Effects of Valproic Acid on Cerebral Nutrient Carriers' Expression in the Rat

Objective: The antiepileptic drug valproate has been shown to affect the expression of carriers for essential compounds and drugs in extracerebral tissues. The aim of the current study was to evaluate in vivo the effect of valproate treatment on the cerebral expression of carriers and selected genes of the blood-brain barrier (BBB) in the rat.Methods: Male Wistar rats were treated daily for 7 days by intraperitoneal injections of valproate (75, 150, or 300 mg/kg/day) or the vehicle. mRNA was isolated from the cerebral cortex and the hippocampus. Transcript levels of 37 genes were measured using a customized gene expression assay. Quantitative histone acetylation was evaluated by western blotting. Glucose6-phosphate (G6P) tissue levels were used as a surrogate of cerebral glucose concentrations.Results: Valproate treatment was associated with significant reduction (up to 22%; P < 0.05) in cortical and hippocampal claudin 5-normalized Slc2a1 (Glut1) mRNA expression. G6P levels were not significantly altered, but were correlated with Slc2a1 transcript levels (r = 0.499; P < 0.02). None of the other 36 screened genes were significantly affected by valproate. Cortical histone hyperacetylation indicated cerebral activity of valproate on a major pathway regulating gene expression (P < 0.02).Significance: The effect of valproate on nutrient carriers appears to be tissue-specific and even brain area-specific. If validated in humans, the changes in Glut1 expression might have clinical implications in positron emission tomography (PET) imaging. Further studies are required for elucidating the relevance of these findings to the clinic

Visualization of both proximal M2-MCA segments in patients (the Tilted-V Sign) with acute M1-MCA occlusion stroke is associated with better procedural and prognostic outcomes

IntroductionWe aimed to assess the clinical significance of M1-MCA occlusion with visualization of both MCA-M2 segments [“Tilted-V sign” (TVS)] on initial CT angiography (CTA) in patients with acute ischemic stroke (AIS) undergoing endovascular thrombectomy (EVT).MethodsData for patients with consecutive AIS undergoing EVT for large vessel occlusion (LVO) in two academic centers are recorded in ongoing databases. Patients who underwent EVT for M1-MCA occlusions ≤ 6 h from symptom onset were included in this retrospective analysis.ResultsA total of 346 patients met the inclusion criteria; 189 (55%) had positive TVS. Patients with positive TVS were younger (68 ± 14 vs. 71 ± 14 years, P = 0.028), with similar rates of vascular risk factors and baseline modified Rankin scores (mRS) 0–2. The rates of achieving thrombolysis in cerebral ischemia (TICI) 2b-3 were similar to the two groups (79%), although successful first-pass recanalization was more common with TVS (64 vs. 36%, p = 0.01). On multivariate analysis, higher collateral score [odds ratio (OR) 1.38 per unit increase, p = 0.008] and lower age (OR 0.98 per year increase, p = 0.046) were significant predictors of TVS. Patients with positive TVS had higher post-procedural Alberta Stroke Program Early CT Score (ASPECTS; 6.9 ± 2.2 vs. 5.2 ± 2.3, p = 0.001), were discharged with lower National Institutes of Health Stroke Score (NIHSS; 6±6 vs. 9±7, p = 0.003) and higher rates of mRS 0–2 (29.5 vs. 12%, p = 0.001), and had lower rates of 90-day mortality (13.2 vs. 21.6%, p = 0.038). However, TVS was not an independent predictor of functional independence (OR 2.51; 95% CI 0.7–8.3).ConclusionTilted-V Sign, an easily identifiable radiological marker, is associated with fewer recanalization attempts, better functional outcomes, and reduced mortality

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

Safety and Efficacy of Intravenous Alteplase before Endovascular Thrombectomy: A Pooled Analysis with Focus on the Elderly

Current guidelines advocate intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) for all patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). We evaluated outcomes with and without IVT pretreatment. Our institutional protocols allow AIS patients presenting early (<4 h from onset or last seen normal) who have an Alberta Stroke Program Early CT Score (ASPECTS) ≥6 to undergo EVT without IVT pretreatment if the endovascular team is in the hospital (direct EVT). Rates of recanalization and hemorrhagic transformation (HT) and neurological outcomes were retrospectively compared in consecutive patients undergoing IVT+EVT vs. direct EVT with subanalyses in those ≥80 years and ≥85 years. In the overall cohort (IVT+EVT = 147, direct EVT = 162), and in subsets of patients ≥80 years (IVT+EVT = 51, direct EVT = 50) and ≥85 years (IVT+EVT = 19, direct EVT = 32), the IVT+EVT cohort and the direct EVT group had similar baseline characteristics, underwent EVT after a comparable interval from symptom onset, and reached similar rates of target vessel recanalization. No differences were observed in the HT frequency, or in disability at discharge or after 90 days. Patients receiving direct EVT underwent more stenting of the carotid artery due to stenosis during the EVT procedure (22% vs. 6%, p = 0.001). Direct EVT and IVT+EVT had comparable neurological outcomes in the overall cohort and in the subgroups of patients ≥80 and ≥85 years, suggesting that direct EVT should be considered in patients with an elevated risk for HT

Hemorrhagic Transformation in Acute Ischemic Stroke: A Quantitative Systematic Review

The prevalence and risk factors of hemorrhagic transformation (HT) after acute ischemic stroke HT have not been adequately delineated. We performed a systematic review and meta-analysis to identify English-language prospective observational MEDLINE and EMBASE-listed reports of acute ischemic stroke with HT published from 1985–2017. Studies that used the ECASS-2 definitions of hemorrhagic transformation subtypes, hemorrhagic infarction (HI), and parenchymal hematoma (PH) were included. Patients treated with intravenous thrombolysis with tissue plasminogen activator (IV-tPA) were compared with those who did not receive thrombolysis. A total of 65 studies with 17,259 patients met inclusion criteria. Overall, HT prevalence was 27%; 32% in patients receiving IV-tPA vs. 20% in those without. Overall PH prevalence was 9%; 12% in IV-tPA treated patients vs. 5% in those without. HT was associated with a history of atrial fibrillation (OR 2.94) and use of anticoagulants (OR 2.47). HT patients had higher NIHSS (Hedge’s-G 0.96) and larger infarct volume (diffusion-weighted MRI, Hedge’s-G 0.8). In IV-tPA treated patients, PH correlated with antiplatelet (OR 3) and statin treatment (OR 4). HT (OR 3) and PH (OR 8) were associated with a poor outcome at 90-day (mRS 5–6). Hemorrhagic transformation is a frequent complication of acute ischemic stroke and is associated with poor outcome. Recognition of risk factors for HT and PH may reduce their incidence and severity.Medicine, Faculty ofNon UBCMedicine, Department ofNeurology, Division ofReviewedFacultyResearche

Effects in Israel of Arab and Jewish Ethnicity on Intracerebral Hemorrhage

Intracerebral hemorrhages (ICH) characteristics reportedly differ between different ethnic groups. We aimed to compare the characteristics of Jewish and Arab ICH patients in Israel. Consecutive patients with primary ICH were included in a prospective institutional database. Demographics, vascular risk factors, clinical and radiological parameters were compared between Arab and Jewish ICH patients residing in Jerusalem. The study included 455 patients (311 Jews). Arab patients were younger (66.1 ± 13.4 vs. 72.2 ± 12.2 years, p < 0.001) and had higher rates of diabetes (60% vs. 29%, p < 0.001) and smoking (26% vs. 11%, p < 0.001). Arab patients had higher rates of deep ICH (74% vs. 62%, p = 0.01) and lower rates of lobar ICH (18% vs. 31%, p = 0.003). In a sub-analysis of deep ICH patients only, Arab patients were younger (64.3 ± 12.9 vs. 71.4 ± 11.8 years, p < 0.001) and less frequently male (56% vs. 68%, p = 0.042), with higher rates of diabetes (61% vs. 35%, p < 0.001) and smoking (31% vs. 14%, p < 0.001). In conclusion, the two ethnic populations in Israel differ in the causes and attributes of ICH. Heavy smoking and poorly controlled diabetes are commonly associated with deep ICH in the Arab population and may offer specific targets for secondary prevention in this population

Comparison of Doppler Ultrasound and Computerized Tomographic Angiography in Evaluation of Cervical Arteries Stenosis in Stroke Patients, a Retrospective Single-Center Study

There are different diagnostic modalities to investigate atherosclerosis cervical artery disease in suspected stroke patients. We aimed to test the concordance of findings of the two most widely used diagnostic modalities in stroke patients: duplex ultrasound (DUS) and computerized tomographic angiography (CTA). A total of 100 stroke patients were retrospectively included in the study, all of them had DUS followed by CTA. Discrepancies of DUS compared to the CTA results in both the internal carotid and vertebral arteries were found in 44% of the patients. The patients with significant differences in diagnostic results were characterized by older age. Evaluation of the degree of carotid artery stenosis revealed vast differences in patients with 50–69% stenosis found by DUS, in which 45.5% of them had a different percentage of stenosis found by CTA. In studying the degree of stenosis of the vertebral artery, only 47.1% of the patients with more than 50% stenosis found by DUS had the same results with CTA, while the remaining revealed normal or less than 50% stenosis by CTA. The current study emphasizes that CTA is more accurate than DUS in the evaluation of stenosis of the cervical arteries including both the internal carotid and vertebral arteries

Comparison of Doppler Ultrasound and Computerized Tomographic Angiography in Evaluation of Cervical Arteries Stenosis in Stroke Patients, a Retrospective Single-Center Study

There are different diagnostic modalities to investigate atherosclerosis cervical artery disease in suspected stroke patients. We aimed to test the concordance of findings of the two most widely used diagnostic modalities in stroke patients: duplex ultrasound (DUS) and computerized tomographic angiography (CTA). A total of 100 stroke patients were retrospectively included in the study, all of them had DUS followed by CTA. Discrepancies of DUS compared to the CTA results in both the internal carotid and vertebral arteries were found in 44% of the patients. The patients with significant differences in diagnostic results were characterized by older age. Evaluation of the degree of carotid artery stenosis revealed vast differences in patients with 50–69% stenosis found by DUS, in which 45.5% of them had a different percentage of stenosis found by CTA. In studying the degree of stenosis of the vertebral artery, only 47.1% of the patients with more than 50% stenosis found by DUS had the same results with CTA, while the remaining revealed normal or less than 50% stenosis by CTA. The current study emphasizes that CTA is more accurate than DUS in the evaluation of stenosis of the cervical arteries including both the internal carotid and vertebral arteries

Effects in Israel of Arab and Jewish Ethnicity on Intracerebral Hemorrhage

Intracerebral hemorrhages (ICH) characteristics reportedly differ between different ethnic groups. We aimed to compare the characteristics of Jewish and Arab ICH patients in Israel. Consecutive patients with primary ICH were included in a prospective institutional database. Demographics, vascular risk factors, clinical and radiological parameters were compared between Arab and Jewish ICH patients residing in Jerusalem. The study included 455 patients (311 Jews). Arab patients were younger (66.1 ± 13.4 vs. 72.2 ± 12.2 years, p p p p = 0.01) and lower rates of lobar ICH (18% vs. 31%, p = 0.003). In a sub-analysis of deep ICH patients only, Arab patients were younger (64.3 ± 12.9 vs. 71.4 ± 11.8 years, p p = 0.042), with higher rates of diabetes (61% vs. 35%, p p < 0.001). In conclusion, the two ethnic populations in Israel differ in the causes and attributes of ICH. Heavy smoking and poorly controlled diabetes are commonly associated with deep ICH in the Arab population and may offer specific targets for secondary prevention in this population

Characteristics of Multiple Acute Concomitant Cerebral Infarcts Involving Different Arterial Territories

(1) Background: Multiple acute concomitant cerebral infarcts (MACCI) are relatively uncommon. Data regarding the characteristics and outcomes of patients with MACCI are lacking. We, therefore, aimed to characterize the clinical features of MACCI. (2) Methods: Patients with MACCI were identified from a prospective registry of stroke patients admitted to a tertiary teaching center. Patients with an acute single embolic stroke (ASES) involving only one vascular bed served as controls. (3) Results: MACCI was diagnosed in 103 patients who were compared to 150 patients with ASES. MACCI patients were significantly older (p = 0.010), more often had a history of diabetes (p = 0.011) and had lower rates of ischemic heart disease (p = 0.022). On admission, MACCI patients had significantly higher rates of focal signs (p p p = 0.036). The favorable functional outcome was significantly less common in patients with MACCI (p = 0.006). In the multivariable analysis, MACCI was associated with lower chances of achieving favorable outcomes (odds ratio: 0.190, 95% CI: 0.070–0.502). (4) Conclusions: There are important differences in clinical presentation, comorbidities and outcomes between MACCI and ASES. MACCI is less often associated with favorable outcomes and could represent a more severe form of a stroke compared with a single embolic stroke