Genistein-3'-sodium sulfonate Attenuates Neuroinflammation in Stroke Rats by Down-Regulating Microglial M1 Polarization through α7nAChR-NF-κB Signaling Pathway.

Microglial M1 depolarization mediated prolonged inflammation contributing to brain injury in ischemic stroke. Our previous study revealed that Genistein-3'-sodium sulfonate (GSS) exerted neuroprotective effects in ischemic stroke. This study aimed to explore whether GSS protected against brain injury in ischemic stroke by regulating microglial M1 depolarization and its underlying mechanisms. We established transient middle cerebral artery occlusion and reperfusion (tMCAO) model in rats and used lipopolysaccharide (LPS)-stimulated BV2 microglial cells as in vitro model. Our results showed that GSS treatment significantly reduced the brain infarcted volume and improved the neurological function in tMCAO rats. Meanwhile, GSS treatment also dramatically reduced microglia M1 depolarization and IL-1ß level, reversed α7nAChR expression, and inhibited the activation of NF-κB signaling in the ischemic penumbra brain regions. These effects of GSS were further verified in LPS-induced M1 depolarization of BV2 cells. Furthermore, pretreatment of α7nAChR inhibitor (α-BTX) significantly restrained the neuroprotective effect of GSS treatment in tMCAO rats. α-BTX also blunted the regulating effects of GSS on neuroinflammation, M1 depolarization and NF-κB signaling activation. This study demonstrates that GSS protects against brain injury in ischemic stroke by reducing microglia M1 depolarization to suppress neuroinflammation in peri-infarcted brain regions through upregulating α7nAChR and thereby inhibition of NF-κB signaling. Our findings uncover a potential molecular mechanism for GSS treatment in ischemic stroke.

Classification of Peritumoral Veins in Convexity and Parasagittal Meningiomas and Its Significance in Preventing Cerebral Venous Infarction.

OBJECTIVE: The medium (2-4 cm) convexity located closer to the sinus and parasagittal meningiomas (Sindou type I-Ⅲ) without obvious invasion of the superior sagittal sinus are considered simple to operate on. However, the tumors are often accompanied by the cortical bridging vein. Because of lack of collateral vein circulation in cortical areas, the damage of peritumoral veins will subsequently lead to venous infarction. To avoid the serious complications caused by intraoperative injury of peritumoral veins, it is necessary to define the classification of the progression of peritumoral veins and tumors to guide surgical safety. METHODS: The clinical information of 57 patients with convexity and parasagittal meningiomas was collected and retrospectively analyzed. All patients underwent preoperative magnetic resonance imaging and magnetic resonance venography scanning to observe the imaging characteristics of peritumoral veins and preoperative evaluation. The actual relationship between the tumor and peritumoral vein was observed intraoperatively. Postoperative computed tomography and magnetic resonance imaging were used to determine tumor resection and the presence of venous infarction. RESULTS: According to preoperative magnetic resonance venography and intraoperative findings, we divided the peritumoral veins into 3 types: type A (n = 33, 57.9%), the vein surrounds the tumor; type B (n = 15, 26.3%), the vein is located on the ventral side of the tumor; and type C (n = 9, 15.8%), the vein is located on the dorsal side of the tumor. Peritumoral vein injury occurred in 6 cases followed by serious complications. Treatments were as follows: 4 cases underwent decompression and 2 cases were treated conservatively. The prognosis Glasgow Outcome Scale (GOS) scores were as follows: 3 cases were score 5 for injury of posterior frontal vein or middle frontal vein, 2 cases were score 3 for injury of the central vein, 1 case was score 1 for death due to injury of the central vein. All cases were followed up for 6 months. CONCLUSIONS: Attention should be paid to the peritumoral vein of special meningiomas. Injured vein in the medial third of superior sagittal sinus carries a high rate of postoperative morbidity. Understanding the type of peritumoral veins preoperatively can be used as a guide in determining the corresponding protective strategy during surgery, which can significantly decrease postoperative disability and improve quality of life.

Protective effect of grape seed extract and orlistat co-treatment against stroke: Effect on oxidative stress and energy failure.

Ischemic stroke is a major health concern and a leading cause of mortality worldwide. Oxidative stress is an early event in the course of stroke inducing neuro-inflammation and cell death. Grape seed extract (GSE) is a natural phytochemical mixture exhibiting antioxidant, anti-inflammatory and neuroprotective properties. Orlistat (ORL) is an anti-obesity agent and a gastro-intestinal lipase inhibitor which showed recently beneficial effects on brain lipotoxicity. Recent studies reported the increase of lipase activity upon stroke which led us to investigate the neuroprotective effect of ORL on rat brain I/R injury as well as the putative synergism with GSE. I/R insult infarcted the brain parenchyma as assessed by TTC staining, induced an oxidative stress as revealed by increased lipoperoxidation along with alteration of antioxidant enzymes activities which was corrected using the cotreatment of ORL + GSE. I/R also disturbed the main metabolic pathways involved in brain fueling as glycolysis, neoglucogenesis, glycogenolysis, TCA cycle and electron transfer chain (ETC) complexes. These disturbances were also corrected with the cotreatment ORL + GSE which maintained energetic activities near to the control level. I/R also disrupted transition metals distribution, along with associated enzymes as tyrosinase, LDH or glutamine synthetase activities and induced hippocampal inflammation as revealed by glycogen depletion from dentate gyrus area along with depressed anti-inflammatory IL1ß cytokine and increased pro-inflammatory CD68 antigen. Interestingly almost all I/R-induced disturbances were corrected either partially upon ORL and GSE on their own and the best neuroprotection was obtained in the presence of both drugs (ORL + GSE) enabling robust neuroprotection of the sub granular zone within hippocampal dentate gyrus area.

H2S prevents peripheral immune cell invasion, increasing [Ca2+]i and excessive phagocytosis following hypoxia-ischemia injury in neonatal mice.

We previously reported that L-Cysteine, H2S donor, remarkably attenuated neuroinflammation following hypoxia-ischemia (HI) brain injury in neonatal mice. However, its anti-inflammatory mechanism for HI insult is still unknown. The study focus on the effects of L-Cysteine on immune cell populations, Ca2+ mobilization and phagocytosis after neonatal HI. We found that L-Cysteine treatment skewed CD11b+/CD45low microglia and CD11b+/CD45high brain monocytes/macrophages towards a more anti-inflammatory property 72 h after HI-injured brain. Moreover, L-Cysteine treatment reduced cerebral infiltration of CD4 T cells 7 days following HI insult. Furthermore, CD4 T cell subset analysis revealed that L-Cysteine treatment decreased Th1 and Th2 counts, while increased Th17/Th2 ratio. Moreover, L-Cysteine treatment suppressed LPS-induced cytosolic Ca2+ and LPS-stimulated phagocytosis in primary microglia. The anti-inflammatory effect of L-Cysteine was associated with improving neurobehavioral impairment following HI insult. Our results demonstrate L-Cysteine treatment suppressed the invasion of peripheral immune cells, increasing [Ca2+]i and excessive phagocytosis to improve neurobehavioral deficits following hypoxia-ischemia injury in neonatal mice by H2S release.

Protective Effect of Eichhornia Crassipes Against Cerebral Ischemia Reperfusion Injury in Normal and Diabetic rats.

Eichhornia crassipes (EC) is well reported to modify inflammatory response, oxidative stress which are key pathophysiological finding of cerebral reperfusion injury, alongside it is reported to reduce cholesterol and blood glucose levels, and therefore present work was designed to investigate the effect of EC on cerebral reperfusion injury in normal and diabetic rats. Each protocol comprised cerebral ischemia (CI) for 30 min followed by reperfusion(R) for 1 h. Animals were treated with EC (100 mg/kg p.o) for seven days. At the end of the experiment, brain tissue was utilized for the measurement of oxidative stress markers, inflammatory response, infarct size and histopathological findings. EC treated rats demonstrated a significant reduction in infarct sizes when compared with CI/R and Diabetic CI/R (DCI/R) group of rats. EC treatment demonstrated a significant decreased in malondialdehyde, nitric oxide and blood glucose levels and a significant increase in the level of reduced glutathione, superoxide dismutase catalase and insulin levels, showed modification in oxidative stress. EC treatment confirmed a significant decrease in myeloperoxidase, C - reactive protein and TNF-α levels indicated a change in the inflammatory response. Histopathological findings revealed a reversal of damage in EC treated rats. EC treatmen reduced DNA fragmentation of brain tissue in treated animals. EC was found to be cerebroprotective against CI/R along with DCI/R group of rats by anti-inflammatory and antioxidant activities.

D-Carvone inhibit cerebral ischemia/reperfusion induced inflammatory response TLR4/NLRP3 signaling pathway.

To explore the present treatment strategies for ischemic stroke lowered by ischemia-reperfusion (I/R) injury, to hypothesize the effect of d-Carvone on cerebral I/R brain injury induced neuroinflammation through oxidative stress markers mechanism via NRLP3 and TLR4 marker expressions in rat model. The rats were divided into four groups: Sham, I/R vehicle, I/R + D-carvone (10 mg/kg/bw), I/R + D-carvone (20 mg/kg/bw). Supplementation of d-carvone at dose of 10 and 20 m/kg/bw increased the water content, reduced infract volume, attenuated neurological score depicts, furthermore it had antioxidative, anti-inflammatory, and anti-apoptotic effects against cerebral I/R brain injury. In the brain tissues decreased proinflammatory cytokines IL-1ß and TNF-α reduced interleukins IL-6, IL-4, IL-10 & VEGF dose dependently, and mRNA expressions of NLRP3, caspase -1, TNF-α, ASC, IL-1ß and TLR3 down regulated in cerebral I/R induced rats. Finally d- carvone can successfully improve the cerebral I/R induced rats neuroinflammation, in the hippocampus and cortical areas of the brain finally reduces cerebral I/R induced injury. These results were hypothesized that d-carvone contributed to cerebral stroke associated with the TLR3, giving an excellent therapeutic approach for cerebral I/R brain injury.

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

BACKGROUND AND PURPOSE: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. METHODS: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. RESULTS: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. CONCLUSIONS: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Long Non-Coding RNA (lncRNA) NEAT1 Aggravates Cerebral Ischemia-Reperfusion Injury by Suppressing the Inhibitory Effect of miR-214 on PTEN.

BACKGROUND Cerebral ischemia-reperfusion injury is a form of serious nervous system injury. Activation of the PI3K/Akt pathway can effectively relieve cerebral ischemia-reperfusion injury. miR-214 can target and inhibit the expression of PTEN, thereby alleviating its inhibitory effect on the PI3K/Akt pathway. Moreover, lncRNA NEAT1 was reported to affect proliferation and metastasis of tumor cells by targeting and suppressing the expression of miR-214. However, whether lncRNA NEAT1 affects the cerebral ischemia-reperfusion-induced damage by regulating the miR-214/PTEN/PI3K/Akt pathway is unclear. MATERIAL AND METHODS The miR-214 agomir and miR-214 antagomir were designed and injected into the encephalocele of MCAO rats. Next, the production of oxidative stress kinase and apoptosis of brain cells were detected using commercial kits. The levels of PTEN, PI3K, Akt, p-Akt, and VEGF in brain tissues were determined. Next, the targeting effect of lncRNA NEAT1 and miR-214 was determined with luciferase reporter assay. RESULTS Overexpression of miR-214 relieved the apoptosis and oxidative stress of brain tissues. Overexpression of miR-214 promoted the expression of PI3K, Akt, p-Akt, and VEGF by inhibiting the production of PTEN. However, overexpression of lncRNA NEAT1 repressed the remission effect of miR-214 on cerebral ischemia-reperfusion-induced damage and inhibited the production of PI3K, Akt, p-Akt, and VEGF by rescuing the levels of PTEN. CONCLUSIONS lncRNA NEAT1 aggravates cerebral ischemia-reperfusion injury by abolishing the activation effect of miR-214 on the PI3K/Akt pathway.

Historia natural del cierre percutáneo de foramen oval permeable / Natural history of patent foramen ovales closure

INTRODUCCIÓN: El cierre percutáneo del foramen oval permeable (FOP) se ha posicionado como el tratamiento de elección para la prevención secundaria de pacientes con infartos encefálicos (IE) criptogénicos asociados a FOP. OBJETIVO: Revisar los cierres de FOP realizados en nuestra institución, evaluando las características clínicas y del procedimiento, los resultados a mediano plazo luego del procedimiento y la tendencia en el número de intervenciones durante el período estudiado. MÉTODOS: Se incluyeron 101 pacientes consecutivos en que se realizó cierre de FOP, con una mediana de seguimiento de 4,6 años. Se analizaron las características basales de los pacientes, la indicación del cierre de FOP, el éxito del procedimiento y la presencia de shunt residual en ecocardiografía al año. Se realizó una encuesta telefónica estructurada a todos los pacientes, en la cual se preguntó por nuevo IE o crisis isquémica transitoria (CIT), otros eventos cardiovasculares y la presencia de sangrados. El seguimiento fue completado en el 95%. Se calculó el puntaje RoPE ("Risk of Paradoxical Embolism") el cual provee una estimación de la posibilidad de que ese IE se haya debido al FOP y del riesgo de repetir un nuevo IE en caso de no cerrar el FOP para cada paciente. RESULTADOS: La edad promedio fue de 49,1±13,7 años, con 53% mujeres. Sólo en 3 pacientes se diagnosticó una trombofilia. En 96 pacientes la indicación fue para prevención de embolía paradojal e IE (74% IE, 17% CIT y 4% embolía periférica), mientras que en 5% por síndrome de ortodeoxia/platipnea. El cierre de FOP fue exitoso en todos los pacientes. Shunt residual en ecocardiograma al año se observó en 5% - ninguno de estos pacientes presentó un nuevo evento encefálico durante el seguimiento. Se registraron 2 nuevos IE (4 IE por 1000 pacientes/año) y 1 nueva CIT (2 CIT por 1000 pacientes/año) en el seguimiento, con un promedio de presentación de 3,6 años post procedimiento. Esta tasa de eventos fue significativamente menor a lo predicho por el puntaje RoPE en nuestra cohorte. Se observó un marcado aumento en el número de procedimientos desde el año 2017 en adelante. CONCLUSIONES: En nuestra cohorte, el cierre de FOP fue un procedimiento exitoso y seguro. Se asoció a una baja tasa de nuevos eventos cerebrales, marcadamente menor a lo estimado por el puntaje de riesgo actualmente disponible (RoPE).

INTRODUCTION: The percutaneous closure of a patent foramen ovale (PFO) has been established as the preferred treatment for those with an ischemic stroke (IS) and associated PFO. AIMS: To review the PFO closure experience at our institution, characterizing the patients and procedures, mid-term results and the trend in the number of interventions during the study period. METHODS: One hundred and one consecutive patients undergoing PFO closure were included, with a median follow-up of 4.6 years. Baseline demographics, PFO closure indications, procedural success rates and residual shunt at 1-year were recorded. A telephonic survey was performed to complete follow-up, asking for new IS or transient ischemic attacks (TIA), other cardiovascular events and bleeding. Follow-up was completed by 95%. The RoPE score was calculated for each patient, providing an estimate of the chance a given IS being due to a PFO and the risk of a new event when the defect is not closed. RESULTS: Mean age was 49.1±13.7 years and 53% were females. Whereas the indication for PFO closure was paradoxical embolism in 96 patients (74% IS, 17% TIA and 4% peripheral embolism), in 5 it was for platypnea-orthodeoxia syndrome. All patients had a successful PFO closure procedure. Residual shunt at 1 year was found in 5% - yet, none of these patients experienced a new stroke during the study period. During follow-up there were 2 new IS (4 IS per 1,000 patients/year) and 1 new TIA (2 TIA per 1,000 patients/year), with a mean incidence time of 3.6 years after the procedure. This rate of new events was significantly lower than the one predicted by the RoPE score. From 2017 onwards, there was a marked increase in the number of procedures performed at our institution. CONCLUSION: In this cohort, PFO closure was a successful and safe procedure. It was associated to a low rate of new cerebral events during mid-term follow-up, markedly lower than the RoPE predicted rate.

Protective effect of smoking cessation on subsequent myocardial infarction and ischemic stroke independent of weight gain: A nationwide cohort study.

Smoking cessation reduces the cardiovascular risk but increases body weight. We investigated the risk of subsequent myocardial infarction and ischemic stroke according to weight gain after smoking cessation, using a nationwide population based cohort. We enrolled 3,797,572 Korean adults aged over 40 years who participated in national health screenings between 2009 and 2010. Subjects who quit smoking were classified into three subgroups according to the weight change between baseline and 4 years prior. Myocardial infarctions and ischemic strokes were followed until the end of 2015. We compared the hazard ratios among smoking cessation subgroups, non-smokers, and current smokers. The mean changes in weight (1.5 ± 3.9 kg) of the smoking cessation group were higher than those of the other groups (p < 0.0001). A total of 31,277 and 46,811 subjects were newly diagnosed with myocardial infarction and ischemic stroke, respectively. Regardless of weight change, all subgroups of smoking cessation had significantly less risk than current smokers. The subgroup of smoking cessation with weight gain over 4kg showed the lowest risk for myocardial infarctions (hazard ratio 0.646, 95% confidence interval 0.583-0.714, p < 0.0001) and ischemic strokes (hazard ratio 0.648, 95% confidence interval 0.591-0.71, p < 0.0001) after multivariable adjustment. In conclusion, weight gain after smoking cessation did not adversely affect the cardiovascular protective effect.

Different Effects of Volatile and Nonvolatile Anesthetic Agents on Long-Term Survival in an Experimental Model of Hemorrhagic Shock.

BACKGROUND: We investigated whether the cardioprotective, volatile gas anesthetic agent, isoflurane, could improve survival and organ function from hemorrhagic shock in an experimental rat model, compared to standard nonvolatile anesthetic agent ketamine/xylazine. METHODS: Sprague Dawley rats (both genders) were randomized to receive either intraperitoneal ketamine/xylazine (K/X, 90 and 10 mg/kg; n = 12) or isoflurane (5% isoflurane induction and 2% maintenance in room air; n = 12) for anesthesia. Blood was withdrawn to maintain mean arterial blood pressure at 30 mm Hg for 1 hour, followed by 30 minutes of resuscitation with shed blood. Rats were allowed to recover and survive for 6 weeks. RESULTS: During the shock phase, the total withdrawn blood volume (expressed as % of estimated total blood volume) to maintain a level of hypotension of 30 mm Hg was significantly higher in the isoflurane group (51.0% ± 1.5%) than in the K/X group (45.3% ± 1.8%; P = .023). Recovery of blood pressure during the resuscitation phase was significantly improved in the isoflurane group compared to the K/X group. The survival rate at 6 weeks was 1 (8.3%) of 12 in rats receiving K/X and 10 (83.3%) of 12 in rats receiving isoflurane (P < .001). Histology performed at 6 weeks demonstrated brain infarction in the 1 surviving rat receiving K/X; no brain infarction occurred in the 10 surviving rats that received isoflurane. No infarction was detected in heart, lung, liver, or kidneys among the surviving rats. CONCLUSIONS: Isoflurane improved blood pressure response to resuscitation and resulted in significantly higher long-term survival rate.

The difference of burden of ectopic beats in different types of atrial fibrillation and the effect of atrial fibrillation type on stroke risk in a prospective cohort of patients with atrial fibrillation (CODE-AF registry).

The relationship between atrial fibrillation (AF) type and stroke risk is still controversial. We investigated the difference of burden of atrial ectopic beats in different types of AF and the effect of the AF type on stroke risk in patients with non-valvular AF. In the prospective, multicenter observational registry with more than about 10,000 AF patients, 8883 non-valvular AF patients (mean age, 67.0 years; 36% were women) with eligible follow-up visits participated. We compared the burden of ectopic beats and stroke risk between patients with paroxysmal AF (n = 5,808) and non-paroxysmal AF (n = 3,075). The patients with a non-paroxysmal type of AF were older, male-predominant and had a higher prevalence of comorbidities and had more anticoagulation and rhythm control treatment than those with paroxysmal AF. In terms of the difference in burden of ectopic beats, patients with non-paroxysmal AF had a higher proportion of atrial premature beats (APBs) (paroxysmal vs. non-paroxysmal, median 3% vs. 5%; p = 0.001) in 24 hours Holter monitoring. During a median follow-up period of 16.8 months (Interquartile range [IQR], 11.67-20.52), a total of 82 (0.92%) patients experienced ischemic stroke with incidence rates of 0.50 and 1.09 events per 100 person-year for paroxysmal and non-paroxysmal AF, respectively. The cumulative incidence of stroke events was significantly higher in non-paroxysmal AF than in paroxysmal AF (p < 0.001). The risk of ischemic stroke was higher in non-paroxysmal AF with an adjusted hazard ratio (HR) of 2.08 (95% confidence interval [CI], 1.33-3.25; p = 0.001) than in paroxysmal AF. The type of AF was associated with an increased risk of stroke, along with the difference of burden of ectopic beats (specially in APBs) in different types of AF. These results suggest that the type of AF should be considered in stroke prevention and decision-making for oral anticoagulation in AF patients.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient. OBJECTIVES: To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD. SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 14 November 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 07 October 2019. SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention. Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents). The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence). No deaths were reported in either trial. Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence). Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial) Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence). We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence). The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence). Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence). Neither trial reported on quality of life or cognitive function. AUTHORS' CONCLUSIONS: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions. Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention. All other evidence in this review is of very low-quality.

Development of a Neuroprotective Erythropoietin Modified with a Novel Carrier for the Blood-Brain Barrier.

Extremely high doses of erythropoietin (EPO) has been used for neuroprotection in ischemia-reperfusion brain injury to deliver sufficient amounts of EPO across the blood-brain barrier (BBB); however, harmful outcomes were observed afterward. We aimed to test the ability of HBHAc (heparin-binding haemagglutinin adhesion c), an intracellular delivery peptide for macromolecules, as an EPO carrier across the BBB. The cellular internalization and transcytosis ability of HBHAc-modified EPO (EPO-HBHAc) were evaluated in bEnd.3 cells and in the bEnd.3/CTX TNA2 co-culture BBB model, respectively. Subsequently, the NMDA-induced-toxicity model and ischemia-reperfusion rat model were used to understand the neuronal protective activity of EPO-HBHAc. The biodistribution of EPO-HBHAc was demonstrated in rats by the quantification of EPO-HBHAc in the brain, plasma, and organs by ELISA. Our results demonstrate that EPO-HBHAc exhibited significantly higher cellular internalization in dose- and time-dependent manners and better transcytosis ability than EPO. In addition, the transported EPO-HBHAc in the co-culture transwell system maintained the neuronal protective activity when primary rat cortical neurons underwent NMDA-induced toxicity. The calculated cerebral infarction area of rats treated with EPO-HBHAc was significantly reduced compared to that of rats treated with EPO (29.9 ± 7.0% vs 48.9 ± 7.9%) 24 h after occlusion in 3VO rat experiments. Moreover, the EPO amount in both CSF and damaged cortex from the EPO-HBHAc group was 4.0-fold and 3.0-fold higher than the EPO group, respectively. These results suggest that HBHAc would be a favorable tool for EPO brain delivery and would further extend the clinical applications of EPO in neuroprotection.

Preventing Covert Brain Infarct-Related Cognitive Impairment and Dementia.

Covert brain infarcts (CBIs) are five times more prevalent than symptomatic brain infarcts. CBIs are associated with cognitive impairment and therefore may be a target for preventing cognitive decline and dementia. This review focuses on strategies for preventing CBI-related cognitive impairment, either by preventing incident or recurrent CBI or by enhancing cognitive reserve. CBIs begin to become prevalent during midlife and are highly prevalent in later life. The distribution of vascular pathologies of CBI differs from those that cause symptomatic stroke; therefore, preventive treatments may need to differ as well. Only a few randomized clinical trials have provided data on CBI prevention, without conclusive results. Limited data suggest that higher early-life education, hypothesized to enhance cognitive reserve, can protect the brain from effects of CBI.

Effects of butylphthalide injection on treatment of transient ischemic attack as shown by diffusion-weighted magnetic resonance imaging abnormality.

Background and Objective: Transient ischemic attack (TIA) is a serious condition that is often called a warning stroke. The risk of cerebral infarction in patients with TIA and positive DWI findings is greater than that in patients with TIA and normal DWI findings. Butylphthalide injection is a new type of brain protective drug. The study aimed to determine the efficacy and safety of butylphthalide injection for treating TIA as shown by DWI abnormality progressing to infarction.Methods: We studied 98 patients with positive DWI findings among 260 patients with TIA, and randomly divided into the experimental (treatment with butylphthalide injection) and control (treatment with aspirin) groups. The number of cerebral infarctions in the two groups was recorded on 7th, 14th, 30th and 90th day, and adverse reactions were observed. The number of cerebral infarctions was compared among the different ABCD2 scores of patients with TIA and positive DWI findings.Results: The incidence of cerebral infarction in the experimental group was significantly lower than that in the control group (p < .05). The incidence of cerebral infarction with an ABCD2 score less than 3 points was significantly lower than that with an ABCD2 score of more than 3 points (p < .05), with less adverse reactions.Conclusion: Butylphthalide injection is helpful and safe for preventing stroke following TIA, and treating TIA with positive DWI and progression to infarction.

Zafirlukast protects blood-brain barrier integrity from ischemic brain injury.

Stroke has been considered the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Some of the main features of ischemic stroke are increased brain permeability, ischemia/reperfusion injury, oxidative stress, and acute inflammation. Antagonism of cysLT1R has been shown to provide cardiovascular and neural benefits. In the present study, we investigated the effects of the cysLT1R antagonist zafirlukast both in vivo and in vitro using a middle cerebral artery occlusion (MCAO) mouse model and human brain microvascular endothelial cells (HBMVECs). In vivo, we found that zafirlukast pretreatment could reduce MCAO-induced increased brain permeability by rescuing the expression levels of the tight junction proteins occludin and ZO-1. In vitro, we found that zafirlukast could suppress the increase in endothelial monolayer permeability induced by OGD/R via rescue of occludin and ZO-1 expression; additionally, we found that zafirlukast prevented OGD/R-induced degradation of the extracellular matrix via inhibition of MMP-2 and MMP-9 expression. Finally, we found that zafirlukast could also inhibit OGD/R-induced activation of the critical proinflammatory regulator NF-κB by preventing phosphorylation and nuclear translocation of p65 protein. Together, our findings demonstrate a promising role for zafirlukast in preventing damage induced by ischemic stroke and reperfusion injury.

Transluminal balloon angioplasty for cerebral vasospasm after spontaneous subarachnoid hemorrhage: A single-center experience.

OBJECTIVES: After spontaneous subarachnoid hemorrhage (sSAH), cerebral vasospasm (CVS) is a common complication, potentially resulting in infarction mainly responsible for a poor outcome. Intra-arterial vasodilators lead to transient increase of brain perfusion, but only transluminal balloon angioplasty (TBA) promises longer-lasting effects, though it poses the risk of severe complications. Until now, the precise impact of TBA on the course of CVS is not yet finally clarified. Thus we aimed to identify risk factors of recurrent CVS and vasospasm-related infarction following TBA. PATIENTS AND METHODS: We analyzed 35 patients with CVS after sSAH who received TBA (41 procedures, 99 vessel segments). Gender, age, WFNS grade and Fisher scale, occurrence of intraventricular and intracerebral hemorrhage, localization of the aneurysm and the initial treatment modality were obtained. We assessed functional outcome after 3 months and in-hospital mortality. TBA was analyzed concerning time point, localization, technique, complications and angiographic response. Furthermore, recurrence of CVS and vasospasm-related infarction after TBA were described and risk factors were identified with logistic regression analyses. RESULTS: In 7 of 35 patients (20%) and in 16 of 99 vessel segments (16%) previously treated with TBA, we found recurrent CVS. Vasospasm-related infarction occurred in 18 cases (18%) in the arterial territories of the TBA-treated vessel segments. The angiographic effect after TBA was mostly classified as good (87%), good response was negatively associated with recurrent CVS (p = 0.004) and vasospasm-related infarction (p = 0.001). We identified only the male gender as a risk factor for vasospasm-related infarction after TBA (p = 0.040). In connection with TBA, only one complication occurred (intracranial dissection). CONCLUSION: Our data support TBA as a safe and effective therapy for CVS. Nevertheless, recurrent CVS and vasospasm-related infarction were common after TBA and not predictable by clinical conditions on admission or the localization of CVS. A moderate or poor angiographic response after TBA was identified as a risk factor for both, recurrent CVS and vasospasm-related infarction, while male gender was associated with a higher risk of vasospasm-related infarction. Our results augment the still sparse evidence concerning optimal patient selection for this method and provide new aspects for individual therapy decisions.

Astragaloside IV alleviates ischemia reperfusion-induced apoptosis by inhibiting the activation of key factors in death receptor pathway and mitochondrial pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Apoptosis plays an important role in cerebral ischemia-reperfusion injury and triggers a series of pathological changes which may even be life-threatening. Astragaloside-IV (AS-IV), a natural compound extracted from Astragalus (Astragalus membranaceus (Fisch.) Bunge., Leguminosae, Huangqi in Chinese), showed neuroprotective effects in the study of cerebral ischemia-reperfusion injury. In this study we investigate the effects of AS-IV on apoptosis induced by transient cerebral ischemia and reperfusion in rats, as well as the associated regulatory factors. METHODS: AS-IV was administrated to male Sprague-Dawley (SD) rats after transient cerebral ischemia and reperfusion surgery (12.5, 25, and 50 mg/kg, once per day, continued for 7 days after surgey). After seven days of continuous administration, neurological function, cerebral infarction volume, and pathological changes of brain tissue were detected. Fas, FasL, Caspase-8, Bax, and Bcl-2 mRNA levels were determined by real-time PCR. Caspase-8, Bid, Cytochrome C (Cyto C), cleaved Caspase-3 proteins were determined by western blot and immunohistochemistry was used to quantify Cyto C. RESULTS: AS-IV significantly attenuated the neurological deficit in rats with ischemica-reperfusion injury, and reduced cerebral infarction and neuronal apoptosis. AS-IV inhibited the mRNA upregulation of Fas, FasL, Caspase-8, and Bax/Bcl-2. Furthermore, the protein level of apoptosis cytokines Caspase-8, Bid, cleaved Caspase-3 and Cyto C were also inhibited after ischemia reperfusion, suggesting that AS-IV might alleviate ischemia reperfusion-induced apoptosis by inhibiting the activation of key factors in death receptor pathway and mitochondrial pathway.

Long-Term Outcomes of Indirect Bypass for 629 Children With Moyamoya Disease: Longitudinal and Cross-Sectional Analysis.

Background and Purpose- In pediatric moyamoya disease, there are few reports on the efficacy of surgical intervention for stroke prevention. We evaluated the long-term outcomes of indirect bypass surgery on a relatively large number of children with moyamoya disease in a single center. Methods- From August 1988 to December 2012, 772 children underwent indirect bypass surgery. This study included 629 patients who were followed up for >5 years, excluding patients with moyamoya syndrome. The mean clinical follow-up duration was 12 years (range, 5-29 years). Cross-sectional analysis was performed based on either Karnofsky Performance Scale or Lansky Play Performance Scale to evaluate overall clinical outcomes and factors associated with unfavorable outcomes. To analyze the longitudinal effect of surgery, the annual risk of symptomatic infarction or hemorrhage on the operated hemisphere after indirect bypass surgery was calculated with a person-year method, and the event-free survival rate was evaluated using the Kaplan-Meier method. Results- The overall clinical outcome was favorable in 95% of the patients. The annual risks of symptomatic infarction and hemorrhage on the operated hemispheres were 0.08% and 0.04%, respectively. Furthermore, the 10-year event-free survival rates for symptomatic infarction and hemorrhage were 99.2% and 99.8%. Conclusions- Indirect bypass surgery could provide satisfactory long-term improvement in overall clinical outcome and prevention of recurrent stroke in children with moyamoya disease.