Comparison of Outcomes between Stent Retriever Combined with Contact Aspiration and Contact Aspiration Alone in Patients without Hyperdense Artery Sign/Susceptibility Vessel Sign.

PURPOSE: To examine the relationship between hyperdense artery sign (HAS)/susceptibility vessel sign (SVS) and thrombus composition and evaluate the effect of HAS/SVS status on the association between first-line thrombectomy techniques and outcomes in patients with acute anterior circulation large vessel occlusion (LVO). MATERIALS AND METHODS: From January 2018 to June 2021, 103 consecutive patients with acute anterior circulation LVO (75 [63.1%] men; median age, 66 years) who underwent thrombectomy and for whom the removed clot was available for histological analyses were retrospectively reviewed. The presence of HAS and SVS was assessed on unenhanced computed tomography (CT) and susceptibility-weighted imaging, respectively. Association of first-line thrombectomy techniques (stent retriever [SR] combined with contact aspiration [CA] vs CA alone) with outcomes was assessed according to HAS/SVS status. RESULTS: Among the included patients, 55 (53.4%) were HAS/SVS-negative, and 69 (67.0%) underwent first-line SR + CA. Higher relative densities of fibrin/platelets (0.56 vs 0.51; P < .001) and lower relative densities of erythrocytes (0.32 vs 0.42; P < .001) were observed in HAS/SVS-negative patients compared with HAS/SVS-positive patients. First-line SR + CA was associated with reduced odds of distal embolization (adjusted odds ratio, 0.18; 95% CI, 0.04-0.83; P = .027) and a more favorable 90-day functional outcome (adjusted odds ratio, 5.29; 95% CI, 1.06-26.34; P = .042) in HAS/SVS-negative patients and a longer recanalization time (53 vs 25 minutes; P = .025) and higher risk of subarachnoid hemorrhage (24.2% vs 0%; P = .044) in HAS/SVS-positive patients. CONCLUSIONS: Absence of HAS/SVS may indicate a higher density of fibrin/platelets in the thrombus, and first-line SR + CA yielded superior functional outcomes than CA alone in patients with acute LVO without HAS/SVS.

Myrtenol improves brain damage and promotes angiogenesis in rats with cerebral infarction by activating the ERK1/2 signalling pathway.

CONTEXT: Cerebral ischaemia/reperfusion (I/R) injury has a high disability and fatality worldwide. Myrtenol has protective effects on myocardial I/R injury through antioxidant and anti-apoptotic effects. OBJECTIVE: This study investigated the effect of myrtenol on cerebral ischaemia/reperfusion (I/R) injury and the underlying mechanism. MATERIALS AND METHODS: Cerebral I/R injury was induced in adult Sprague-Dawley rats by middle cerebral artery occlusion (MCAO) for 90 min. MCAO rats were treated with or without myrtenol (10, 30, or 50 mg/kg/day) or/and U0126 (10 µL) intraperitoneally for 7 days. RESULTS: In the present study, myrtenol had no toxicity at concentrations up to 1.3 g/kg. Myrtenol treatment improved neurological function of MCAO rats, with significantly (p < 0.05) improved neurological deficits (4.31 ± 1.29 vs. 0.00) and reduced brain edoema (78.95 ± 2.27% vs. 85.48 ± 1.24%). Myrtenol extenuated brain tissue injury and neuronal apoptosis, with increased Bcl-2 expression (0.48-fold) and decreased Bax expression (2.02-fold) and caspase-3 activity (1.36-fold). Myrtenol promoted angiogenesis in the brain tissues of MCAO rats, which was reflected by increased VEGF (0.86-fold) and FGF2 (0.51-fold). Myrtenol promoted the phosphorylation of MEK1/2 (0.80-fold) and ERK1/2 (0.97-fold) in MCAO rats. U0126, the inhibitor of ERK1/2 pathway, reversed the protective effects of myrtenol on brain tissue damage and angiogenesis in MCAO rats. DISCUSSION AND CONCLUSIONS: Myrtenol reduced brain damage and angiogenesis through activating the ERK1/2 signalling pathway, which may provide a novel alternative strategy for preventing cerebral I/R injury. Further in vitro work detailing its mechanism-of-action for improving ischaemic cerebral infarction is needed.

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.

The Clinical Application of Nerve Injury Unit Mode in Patients with Moderate or Severe Traumatic Brain Injury.

OBJECTIVE: To explore the efficacy of nerve injury unit mode and conventional management mode for the treatment of patients with moderate or severe traumatic brain injury (TBI). METHODS: Eighty patients with TBI in our hospital from July 2016 to December 2017 were included as observation groups (Treated with injury unit mode). Eighty-three patients with TBI from January 2015 to June 2016 were included as control group (Treated with conventional management mode). The incidence of complications, satisfaction rate, Glasgow Coma Scale (GCS) scores, Barthel index (BI), National Institutes of Health Stroke Scale (NIHSS) scores and average length of hospital stay of 2 groups were compared. RESULTS: Observation group achieved lower incidence of complications, higher satisfaction rate, higher GCS scores, higher GOS prognosis scores, higher BI, lower NIHSS scores, and shorter average length of hospital stay compared with control group (P < 0.05). There were no significant differences in the average hospitalization cost between 2 groups (P > 0.05). CONCLUSION: For patients with TBI, the nerve injury unit mode can reduce the incidence of complications, improve patient satisfaction rate, shorten the hospitalization time, enhance the daily living ability, improve the patient's neurological function, improve the ability to return to society and have a significant role in promoting the rehabilitation of patients.

LncRNA-FENDRR mediates VEGFA to promote the apoptosis of brain microvascular endothelial cells via regulating miR-126 in mice with hypertensive intracerebral hemorrhage.

BACKGROUND: LncRNA-FENDRR is a kind of endothelial genes critical for vascular development. Moreover, miR-126 and vascular endothelial growth factor A (VEGFA) are also involved in the physiological process of vascular endothelial cells. This study aimed to the underlying mechanism of FENDRR involving miR-126 and VEGFA in hypertensive intracerebral hemorrhage (HICH). METHODS: C57BL/6 mice were chosen to establish HICH model. The expression of FENDRR, miR-126, and VEGFA at mRNA level was determined by qRT-PCR. The protein expression of VEGFA was assessed using Western blot. RIP assay and RNA pull-down assay were used to the relationship between FENDRR and miR-126. Flow cytometry was used to analyze cell apoptosis. RESULTS: The levels of FENDRR and VEGFA were increased, and miR-126 expression was decreased in vascular endothelial cells (VECs) from the right brain of model mice and human brain microvascular endothelial cells (HBMECs) treated by thrombin. Overexpression of FENDRR promoted the apoptosis of HBMECs. FENDRR regulating VEGFA participated in HBMECs apoptosis through targeting miR-126. Downregulation of FENDRR was indicated to relieve the HICH in mice. CONCLUSIONS: FENDRR could promote the apoptosis of HBMECs via miR-126 regulating VEGFA in HICH.

Comparison of clinical outcomes in patients with acute ischemic stroke who underwent endovascular treatment using different perfusion modalities: a real-world multicenter study.

Background: Advanced perfusion modalities are increasingly popular for various diseases. However, few studies have focused on contrasting perfusion patterns. Objective: This study aimed to compare the time efficiency and clinical outcomes of patients with acute ischemic stroke (AIS) who underwent endovascular treatment (EVT) before one-stop arterial spin labeling (ASL) and computed tomography perfusion (CTP) protocols. Methods: This study retrospectively included 326 patients with AIS who had accepted EVT within 24 h of onset from four comprehensive stroke centers between October 2017 and September 2022. After 1:1 matching of the propensity scores, 202 patients were separated into two groups: the ASL group (n = 101) and the CTP group (n = 101). Results: Functional independence at 90 days (modified Rankin Scale [mRS] 0-2; p = 0.574), onset-to-puncture time (p = 0.231), door-to-puncture time (p = 0.136), and door-to-perfusion time (p = 0.646) were not significantly different between the two groups. The proportion of EVT complications (31.7% in the ASL group vs. 14.9% in the CTP group, p = 0.005) and symptomatic intracranial hemorrhage (sICH) at 24 h (23.8% in the ASL group vs. 9.9% in the CTP group, p = 0.008) in the CTP group were lower than the ASL group. The ischemic core volume was a common predictor of favorable outcomes in both ASL (p < 0.001) and CTP (p < 0.001) groups. Conclusion: There were no significant differences in time efficiency and efficacy outcomes between the two groups of patients receiving one-stop ASL and CTP. The proportion of sICH at 24 h and EVT complications of patients in the CTP group was lower than the ASL group. The ischemic core volume was an independent predictor for favorable outcomes.

Aggregation-induced emission enhancement (AIEE) of tetrarhenium(I) metallacycles and their application as luminescent sensors for nitroaromatics and antibiotics.

The self-assembly of tetrarhenium metallacycles [{Re(CO)3}2(µ-dhaq)(µ-N-N)]2 (3a, N-N = 1,3-bis(1-butylbenzimidazol-2-yl)benzene; 3b, N-N = 1,3-bis(1-octylbenzimidazol-2-yl)benzene), (H2-dhaq = 1,4-dihydroxy-9,10-anthraquinone) and [{Re(CO)3}2(µ-thaq)(µ-N-N)]2 (4, N-N = 1,3-bis(1-butylbenzimidazol-2-yl)benzene), (H2-thaq = 1,2,4-trihydroxy-9,10-anthraquinone) under solvothermal conditions is described. The metallacycles 3a,b and 4 underwent aggregation-induced emission enhancement (AIEE) in THF upon the incremental addition of water. TEM images revealed that metallacycle 3a in a 60% aqueous THF solution formed rectangular aggregates with a wide size distribution, while a 90% aqueous THF solution resulted in the formation of a mixture of nanorods and amorphous aggregates due to rapid and abrupt aggregation. UV-vis and emission spectral profiles supported the formation of nanoaggregates of metallacycles 3a,b and 4 upon the gradual addition of water to a THF solution containing metallacycles. Further studies indicated that these nanoaggregates were excellent probes for the sensitive and selective detection of nitro group containing picric acid (PA) derivatives as well as antibiotics.

Bacterial Signatures of Cerebral Thrombi in Large Vessel Occlusion Stroke.

It is important to understand the microbial features of the cerebral thrombus and its clinical relevance in stroke patients, of which data were scarce. We aimed to investigate the microbial features of cerebral thrombi retrieved via thrombectomy in stroke patients with large vessel occlusion (LVO) and their correlations with 3-month mortality. In a prospective cohort study, thrombus samples were collected during mechanical thrombectomy in LVO stroke patients with successful revascularization at a tertiary hospital. Oral, fecal, and isolated plasma samples were collected within 12 h of admission. The microbial compositions of all samples were compared using 16S rRNA gene amplicon next-generation sequencing. Fluorescent in situ hybridization (FISH) was used to detect bacteria in thrombus samples. The primary outcome was 3-month mortality. Perioperative adverse events (AEs) within 48 h were also recorded. Bacterial DNA was detected in 96.2% of thrombus samples from 104 patients, and clusters of bacterial signals were seen in the thrombi with FISH. Compared with fecal and oral samples, the thrombus microbiota was mainly characterized by excessive enrichment of Proteobacteria, mainly originating from plasma. The bacterial concentrations, dominant bacteria, and distribution patterns differed in thrombi obtained from cardioembolic and large-artery atherosclerotic strokes. Higher abundances of Acinetobacter and Enterobacteriaceae were associated with a higher risk of perioperative AEs, and a higher abundance of Acinetobacter was independently associated with a higher risk of 90-day mortality. This study demonstrated the presence of bacteria in cerebral thrombi retrieved with thrombectomy in LVO strokes, with some bacteria associated with patients' prognoses. IMPORTANCE In this study, we (i) checked for the presence of bacteria in cerebral thrombi in over 95% of the LVO stroke patients using 16S rRNA sequencing, in contrast with periprocedural control samples that are bacteria negative; (ii) visualized clusters of bacterial signals in the thrombi using FISH; and (iii) cultivated Lactobacillus vaginalis, Bacillus cereus, and Kocuria marina in the bacterial culture of the tissue fragment solution of thrombus aspirates. We found excessive enrichment of Proteobacteria in the thrombi, mainly originating from plasma, as indicated with fast expectation-maximization microbial source tracking (FEAST). Different bacterial concentrations, dominant bacteria, and distribution patterns were found in thrombi obtained from cardioembolic and large-artery atherosclerotic LVO strokes. There was an association between higher abundances of Acinetobacter and Enterobacteriaceae in the thrombi and a higher risk of perioperative adverse events and an association between a higher abundance of Acinetobacter in the thrombi and a higher risk of 90-day mortality.

Development of Machine Learning Tools for Predicting Coronary Artery Disease in the Chinese Population.

Purpose: Coronary artery disease (CAD) is one of the major cardiovascular diseases and the leading cause of death globally. Blood lipid profile is associated with CAD early risk. Therefore, we aim to establish machine learning models utilizing blood lipid profile to predict CAD risk. Methods: In this study, 193 non-CAD controls and 2001 newly-diagnosed CAD patients (1647 CAD patients who received lipid-lowering therapy and 354 who did not) were recruited. Clinical data and the result of routine blood lipids tests were collected. Moreover, low-density lipoprotein cholesterol (LDL-C) subfractions (LDLC-1 to LDLC-7) were classified and quantified using the Lipoprint system. Six predictive models (k-nearest neighbor classifier (KNN), logistic regression (LR), support vector machine (SVM), decision tree (DT), multilayer perceptron (MLP), and extreme gradient boosting (XGBoost)) were established and evaluated by the confusion matrix, area under the receiver operating characteristic (ROC) curve (AUC), recall (sensitivity), accuracy, precision, and F1 score. The selected features were analyzed and ranked. Results: While predicting the CAD development risk of the CAD patients without lipid-lowering therapy in the test set, all models obtained AUC values above 0.94, and the accuracy, precision, recall, and F1 score were above 0.84, 0.85, 0.92, and 0.88, respectively. While predicting the CAD development risk of all CAD patients in the test set, all models obtained AUC values above 0.91, and the accuracy, precision, recall, and F1 score were above 0.87, 0.94, 0.87, and 0.92, respectively. Importantly, small dense LDL-C (sdLDL-C) and LDLC-4 play pivotal roles in predicting CAD risk. Conclusions: In the present study, machine learning tools combining both clinical data and blood lipid profile showed excellent overall predictive power. It suggests that machine learning tools are suitable for predicting the risk of CAD development in the near future.

Outcome of endovascular treatment within and beyond 6 h without perfusion software.

Endovascular treatment (EVT) has been accepted as the standard of care for patients with acute ischemic stroke. The aim of the present study was to compare clinical outcomes of patients who received EVT within and beyond 6 h from symptom onset to groin puncture without perfusion software in Guangdong district, China. Between March 2017 and May 2018, acute ischemic stroke patients who received EVT from 6 comprehensive stroke centers, were enrolled into the registry study. In this subgroup study, we included all patients who had acute proximal large vessel occlusion in the anterior circulation. The demographic, clinical and neuroimaging data were collected from each center. A total of 192 patients were included in this subgroup study. They were divided into two groups: group A (n = 125), within 6 h; group B (n = 67), 6-24 h from symptom onset to groin puncture. There were no substantial differences between these two groups in terms of 90 days favorable outcome (modified Rankin scale [mRS] ≤ 2, P = 0.051) and mortality (P = 0.083), and the risk of symptomatic intracranial hemorrhage at 24 h (P = 0.425). The NIHSS (median 16, IQR12-20, group A; median 12, IQR8-18, group B; P = 0.009) and ASPECTS (median 10, IQR8-10, group A; median 9, IQR8-10, group B; P = 0.034) at baseline were higher in group A. The anesthesia method (general anesthesia, 21.3%, group A vs. 1.5% group B, P = 0.001) were also statistically different between the two groups. The NIHSS and ASPECTS were higher, and general anesthesia was also more widely used in group A. Clinical outcomes were not significantly different within 6 h versus 6-24 h from symptom onset to groin puncture in this real world study.

High-Degree Middle Cerebral Artery Stenosis : Can Advanced 3D DSA-MRI Fusion Imaging Better Illustrate Plaques and Perforators?

PURPOSE: Endovascular treatment in severe middle cerebral artery (MCA) stenosis is controversial owing to high rates of periprocedural complications, especially occlusion of the lenticulostriate arteries (LSA). The characteristics of LSAs and the spatial relationships between MCA plaques and LSAs using the fusion of three-dimensional (3D) digital subtraction angiography (DSA) and magnetic resonance imaging (3D DSA-MRI fusion) were investigated. METHODS: We retrospectively analyzed data from 32 ischemic stroke or transient ischemic attack patients with severe MCA stenosis, who underwent MRI and DSA within 2 weeks after symptom onset. The patients were divided into culprit and non-culprit MCA stenosis groups. The 3D DSA-MRI fusion was performed on dedicated workstations, which allowed automated overlays of the target vessels. The characteristics of LSAs, plaque distribution and lesion patterns, and their relationships were evaluated. RESULTS: The 3D DSA-MRI fusion image was able to illustrate the spatial relationships between MCA plaques and LSA orifices. Of 42 LSA stems in 32 patients, 10 had MCA plaque over the LSA orifice and were all found in the culprit MCA stenosis group. Over half (51.9%) of the LSA stems in patients with culprit MCA stenosis originated from the stenotic MCA segment. The MCA plaque-LSA orifice spatial relationships were classified into four types, which were significantly different between the two groups (p = 0.016). CONCLUSION: The 3D DSA-MRI fusion technique enables visualization of the LSA orifice and MCA plaque and their spatial relationships. This classification of the type of spatial relationships can provide insights into the pathogenesis of MCA stroke and useful guides for treatment strategies.

Predicting mortality in acute ischaemic stroke treated with mechanical thrombectomy: analysis of a multicentre prospective registry.

OBJECTIVES: We aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT). DESIGN: Analysis of a multicentre prospective registry. SETTING: In six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively. PARTICIPANTS: 224 patients with AIS were treated by MT. RESULTS: Of 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality. CONCLUSIONS: We developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR-OOC-17013052).

The protective action of topiramate on dopaminergic neurons.

BACKGROUND: The present study analyzed the neuroprotective effects of topiramate on 6-hydroxydopamine (6-OHDA)-induced toxicity in primary dopaminergic mesencephalic neuronal cell cultures. MATERIAL/METHODS: Through the use of tyrosine hydroxylase and microtubule-associated protein 2 immunocytochemistry, the morphology and development of dopaminergic neurons was observed. Hoechst33258 and propidium iodide (PI) double staining was used to determine cell membrane penetrability and apoptosis by fluorescent microscopy. Methyl thiazole tetrazolium was used to assay cell viability and metabolism. The cells were assigned to 3 groups: (1) control: primary cultured neurons; (2) 6-OHDA: primary cultured neurons and 6-OHDA; and (3) topiramate (TPM) protection: primary cultured neurons and 6-OHDA, treated with various concentrations (10, 50, and 100 microM) of TPM. RESULTS: Hoechst 33258 and PI double immunofluorescence revealed that the number of dying cells after 6-OHDA treatment was greater than after TPM treatment. Compared with the 6-OHDA group, there were more neurons with greater cell viability in the 6-OHDA plus TPM group. CONCLUSIONS: Topiramate was shown to provide protection to dopaminergic neurons exposed to 6-OHDA by reducing cell apoptosis and enhancing cell viability. The neuroprotective effects of TPM were dose-dependent.

The Prognostic Value of Homocysteine in Acute Ischemic Stroke Patients: A Systematic Review and Meta-Analysis.

Background: This comprehensive meta-analysis aimed to assess whether an increased homocysteine (Hcy) level is an independent predictor of unfavorable outcomes in acute ischemic stroke (AIS) patients. Methods: A comprehensive literature search was conducted up to August 1, 2020 to collect studies reporting Hcy levels in AIS patients. We analyzed all the data using Review Manager 5.3 software. Results: Seventeen studies with 15,636 AIS patients were selected for evaluation. A higher Hcy level was associated with a poorer survival outcome (OR 1.43, 95% CI: 1.25-1.63). Compared with the AIS group, Hcy levels were significantly lower in the healthy control patients, with an SMD of 5.11 and 95% CI (1.87-8.35). Analysis of the different subgroups of AIS demonstrated significant associations between high Hcy levels and survival outcomes only in Caucasian and Asian patients. Moreover, whereas high Hcy levels were closely associated with gender, B12 deficiency, smoking, and patients who received tissue plasminogen activator treatment, no significant difference was found between increased Hcy levels and age, drinking, hypertension, diabetes mellitus, and hyperlipidemia. In addition, the cut-off value (20.0 µmol/L) might be an optimum cut-off index for AIS patients in clinical practice. Conclusion: This meta-analysis reveals that the Hcy level may serve as an independent predictor for unfavorable survival outcomes in AIS patients, particularly in Caucasian and Asian AIS patients. Further studies can be conducted to clarify this relationship.

Differences in Pathological Composition Among Large Artery Occlusion Cerebral Thrombi, Valvular Heart Disease Atrial Thrombi and Carotid Endarterectomy Plaques.

Background and Purpose: Acute ischemic stroke (AIS) with large artery occlusion (LAO) may lead to severe disability or death if not promptly treated. To determine the source of cerebral artery occlusion thrombosis, we studied the pathological components of cerebral artery thrombosis with different etiological classifications to guide clinical formulation of preventive treatment. Materials and Methods: Eighty-eight thrombi from AIS patients with LAO, 12 atrial thrombi from patients with valvular heart disease (VHD), and 11 plaques obtained by carotid endarterectomy (CEA) from patients with carotid artery stenosis were included in this retrospective study. The hematoxylin and eosin-stained specimens were quantitatively analyzed for erythrocytes, white blood cells (WBCs) and fibrin; platelets were shown by immunohistochemistry for CD31. Results: The thrombi of VHD showed the highest percentage of fibrin, followed by those of cardioembolism (CE) and stroke of undetermined etiology (SUE), and these values were higher than those of the other groups. Plaques obtained by CEA showed the highest erythrocyte number, followed by the large artery atherosclerosis (LAA) thrombi, and showed significantly noticeable differences between other stroke subtypes. The proportions of fibrin and erythrocytes in the thrombi of CE and SUE were most similar to those in the thrombi of VHD, and the LAA thrombi were the closest to those obtained by CEA. CE thrombi and CEA plaques had a higher percentage of WBCs than thrombi of other stroke thrombus subtypes and VHD. Conclusions: CE and most cryptogenic thrombi may originate from the heart, and the formation of carotid atherosclerotic plaques may be related to atherosclerotic cerebral embolism. Inflammation may be involved in their formation.

Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists?

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA(A) receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA(A) receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABA(A) receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

Different Benzodiazepines Bind with Distinct Binding Modes to GABAA Receptors.

Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is controversially debated in the literature, and in silico studies led to discrepant binding mode hypotheses. In this study, computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the seven-membered diazepine ring), could possibly provide experimental evidence that supports or contradicts the proposed binding modes. Thus, we investigated three pairs of R and S isomers of structurally different chemotypes, namely, diazepam, imidazobenzodiazepine, and triazolam derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrophysiology in α1ß3γ2-, α2ß3γ2-, α3ß3γ2-, and α5ß3γ2-containing GABAA receptors to determine the ligand binding and functional activity of the three chemotypes. Interestingly, both imidazobenzodiazepine isomers displayed comparable binding affinities, while for the other two chemotypes, a discrepancy in binding affinities of the different isomers was observed. Specifically, the R isomers displayed a loss of binding, whereas the S isomers remained active. These findings are in accordance with the results of our in silico studies suggesting the usage of a different binding mode of imidazobenzodiazepines compared to those of the other two tested chemotypes. Hence, we conclude that different chemically related benzodiazepine ligands interact via distinct binding modes rather than by using a common binding mode.

Cascade approach toward the core structure of neosarpagine.

[reaction: see text] A palladium-catalyzed domino sequence was developed to rapidly construct the core structure of neosarpagine and other quinuclidine-related alkaloids. The cyclization of ketone 11 to ethylidene 4 with Pd(dba)2, DPEphos, LiHMDS, and ZnCl2 in THF represents a new domino process wherein a nonstabilized enolate served as a nucleophile.

Enhanced sucrose pellet consumption induced by benzodiazepine-type drugs in squirrel monkeys: role of GABAA receptor subtypes.

RATIONALE: Benzodiazepine agonists characteristically increase food intake in humans and non-human subjects, and the underlying mechanisms of this effect are not understood completely. OBJECTIVE: Compounds with selectivity for GABAA receptor subtypes were used to evaluate the role of GABAA receptors containing alpha1 and alpha5 subunits (alpha1GABAA and alpha5GABAA receptors, respectively) in benzodiazepine-induced increases in sucrose pellet consumption. MATERIALS AND METHODS: Adult male squirrel monkeys (N=4-6), maintained under free-feeding conditions, were administered with intramuscular injections of the nonselective benzodiazepines diazepam and alprazolam, the alpha1GABAA-preferring compounds zolpidem and zaleplon, or the alpha5GABAA-preferring agonist QH-ii-066 before daily 10-min periods when sucrose pellets were available. In a separate experiment, observable behavioral effects (e.g., ataxia and procumbent posture) were quantified after administration of alprazolam, zaleplon, and QH-ii-066. To further assess the roles of GABAA receptor subtypes, zolpidem-induced increases in pellet consumption were re-evaluated after pretreatment with nonselective antagonist flumazenil, the alpha1GABAA-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (BCCT), or QH-ii-066. RESULTS: Alprazolam, diazepam, zolpidem, and zaleplon but not QH-ii-066 significantly increased sucrose pellet consumption. In addition, all agonists decreased locomotion and environment-directed behavior as well as engendered ataxia and procumbent posture. For all compounds except QH-ii-066, these behaviors occurred at doses similar to those that increased pellet consumption. Flumazenil and BCCT, but not QH-ii-066, antagonized zolpidem-induced increases in pellet consumption in a surmountable fashion. CONCLUSION: These results suggest that the alpha1GABAA receptor subtype plays a key role in benzodiazepine-induced increases in consumption of palatable food, whereas the alpha5GABAA receptor subtype may not be involved in this effect.