enhance autophagy, chloroquine to inhibit autophagy or ZVAD to inhibit apoptosis. The treatment with pharmacological agents continued for 24 hours. Cells were counted with trypan blue on a hemocytometer. Western blot analysis was used to monitor protein changes. shRNA to Atg5 was used to genetically inhibit autophagy. Results: Both pharmacological agents showed decreased lesion size, though enhancement of autophagy with rapamycin exhibited a greater reduction in lesion size as well as increased survival and an improved neurological score. Rapamycin improved survival of neurons after oxidative injury and genetic inhibition of autophagy abrogated rapamycin's positive effect. Conclusions: Rapamycin improves stroke outcome by enhancing autophagy in neuronal cells.

Abstract 84: Where Should Interventions be Focused to Reduce the Black-white Disparity in Stroke Mortality? Insights From the Reasons For Geographic And Racial Differences In Stroke (REGARDS) Study

Introduction: The study of racial disparities in stroke mortality should guide interventions to reduce these disparities. A higher mortality in blacks than whites could result from a higher incidence of stroke in blacks, a higher case-fatality of stroke in blacks, or both. Interventions focusing on primary prevention are needed if incidence is a major contributor to disparities, while interventions addressing treatment are a priority if case-fatality is a major contributor. Hypothesis: Higher stroke mortality in REGARDS will be attributable to higher incidence, higher case fatality, or both. Methods: 29,681 black and white participants aged 45+ were followed for stroke over 7 years. Fatal stroke (stroke mortality) was defined as a stroke event with death within 30-days, incident stroke included all stroke events (regardless of death), and case-fatality as the proportion of stroke events with death within 30-days. Black-white differences in stroke mortality and stroke incidence were assessed using proportional hazards models, and case-fatality using logistic regression (with adjustment for age and sex). Results: There were 954 incident events with 242 deaths within 30-days. We showed higher stroke mortality in blacks, with a black-white disparity in fatal stroke at young ages (at age 45, HR = 4.35; 95% CI: 1.94-9.76), but a declining magnitude of the disparity at older ages (at age 85, HR = 0.87; 95% CI: 0.56 - 1.35). The pattern was similar for incident stroke, although the magnitude of the black-white disparity was smaller (at age 45: HR = 2.40; 95% CI: 1.72 - 3.33; at age 85: HR = 0.95; 95% CI: 0.76 - 1.19). There was no evidence of a black-white disparity in case-fatality rate (OR = 1.26; 95% CI: 0.93 - 1.71). Conclusion: In a nationwide cohort, we found that the black-white disparity in stroke mortality was primarily attributable to a racial disparity in stroke incidence, not case fatality. Thus, interventions designed to reduce the black-white disparity in stroke mortality require a primary prevention focus aimed at reducing the disparity in stroke incidence. While effective interventions to improve stroke outcomes are needed, these data suggest that improving treatment after the initial event will not reduce black-white disparities in stroke mortality.

Abstract T MP112: Physical Activity Improves Stroke Outcome Through Modulation of Neutrophil Polynuclear Mobilization

Introduction: Physical activity has been previously reported to decrease severity of stroke in patient cohorts. Experimentally, in rats submitted to chronic physical activity, the infarct size is decreased and functional outcome is improved, with a decrease of neutrophil polynuclear mobilization. Hypothesis: We assessed the hypothesis that beneficial effect of physical activity observed in stroke could be related to neutrophil modulation. Methods: We recruited patients with supratentorial cerebral ischemia within 48 hours of symptom onset. We evaluated the presence, weekly duration and intensity (light, moderate, heavy) of previous physical activity. The primary end-point was the initial severity assessed by the NIHSS. The secondary end-point was neutrophil polynuclear count. Myeloperoxydase, chemokines (Monocyte Chemoattractant Protein-1, C-X-C chemokine 10), adhesion proteins (InterCellular Adhesion Molecule-1, vascular cell adhesion molecule1), von Willebrand factor, cytokines (interleukins-6, -8, -10) were dosed in plasma through Luminex methodology. Results: Of the 434 patients (mean age of 67 ± 15 years, 53% of men), 227 (52.3%) had a regular physical activity before ischemic event. Previous regular physical activity was independently associated with a lower severity of ischemic event assessed by the NIHSS (4.0 [1-9] vs 6.0 [2-15] ; p<0.002) and lower concentrations of neutrophil polynuclear (5.0 [3.8-6.4] vs 5.7 [4.1-7.7]; p<0.003), chemokines, interleukins, Von Willebrand factor, and myeloperoxydase. There was no strong evidence of difference in biological parameters according to duration of physical activity. Patients with moderate and heavy intensity had a lower level of chemokines, interleukins-8 and Von Willebrand factor. Conclusion: In conclusion, previous regular physical activity improves initial stroke severity through decrease of neutrophil polynuclear count. The decrease of attractant chemokines could suggest a decreased mobilization of neutrophils to parenchyma rather than an effect on neutrophil-endothelium interaction since adhesion proteins are not changed.

Abstract W MP108: Identifying Factors Predictive of Good Outcome among Patients with Severe Ischemic Stroke: the BASIC Project

Background: Utilizing a population-based stroke surveillance study, our objective was to identify possible socio-demographic, cultural and psychological factors that influence outcome among patients with severe stroke who survive at least 3 months. Methods: Ischemic strokes (IS) were identified utilizing the Brain Attack Surveillance in Corpus Christi (BASIC) Project. Severe stroke was defined as the highest quartile of the initial NIH Stroke Scale (NIHSS ≥ 8). Functional outcome was assessed at 90 days using the ADL/IADL score (0-4, higher worse). Good outcome was defined as ADL/IADL <3. Single predictor logistic regression models were used to identify predictors of good outcome among those with severe stroke. Backward elimination was then used to select a final set of predictors. Next, models including selected predictors and pre-stroke social support or pre-stroke depression (PHQ-9) were used to evaluate their association with good outcome among a subset of patients who were asked about these factors. Only patients who were able to answer their own questions were asked about depression and social support. Results: From Feb 2009 to Jun 2012, 646 IS patients completed a baseline interview and subsequent 90-day outcome interview. Of 168 with severe stroke, 68 had a good outcome at 3 months (ADL/IADL <3). One year older age (OR=0.94, 95% confidence interval (CI) 0.91, 0.97), Mexican American ethnicity (OR 0.30, 95%CI: 0.13, 0.68), stroke history (OR 0.27, 95%CI: 0.11, 0.66) and higher pre-stroke modified Rankin of 4-5 (OR 0.28, 95%CI: 0.08, 0.93) were associated with lower odds of good outcome. Among the subset of severe stroke patients (N=93) asked about pre-stroke depression and social support, higher pre-stroke depression score was associated with lower odds of good outcome (OR: 0.89, 95%CI 0.79, 0.99) while greater pre-stroke social support was associated with higher odds of good outcome (OR: 1.45, 95% CI 1.13, 1.86). Conclusion: Among IS survivors with severe stroke, pre-stroke depression and social support are important predictors of good outcome. These factors should be considered in crafting interventions to improve stroke outcome. Mexican American ethnicity and history of prior stroke are strongly negatively associated with good stroke outcome.

Factors Associated with Early Hospital Arrival in Patients with Acute Ischemic Stroke.

Background and PurposeFactors associated with early arrival may vary according to the characteristics of the hospital. We investigated the factors associated with early hospital arrival in two different stroke centers located in Korea and Japan.MethodsConsecutive patients with ischemic stroke arrived hospital within 48 hours of onset between January 2011 and December 2012 were identified and the clinical and time variables were retrieved from the prospective stroke registries of Severance Hospital of Yonsei University Health System (YUHS; Seoul, Korea) and National Cerebral and Cardiovascular Center (NCVC; Osaka, Japan). Subjects were dichotomized into early (time from onset to arrival ≤4.5 hours) and late (>4.5 hours) arrival groups. Univariate and multivariate analyses were performed to evaluate factors associated with early hospital arrival.ResultsA total of 1,966 subjects (992 from YUHS; 974 from NCVC) were included in this study. The median time from onset to arrival was 6.1 hours [interquartile range, 1.7-17.8 hours]. In multivariate analysis, the factors associated with early arrival were atrial fibrillation (Odds ratio [OR], 1.505; 95% confidence interval [CI], [1.168-1.939]), higher initial National Institute of Health Stroke Scale scores (OR, 1.037; 95% CI [1.023-1.051]), onset during daytime (OR, 2.799; 95% CI [2.173-3.605]), and transport by an emergency medical service (OR, 2.127; 95% CI [1.700-2.661]). These factors were consistently associated with early arrival in both hospitals.ConclusionsDespite differences between the hospitals, there were common factors related to early arrival. Efforts to identify and modify these factors may promote early hospital arrival and improve stroke outcome.

Compound 21 is pro-angiogenic in the brain and results in sustained recovery after ischemic stroke.

Angiotensin II type 2 receptor (AT2R) stimulation is neuroprotective after experimental stroke. However, the therapeutic utility of AT2R stimulation has been hampered by the lack of a specific agonist with favourable bioavailability. Compound 21 (C21) - the first non-peptide AT2R agonist - offers a potential option to enhance stroke recovery. This study aimed to investigate the effect of C21 administration on early and late stroke outcomes, and the molecular mediators involved. Rats were subjected to 3 h or 90 min of middle cerebral artery occlusion (MCAO) and randomized to intraperitoneal C21 (0.03 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 h or 7 days and brains were collected for molecular analysis and immunostaining, respectively. Functional outcome at days 1, 4 and 7 was assessed blindly. C21 angiogenic potential was assessed in vitro. After 3 h of MCAO, C21 treatment reduced infarct size and improved behavioural outcome at 24 h without affecting blood pressure. Co-administration of the AT2R antagonist (PD123319) blocked these effects. On the molecular level, C21 decreased brain haemoglobin content, down-regulated apoptotic and oxidative markers, and increased pro-survival molecules in the brain. After 90 min of MCAO, C21 treatment resulted in sustained functional improvement at 7 days, together with increased vascular density in the ischemic penumbra. In vitro, C21 showed a pro-angiogenic effect that was blocked with brain-derived neurotrophic factor neutralization. These findings demonstrate that a single dose of C21 is neurovascular-protective and improves stroke outcome possibly through increasing neurotrophin activity, mitigating brain inflammation, and promoting antioxidant and pro-angiogenic effects.

Neuroimmunomodulatory effects of transcranial laser therapy combined with intravenous tPA administration for acute cerebral ischemic injury

At present, the only FDA approved treatment for ischemic strokes is intravenous administration of tissue plasminogen activator within 4.5 hours of stroke onset. Owing to this brief window only a small percentage of patients receive tissue plasminogen activator. Transcranial laser therapy has been shown to be effective in animal models of acute ischemic stroke, resulting in significant improvement in neurological score and function. NEST-1 and NEST-2 clinical trials in human patients have demonstrated the safety and positive trends in efficacy of transcranial laser therapy for the treatment of ischemic stroke when initiated close to the time of stroke onset. Combining intravenous tissue plasminogen activator treatment with transcranial laser therapy may provide better functional outcomes. Statins given within 4 weeks of stroke onset improve stroke outcomes at 90 days compared to patients not given statins, and giving statins following transcranial laser therapy may provide an effective treatment for patients not able to be given tissue plasminogen activator due to time constraints.

NOD2 is involved in the inflammatory response after cerebral ischemia-reperfusion injury and triggers NADPH oxidase 2-derived reactive oxygen species.

Background: Increasing evidences suggest that innate immunity is involved in cerebral ischemia-reperfusion (I/R) injury, but the liable innate immune receptors have not been completely elucidated. Here, we explored the role of the nucleotide-binding oligomerization domain (NOD)2, a member of the cytosolic NOD-like receptor family, in acute focal cerebral I/R injury.Methods: An in vivo middle cerebral artery occlusion (MCAO) model that in wild type (WT) and NOD2 deficient (NOD2-/-) mice and in vitro model of oxygen glucose deprivation and reoxygenation (OGD/R) in cultured primary microglia and astrocytes were used to investigate the expression of NOD2 and explore the roles of NOD2 in ischemic stroke.Results: Our results showed that NOD2 expression was significantly increased in microglia and astrocytes in response to the I/R insult. Pretreatment with muramyl dipeptide, an extrinsic ligand of NOD2, significantly increased the infarct volume and neurological dysfunction in mice subjected to MCAO. Genetic ablation of the NOD2 gene significantly improved stroke outcomes and reduced inflammation, as evidenced by a lower expression of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα in conjunction with attenuated activation of nuclear factor κB (NF-κB), p38 mitogen activated protein kinases (MAPK) and JNK. Moreover, NOD2 deficiency prevented the upregulation of the NADPH oxidase (NOX) 2 and ROS generation induced by I/R. Mechanistically, NOD2-induced production of IL-6 in primary cultured microglia was mediated through activation of NOX2.Conclusions: This study showed the contribution of NOD2 to inflammatory response and provided direct evidence that NOX2-mediated oxidative stress as an important target molecule linked NOD2 to inflammatory damage in ischemic stroke. Pharmacological targeting of NOD2-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.

Development-assistance Strategies for Stroke in Low- and Middle-income Countries.

While communicable diseases still pose a serious health threat in developing countries, previously neglected health issues caused by non-communicable diseases such as stroke are rapidly becoming a major burden to these countries. In this review we will discuss the features and current status of stroke in low- and middle-income countries (LMICs). Overall the global burden of hemorrhagic stroke is larger than ischemic stroke, with a disproportionately greater burden, measured in incidence and disability-adjusted life-years, regionally localized in LMICs. Patients in poorer countries suffer due to insufficient primary care needed to control risk factors such as hypertension, and inadequate emergency care systems through which sudden events should be managed. In light of these situations, we emphasize two strategic points for development assistance. First, assistance should be provided for bolstering, integrating, and coordinating both the primary health and emergency care systems, in order to prevent stroke and strengthen stroke management, respectively. Second, the assistance needs to focus on programs at the community level, to reduce life-style risks of stroke in a more sustainable manner, and to improve stroke outcomes more effectively.

Brain transient receptor potential channels and stroke.

Transient receptor potential (TRP) channels have been increasingly implicated in the pathological mechanisms of CNS disorders. TRP expression has been detected in neurons, astrocytes, oligodendrocytes, microglia, and ependymal cells as well as in the cerebral vascular endothelium and smooth muscle. In stroke, TRPC3/4/6, TRPM2/4/7, and TRPV1/3/4 channels have been found to participate in ischemia-induced cell death, whereas other TRP channels, in particular those expressed in nonneuronal cells, have been less well studied. This review summarizes the current knowledge on the expression and functions of the TRP channels in various cell types in the brain and our current understanding of TRP channels in stroke pathophysiology. In an aging society, the occurrence of stroke is expected to increase steadily, and there is an urgent requirement to improve the current stroke management strategy. Therefore, elucidating the roles of TRP channels in stroke could shed light on the development of novel therapeutic strategies and ultimately improve stroke outcome.