Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

Remote ischemic conditioning improves cerebral hemodynamics in symptomatic intracranial atherosclerosis: A PET/CT-guided randomized controlled study.

Patients with symptomatic intracranial arterial stenosis (sICAS) suffer embarrassed hemodynamic status and acute ischemic stroke (AIS) recurrence. We aimed to assess the efficacy of remote ischemic conditioning (RIC) on improving this status by evaluating cerebral blood flow (CBF) and cerebral glucose metabolism (CGM) via PET/CT. Adult patients with unilateral sICAS in middle cerebral artery and/or intracranial segment of internal carotid artery-related AIS or transient ischemic attack within 6 months prior to randomization were enrolled. Individuals who received intravenous thrombolysis or endovascular treatment, or sICAS caused by cardiac embolism, small vessel occlusion, or other determined causes were excluded. Twenty-three eligible patients were randomly assigned to standard medical treatment (SMT) (n = 10) or RIC group (n = 13). The RIC protocol consisted of 5 cycles, each for 5-min bilateral upper limb ischemia and 5-min reperfusion period, twice a day, with a total duration of 3 months. Ten healthy volunteers were enrolled as healthy control group. We tested CBF and CGM at the rest stage and the methazolamide-induced stress stage. All patients received PET/CT at baseline and three-month followup. Both CBF and CGM in ipsilateral hemisphere of sICAS patients were significantly decreased at the rest stage and the stress stage (p < .05), which were improved by three-month RIC (p < .05). The lesions decreased notably in RIC group compared to SMT group (p < .05). RIC ameliorated the hemodynamic status and glucose metabolism in regions at high risk of infarction, which might improve the resistance capacity towards ischemic load in sICAS patients.

A case report: new-onset nummular headache after stenting of the middle cerebral artery.

BACKGROUND: Nummular headache (NH) is categorized as a primary headache in the International Classification of Headache Disorders, Third edition (ICHD-3) diagnostic criteria, but there are secondary etiologies as well. We present a case of secondary NH that associated with vascular lesion. CASE PRESENTATION: We report on a 40-year-old man with a medical history of symptomatic intracranial arterial stenosis who developed a headache after percutaneous transluminal angioplasty and stenting because of Intracranial atherosclerotic stenosis(ICAS). This new-onset headache was a pinprick headache confined to the parietal part of the head and 5 cm in size. This headache most closely resembled the phenotype of a NH. And other causes of secondary headache were excluded. Thus, the diagnosis of NH was highly speculated. This patient represents a rare headache phenomenon after intracranial arterial stent placement. CONCLUSION: This is the first report of NH after stent placement treatment in a patient with ICAS.

Performance and Analysis of the Alchemical Transfer Method for Binding-Free-Energy Predictions of Diverse Ligands.

The Alchemical Transfer Method (ATM) is herein validated against the relative binding-free energies (RBFEs) of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and AToM-OpenMM software to compute the RBFEs of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations. The novel coordinate perturbation scheme and a dual-topology approach of ATM address some of the challenges of single-topology alchemical RBFE methods. Specifically, ATM eliminates the need for splitting electrostatic and Lennard-Jones interactions, atom mapping, defining ligand regions, and postcorrections for charge-changing perturbations. Thus, ATM is simpler and more broadly applicable than conventional alchemical methods, especially for scaffold-hopping and charge-changing transformations. Here, we performed well over 500 RBFE calculations for eight protein targets and found that ATM achieves accuracy comparable to that of existing state-of-the-art methods, albeit with larger statistical fluctuations. We discuss insights into the specific strengths and weaknesses of the ATM method that will inform future deployments. This study confirms that ATM can be applied as a production tool for RBFE predictions across a wide range of perturbation types within a unified, open-source framework.

Taming multiple binding poses in alchemical binding free energy prediction: the ß-cyclodextrin host-guest SAMPL9 blinded challenge.

We apply the Alchemical Transfer Method (ATM) and a bespoke fixed partial charge force field to the SAMPL9 bCD host-guest binding free energy prediction challenge that comprises a combination of complexes formed between five phenothiazine guests and two cyclodextrin hosts. Multiple chemical forms, competing binding poses, and computational modeling challenges pose significant obstacles to obtaining reliable computational predictions for these systems. The phenothiazine guests exist in solution as racemic mixtures of enantiomers related by nitrogen inversions that bind the hosts in various binding poses, each requiring an individual free energy analysis. Due to the large size of the guests and the conformational reorganization of the hosts, which prevent a direct absolute binding free energy route, binding free energies are obtained by a series of absolute and relative binding alchemical steps for each chemical species in each binding pose. Metadynamics-accelerated conformational sampling was found to be necessary to address the poor convergence of some numerical estimates affected by conformational trapping. Despite these challenges, our blinded predictions quantitatively reproduced the experimental affinities for the ß-cyclodextrin host and, to a lesser extent, those with a methylated derivative. The work illustrates the challenges of obtaining reliable free energy data in in silico drug design for even seemingly simple systems and introduces some of the technologies available to tackle them.

Evaluation of peripapillary retinal nerve fiber layer thickness in intracranial atherosclerotic stenosis.

PURPOSE: To evaluate the peripapillary retinal nerve fiber layer thickness (pRNFL) in patients with intracranial atherosclerotic stenosis (ICAS). METHODS: A cross-sectional study was performed in a general hospital. The intracranial atherosclerotic stenosis was evaluated by digital subtraction angiography (DSA), computed tomography angiography (CTA) or magnetic resonance angiography (MRA). High-definition optical coherence tomography (HD-OCT) was used to evaluate the peripapillary retinal nerve fiber layer thickness. RESULTS: A total of 102 patients, including 59(57.8%) patients with ICAS and 43(42.2%) patients without ICAS, were finally analysed in the study. The peripapillary retinal nerve fiber layer thickness (pRNFL) was reduced significantly in the average, the superior and the inferior quadrants of the ipsilateral eyes and in the superior quadrant of the contralateral eyes in patients with ICAS compared with patients without ICAS. After multivariate analysis, only the superior pRNFL thickness in the ipsilateral eyes was significantly associated with ICAS (OR,0.968; 95% CI,0.946-0.991; p = 0.006). The area under receiver operator curve was 0.679 (95% CI,0.576-0.782) for it to identify the presence of ICAS. The cut-off value of the superior pRNFL was 109.5 µm, and the sensitivity and specificity were 50.8% and 83.7%, respectively. CONCLUSION: The superior pRNFL in the ipsilateral eye was significantly associated with ICAS in this study. Larger studies are needed to explore the relation between pRNFL and ICAS further.

Efficacy and Safety of Recanalization Therapy for Acute Ischemic Stroke With Large Vessel Occlusion: A Systematic Review.

BACKGROUND AND PURPOSE: The optimal recanalization strategy for acute ischemic stroke with large vessel occlusion continues to be an area of active interest. Network meta-analysis can provide insight when direct comparative evidence is lacking. METHODS: A systematic review of the literature using PubMed, Embase, the Cochrane Central Register of Controlled Trials, and SinoMed was performed, and a search was conducted for clinical trials on ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and StrokeCenter.org. Four independent reviewers conducted the study selection, data abstraction, and quality assessments. RESULTS: The literature review identified 17 trials including 3236 patients and 8 ongoing clinical trials. Sample sizes ranged from 7 to 656 participants. Intravenous thrombolysis (IVT) was the most common intervention, followed by IVT plus mechanical thrombectomy (MT), IVT plus intraarterial thrombolysis, intraarterial thrombolysis alone, and MT alone. In the pooled network meta-analysis, IVT+MT was associated with a higher rate of independent functioning. In contrast, IVT was ranked as the most ineffective treatment strategy with respect to neurological functions, while direct MT was ranked as the least safe intervention with respect to all-cause mortality. Also, irrespective of assessment tools, endovascular treatment plus IVT led to higher successful recanalization rate than thrombolysis alone. CONCLUSIONS: Compared with other recanalization treatments, IVT+MT seems to be the most effective strategy, without increasing detrimental effects, for thrombolysis-eligible patients with large vessel occlusion-acute ischemic stroke. To improve the current evidentiary basis for recanalization treatment, future trials and real-world studies are warranted and should use unified definitions of symptomatic intracranial hemorrhage and recanalization.

Glycosylated Hemoglobin A1c Predicts Intracerebral Hemorrhage with Acute Ischemic Stroke Post-Mechanical Thrombectomy.

BACKGROUND: Intracerebral hemorrhage, including symptomatic intracerebral hemorrhage, is a serious post-mechanical thrombectomy complication in patients with acute ischemic stroke. We aimed to determine whether glycosylated hemoglobin A1c parameters could predict intracerebral hemorrhage in this patient population. METHODS: We enrolled patients with acute occlusion of the internal carotid artery or proximal middle cerebral artery and who had undergone mechanical thrombectomy. According to the glycosylated hemoglobin A1c level (%) assessed during the hospital stay, the patients were divided into two groups: > 6.5% and ≤ 6.5%. Intracerebral hemorrhage was evaluated and classified based on cranial computed tomography scans obtained within 24-48 h or when neurological conditions worsened. We assessed the outcome at the end of 90 days using the modified Rankin Scale scores. RESULTS: Among 202 patients, 86 (42.6%) suffered intracerebral hemorrhage, while 25 (12.4%) had symptomatic intracerebral hemorrhage; 35.6% of the patients had a favorable outcome (modified Rankin Scale scores 0-2). Multivariable analysis demonstrated an association of glycosylated hemoglobin A1c > 6.5% with intracerebral hemorrhage. Furthermore, glycosylated hemoglobin A1c > 6.5% was independently associated with symptomatic intracerebral hemorrhage (OR, 2.136; 95% CI, 1.279-3.567; P = 0.004). In addition, glycosylated hemoglobin A1c > 6.5% was significantly associated with increased mortality (OR, 1.511; 95% CI, 1.042-2.191; P = 0.029) and negatively associated with favorable outcome (OR, 0.480; 95% CI, 0.296-0.781; P = 0.003) at 90 days. CONCLUSIONS: Glycosylated hemoglobin A1c is an independent predictor of intracerebral hemorrhage (specifically, symptomatic intracerebral hemorrhage) in patients with acute ischemic stroke treated with mechanical thrombectomy. Further studies are needed to validate these findings.

Low-Dose Tirofiban Treatment Improves Neurological Deterioration Outcome After Intravenous Thrombolysis.

Background and Purpose- Early use of antiplatelet drugs within 24 hours after intravenous thrombolysis (IVT) has always been a confusing clinical problem. The purpose of this study was to assess the safety and efficacy of early low-dose tirofiban treatment in patients with early neurological deterioration (END) within the first 24 hours after IVT. Methods- This was a retrospective analysis of prospectively collected data of 1764 consecutive patients with acute ischemic stroke treated with IVT between January 2017 and September 2018. Patients with early neurological deterioration within the first 24 hours after IVT were treated with or without tirofiban. The safety outcomes included symptomatic intracranial hemorrhage, any ICH, severe systemic bleeding, and mortality. Efficacy outcomes included excellent (modified Rankin scale scores 0-1) and favorable (modified Rankin scale scores 0-2) 3-month functional outcomes. Results- Early neurological deterioration occurred in 278 (15.8%) patients. Of the 187 eligible patients, 121 (64.7%) were treated with tirofiban within the first 24 hours after IVT. Adjusted multivariate analysis showed that early tirofiban use was not associated with symptomatic intracranial hemorrhage (adjusted odds ratio [aOR], 1.05; 95% CI, 0.088-11.02; P=1.000), ICH (aOR, 1.13; 95% CI, 0.45-4.25; P=0.512), and mortality (aOR, 0.77; 95% CI, 0.19-2.27; P=0.875) but was significantly associated with excellent (aOR, 2.24; 95% CI, 1.16-3.94; P=0.027) and favorable (aOR, 2.31; 95% CI, 1.48-3.99; P=0.011) functional outcomes. Subgroup analyses suggested that early tirofiban-use efficacy is time dependent, being more effective in patients receiving tirofiban treatment earlier. Conclusions- Low-dose tirofiban use in patients with early neurological deterioration within the first 24 hours after IVT did not increase the risk of symptomatic intracranial hemorrhage, ICH, and mortality, it seems associated with neurological improvement at 3 months. Future randomized clinical trials will be needed to validate these results.

Toward Atomistic Modeling of Irreversible Covalent Inhibitor Binding Kinetics.

Covalent inhibitors have emerged as an important drug class in recent years, largely due to their many unique advantages as compared to noncovalent inhibitors, including longer duration of action, lower prolonged systemic exposure, higher potency, and selectivity. However, the potential off-target toxicity of covalent inhibitors, particularly of irreversible covalent inhibitors, represents a great challenge in covalent drug development. Therefore, accurate calculation of protein covalent inhibitor reaction kinetics to guide the design of selective inhibitors would greatly benefit covalent drug discovery efforts. In the present paper, we present a computational method to calculate the relative reaction kinetics between congeneric irreversible covalent inhibitors and their protein receptors. The method combines density functional theory calculations of the transition state barrier height of the rate-limiting step for reaction between the warhead of the inhibitor and a single protein residue, and molecular-mechanics-based free energy calculations to account for the interactions between the ligand in the transition state and the protein environment. The method was tested on four pharmaceutically interesting irreversible covalent binding systems involving 28 ligands; the mean unsigned error (MUE) of the relative reaction rate for all pairs of ligands between the predictions and experimental results for these tested systems is 0.79 log unit. This is to our knowledge the first time where the reaction kinetics of protein irreversible covalent inhibition have been directly calculated with physics-based free energy calculation methods and transition state theory. We anticipate the outstanding accuracy demonstrated here across a broad range of target classes will have a strong impact on the design of selective covalent inhibitors.

Angioplasty and/or stenting after thrombectomy in patients with underlying intracranial atherosclerotic stenosis.

PURPOSE: To investigate the imaging and clinical outcomes of emergent angioplasty and/or stenting or neither in patients of emergent large-vessel occlusion (ELVO) with underlying severe intracranial atherosclerotic stenosis (ICAS). METHODS: In this multicenter prospective cohort study, we included patients of ELVO with underlying ICAS. Patients received emergent angioplasty and/or stenting or neither after mechanical thrombectomy at the interventionists' discretion. The primary outcome was recanalization rate at 24 h, which was defined as a modified arterial occlusive lesion score of 2 or 3. RESULTS: A total of 113 consecutive patients with underlying ICAS > 70% in anterior cerebral circulation were enrolled in this study. Of these, 81 (71.7%) received emergent angioplasty and/or stenting after thrombectomy. Patients in the emergent angioplasty and/or stenting group were significantly more likely to have recanalization at 24 h (adjusted OR [aOR], 3.782; 95% confidence interval [CI], 1.821-9.125; P = 0.02) and less likely to have early neurologic deterioration (aOR, 0.299; 95% CI, 0.110-0.821; P = 0.01). However, emergent angioplasty and/or stenting was not significantly associated with symptomatic intracranial hemorrhage (aOR, 0.710; 95% CI, 0.199-2.622; P = 0.67), asymptomatic intracranial hemorrhage (aOR, 1.325; 95% CI, 0.567-3.031; P = 0.81), death at 90 days (aOR, 0.581; 95% CI, 0.186-2.314; P = 0.41), and functional independence at 90 days (aOR, 1.752; 95% CI, 0.774-3.257; P = 0.16), compared with patients that received neither. CONCLUSION: Emergent angioplasty and/or stenting is possible in patients of ELVO with ICAS and may reduce the risk of reocclusion and early neurologic deterioration with no increased risk of intracranial hemorrhage and death than those received neither.

Obstructive Sleep Apnea before Ischemic Stroke: Clinical Relevance to Infarction Volume and Neurological Recovery.

BACKGROUND: Obstructive sleep apnea (OSA) is a probable risk factor with speculative roles in the induction or aggravation of acute ischemic stroke (AIS). METHODS: The association between OSA and AIS severity was retrospectively analyzed using clinical data of first-onset AIS patients, admitted to our hospital between January 2013 and September 2016. Eligible patients were categorized based on the presence of OSA prior to stroke. Stroke severity and functional outcomes were evaluated using the National Institute of Health Stroke Severity Scale (NIHSS) and the modified Rankin scale (mRS), respectively. RESULTS: No significant differences were observed among OSA and non-OSA groups for infarction volume, NIHSS at admission and discharge, or mRS at discharge and at the 3-month follow-up (all P > .05). OSA prior to stroke negatively correlated with infarction volume (P = .008), NIHSS at discharge (P = .006), and the 3-month mRS (P = .015). In addition to OSA, it was also found that infarction volume significantly correlated with large artery occlusion (LAO), anterior circulation involvement, neutrophil count, and fibrinogen level; NIHSS at discharge significantly correlated with LAO, transient ischemia attack (TIA), neutrophil count, and thrombolysis; and the 3-month mRS significantly correlated with LAO, TIA, age, neutrophil count, and thrombolysis. CONCLUSIONS: OSA before AIS does not increase the severity of stroke. The negative association between OSA and infarction volume, stroke severity, and clinical outcomes suggests an endogenous neuroprotective effect.

Asymptomatic Intracerebral Hemorrhage May Worsen Clinical Outcomes in Acute Ischemic Stroke Patients Undergoing Thrombectomy.

BACKGROUND: Asymptomatic intracerebral hemorrhage (AICH) is a common phenomenon in patients with acute ischemic stroke (AIS) who were treated with endovascular thrombectomy (ET). This study aimed to evaluate the clinical effects of AICH and its risk factors in this patient population. METHODS: This observational study was based on a prospective registry study. AIS patients with large-vessel occlusion in the anterior circulation and treated with ET were recruited. During thrombectomy procedures, intra-arterial infusion of thrombolytics or antiplatelet and permanent stenting were used as remedial therapies. The primary outcome was the overall distribution of modified Rankin scale (mRS) 90 days after ET. RESULTS: This study included 102 patients (61.1 ± 12.7 years old), in whom 39 patients (38.2%) experienced AICH. At 90-day follow-up, the median mRS was 2 (interquartile range [IQR] 0-3) for patients without AICH and 4 (IQR 2-6) for those with AICH (adjusted P = .005). Fourteen patients with AICH and 7 patients without AICH died, which was significantly different (35.9% versus 11.1%, adjusted P = .015). Thirty-nine patients (61.9%) without AICH and 14 patients (35.9%) with AICH achieved functional independence at 3-month follow-up (adjusted P = .117). The length of intensive care unit staying was 5 days (IQR 2-10) in patients without AICH and 8 days (IQR 3-19) in those with AICH (adjusted P = .840). In multivariate analysis, lower Alberta Stroke Program Early CT Score (ASPECTS) (adjusted P = .003) and adjunctively intra-arterial thrombolysis (adjusted P = .016) were independently associated with AICH. CONCLUSIONS: In AIS patients treated with ET AICH appears to be associated with worse functional outcomes and high mortality. Lower ASPECTS and adjectively intra-arterial thrombolysis were independent risk factors of AICH.

Outcome of endovascular treatment for acute basilar artery occlusion in the modern era: a single institution experience.

PURPOSE: The beneficial effect of endovascular treatment (EVT) for patients with acute basilar artery occlusion (ABAO) remains uncertain. The purpose of the present study was to evaluate clinical outcome of EVT for patients with ABAO and analyze prognostic factors of good outcome. METHODS: From our prospectively established database, we reviewed all patients with ABAO receiving EVT during January 2014 to December 2016. Baseline characteristics and outcomes were evaluated. Favorable functional outcome was defined as modified Rankin Scale score of 0 to 3 assessed at 3-month follow-up. The association between clinical and procedural characteristics and functional outcome was assessed. RESULTS: Of the 68 patients included, 50 patients (73.5%) received mechanical thrombectomy with stent retriever device. Successful reperfusion (thrombolysis in cerebral infarction grades 2b-3) was achieved in 61 patients (89.7%). Overall favorable functional outcome was reached by 31 patients (45.6%). In univariate analysis, Glasgow Coma Scale sum score, baseline National Institutes of Health stroke scale score (NIHSS), and baseline glycemia level were identified predicting good clinical outcome. Multivariate analysis showed that lower NIHSS was the only independent risk factor of favorable functional outcome (OR 0.832; 95% CI, 0.715-0.968; p = 0.018). No difference of favorable outcomes was observed between the subgroups of time to EVT < 6 h and ≽ 6 h. CONCLUSIONS: Data in the present study suggests that EVT for ABAO patients should be reasonable within 24 h of symptom onset. The most important factor determining clinical outcome is initial stroke severity.

A new target for the treatment of trigeminal neuralgia with botulinum toxin type A.

Trigeminal neuralgia (TN) is typically treated pharmacologically with anticonvulsants, but these can be ineffective, or can lose their effectiveness over time. In recent years, botulinum toxin type A (BoNT-A), when injected subcutaneously across multiple sites, can effectively treat TN. However, approximately 30% of TN cases are refractory to subcutaneous BoNT-A treatment. We report here the case of a 79-year-old female patient with TN presenting as severe, episodic pain in the lower left gingival area. She was on anticonvulsant therapy (carbamazepine) for about 3 years prior to BoNT-A treatment. Despite initial relief, the pain not only recurred, but also began to worsen, even as her carbamazepine dose was increased substantially. We injected 50 U of BoNT-A into the oral mucosa of the painful gingival area, but the patient's pain was unaffected. We then changed to an intramuscular injection protocol and injected the same dose of BoNT-A into the left masseter, which produced a good therapeutic effect for about 5 months; she was then administered a second treatment (intra-masseter), and at a 2-week follow-up, still reported being pain-free. This case and a survey of the literature suggest that BoNT-A injection protocols maybe closely correlated with their clinical efficacy in cases of TN, possibly due to the ability of BoNT-A to be transported retrogradely along trigeminal nerve axons. We believe that finding the optimal BoNT-A therapy injection protocol(s) will significantly reduce the number of refractory cases of TN.

Low-Dose Tirofiban Improves Functional Outcome in Acute Ischemic Stroke Patients Treated With Endovascular Thrombectomy.

BACKGROUND AND PURPOSE: Chinese patients largely experience acute ischemic stroke (AIS) because of large artery atherosclerosis rather than cardioembolism, and whether tirofiban is safe and effective in these patients treated with endovascular thrombectomy (ET) is unknown. This study evaluated the safety and efficacy of tirofiban in Chinese patients with AIS treated with ET. METHODS: This observational study is based on a single-center prospective registry study. Patients with AIS undergoing ET with second-generation stent retrievers from January 2013 to February 2017 were treated with ET alone or ET plus low dose of tirofiban. The primary outcome was symptomatic intracerebral hemorrhage (sICH). The secondary outcomes included rate of early reocclusion, any ICH, fatal ICH, and 3-month and long-term functional outcomes. RESULTS: One hundred eighty AIS subjects were included in the analysis, including 90 subjects treated with tirofiban and 90 subjects without tirofiban. Sixty-three subjects (35%) had any ICH, 19 of them (11%) were sICH, and 9 of them (5%) were fatal ICH. Ten subjects (11%) treated with tirofiban experienced sICH and 9 subjects (10%) not given tirofiban experienced sICH, not a significant difference (P=0.808). Early reocclusion happened in 4 of 90 subjects (4.4%) treated with tirofiban and 8 of 90 subjects (8.9%) not treated with tirofiban (P=0.370). One hundred sixty-one subjects (89%) completed long-term follow-up, subjects treated tirofiban were associated with lower odds of death (23% versus 44%, P=0.005) when compared with those who were not treated. Additionally, tirofiban was associated with better odds of long-term functional independence (adjusted odds ratio, 4.37; 95% confidence interval, 1.13-16.97; P=0.033). CONCLUSIONS: In patients with AIS undergoing ET, tirofiban is not associated with higher sICH, it seems to lead to lower odds of deaths and better odds of long-term functional independence. Further investigations are needed to determine the efficacy of tirofiban in preventing early reocclusion, the underlying mechanisms, and its optimal treatment protocol.

Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats.

Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer's disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments.

Genome-Wide Profiling of miRNA and mRNA Expression in Alzheimer's Disease.

BACKGROUND Our study aimed to identify key differentially expressed genes (DEGs) and miRNAs (DEmiRNAs) which can serve as potential biomarkers for diagnosis and therapy of Alzheimer's disease (AD). MATERIAL AND METHODS We performed miRNA and mRNA integrated analysis (MMIA) to identify DEGs and DEmiRNAs of AD. The AD-specific DEmiRNAs-targets interaction network was contrasted. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed. Q-RT-PCR was used to verify the expression of selected DEGs and DEmiRNAs. RESULTS We conducted MMIA of AD based on 1 miRNA dataset and 3 mRNA datasets derived from the Gene Expression Omnibus (GEO) database; 1759 DEGs and 12 DEmiRNAs were obtained. DEGs of AD were significantly enriched in Huntington's disease and AD. LRP1, CDK5R1, PLCb2, NDUFA4, and DLG4 were 5 DEGs regulated by 4 DEmiRNAs, including miR-26b-5p, miR-26a-5p, miR-107, and miR-103a-3p. These 4 miRNAs were the top 4 miRNAs covering most DEGs. According to the qRT-PCR results, the expression of PLCß2, NDUFA4, DLG4, miR-107, and miR-103a-3p was consistent with our integrated analysis. CONCLUSIONS We concluded that LRP1, CDK5R1, PLCß2, NDUFA4, and DLG4 may play a role in AD regulated by miR-26b-5p, miR-26a-5p, miR-107, and miR-103a-3p. Our findings will contribute to identification of biomarkers and new strategies for drug design for AD treatment.

Relationship between Post-Thrombolysis Blood Pressure and Outcome in Acute Ischemic Stroke Patients Undergoing Thrombolysis Therapy.

BACKGROUND: The management of blood pressure (BP) for acute ischemic stroke (AIS) patients undergoing thrombolysis is still under debate. The purpose of this study was (1) to explore the association between post-thrombolysis BP and functional outcome and (2) to examine whether post-thrombolysis BP can predict functional outcome in Chinese AIS patients undergoing thrombolysis therapy. METHODS: From December 2012 to November 2016, AIS patients undergoing thrombolysis were reviewed retrospectively in the Department of Neurology at Xuanwu Hospital. The BP levels were measured before and immediately after thrombolysis. Clinical outcomes, which comprised favorable outcome (modified Rankin Scale score 0-2) and unfavorable outcome (modified Rankin Scale score 3-6) at 3 months, were analyzed by logistic regression model. A receiver operating characteristic curve was used to evaluate the predictive value of post-thrombolysis BP. RESULTS: Patients with unfavorable outcome at 3 months had a higher post-thrombolysis systolic BP than those with favorable outcome (P = .015). Multivariate analysis showed that post-thrombolysis systolic BP below 159.5 mm Hg was associated with favorable outcome. According to the receiver operating characteristic curve, post-thrombolysis systolic BP was a predictor of functional outcome with an area under the curve of .573 (95% confidence interval = .504-.642). CONCLUSIONS: Our study indicated that post-thrombolysis systolic BP is a predictor of functional outcome for Chinese AIS patients undergoing thrombolysis therapy. It is reasonable for AIS patients to keep post-thrombolysis systolic BP below 159.5 mm Hg to obtain a favorable outcome.