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BACKGROUND: This research explored the factors influencing early neurological outcomes (ENO) in patients who had vertebrobasilar artery occlusion (VBAO) and received endovascular treatment (EVT), as well as examining the causal influence of ENO on the prognosis of VBAO patients. METHODS: A retrospective review was carried out on patients from 65 Chinese stroke centers, all within 24 hours of the estimated occlusion time. ENO includes early neurological improvement (ENI) and early neurological deterioration (END), defined as a decrease or an increase of at least 4 points in NIHSS score between baseline and 24 hours after EVT. Death within 24 hours after EVT also consider as END. END was further divided into explainable END and unexplainable END (unEND). Independent predictors of ENO and the association between ENO and outcomes in patients with VBAO were determined using center-adjusted analyses. The study developed a multivariate logistic regression model to examine the comparative risk of unEND versus explainable END on the clinical outcomes in VBAO patients. RESULTS: A total of 2257 patients were included. Glasgow Coma Scale (GCS) (OR 1.16, 95% CI 1.03-1.30) and successful reperfusion (OR 1.15, 95% CI 1.02-1.30) were associated with ENI. Baseline NIHSS (OR 0.60, 95% CI 0.53-0.68), successful reperfusion (OR 0.79, 95% CI 0.71-0.89) and puncture to reperfusion time (OR 1.17, 95% CI 1.03-1.33) were associated with END. When examining three-month prognostic indexes, both END and ENI were found to be linked to the three-month outcomes, but in opposite directions. A subgroup analysis of END suggested that unexplained END typically demonstrated a more favorable prognosis compared to explained END, although the prognosis remained generally unfavorable. CONCLUSIONS: ENO, whether they manifested as early improvement or deterioration, were linked to the prognosis of VBAO patients undergoing EVT. The outcomes after unEND were more favorable than those following explained END.
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BACKGROUND: Among acute vertebrobasilar artery occlusion (VBAO) patients, successful reperfusion is a strong predictor of favorable outcomes. However, failed reperfusion (FR) with endovascular thrombectomy (EVT) in VBAO was observed to occur in 18-50% of cases. We aim to evaluate the safety and efficacy of rescue stenting (RS) for VBAO after failed EVT. METHODS: Patients with VBAO who received EVT were enrolled retrospectively. Propensity score matching was performed as the primary analysis to compare the outcomes between patients with RS and FR. Furthermore, a comparison between using the self-expanding stent (SES) and balloon-mounted stent (BMS) in the RS group was also conducted. The primary and secondary outcomes were defined as a 90-day modified Rankin Scale (mRS) score 0-3, and a 90-day mRS score 0-2, respectively. Safety outcomes included all-cause mortality at 90 days and symptomatic intracranial hemorrhage (sICH). RESULTS: The RS group showed a significantly higher rate of 90-day mRS score 0-3 (46.6% vs 20.7%; adjusted OR (aOR) 5.06, 95% CI 1.88 to 13.59, P=0.001) and a lower rate of 90-day mortality (34.5% vs 55.2%; aOR 0.42, 95% CI 0.23 to 0.90, P=0.026) than the FR group. The rates of 90-day mRS score 0-2 and sICH were not significantly different between the RS group and FR group. There were no differences in all outcomes between SES and BMS groups. CONCLUSIONS: RS appeared to be a safe and effective rescue approach in patients with VBAO who failed EVT, and there was no difference between using SES and BMS.
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Procedimientos Endovasculares , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/cirugía , Accidente Cerebrovascular/etiología , Resultado del Tratamiento , Estudios Retrospectivos , Procedimientos Endovasculares/efectos adversos , Trombectomía/efectos adversos , Hemorragias Intracraneales/etiología , Sistema de Registros , Stents , ArteriasRESUMEN
Background: Inflammatory burden index (IBI) is a systemic inflammation indicator that reflects the inflammatory status. We aimed to investigate the prognostic value of IBI after endovascular thrombectomy (EVT) in patients with acute ischemic stroke. Methods: We enrolled patients treated with EVT from a multicenter cohort between June 2020 and December 2021. The IBI was calculated as C-reaction protein × neutrophil / lymphocyte count. The primary outcome was the unfavorable functional outcome (90-day modified Rankin scale score 3-6). C-statistics and net reclassification indexes were used to assess the predictive accuracy. Multivariable logistic regression models were used to investigate the association between IBI and unfavorable outcome. Results: A total of 295 patients (mean age, 64.0 ± 12.8 years; male, 63.7%) were enrolled in this study. In multivariable models, higher IBI levels were associated with an increased risk of 90-day unfavorable outcome after EVT (per 1-SD: odds ratio, 1.754; 95% confidence interval, 1.241-2.587; P = 0.002). Restricted cubic spline curve displayed a linear relationship between the IBI level and 90-day unfavorable outcome (P for nonlinearity = 0.410). Besides, IBI was a more accurate biomarker for predicting unfavorable outcomes with the highest predictive accuracy and reclassification indexes. Conclusion: This study demonstrated that higher IBI was associated with an increased risk of 90-day unfavorable outcome in acute ischemic stroke treated with EVT.
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BACKGROUND: Acute vertebrobasilar artery occlusion (VBAO) is a devastating disease in stroke patients. This study was aimed to identify the initial symptoms of patients with acute VBAO receiving endovascular treatment and determine its associations with clinical outcomes. METHODS: Patients with VBAO receiving endovascular treatment at 21 stroke centres in China were recruited for this derivation cohort A data-driven approach of latent class analysis was applied to identify distinct symptom typologies of VBAO patients. Multivariable binary and ordinary logistic regressions were used to evaluate the associations between symptom subtypes and clinical outcomes. RESULTS: A total of 548 patients were analysed in this study. Four distinct subgroups were defined: the vestibular symptom group (32.8%), anterior circulation mimic group (26.5%), non-specific symptom group (14.8%) and severe VBAO symptom group (25.9%). Compared with severe VBAO symptoms, non-specific symptoms were independently associated with higher rates of favourable outcome and functional independence at the 3 months [odds ratio (OR) 2.46, 95% confidence interval (CI) 1.15-5.28; OR 3.46, 95% CI 1.54-7.79]and 1 year follow-up (OR 2.25, 95% CI 1.05-4.82; OR 2.69, 95% CI 1.22-5.92), and better functional improvement (shift in mRS score) at the 3 months (OR 2.05, 95% CI 1.15-3.67). CONCLUSION: We identified four distinctive subtypes based on the initial symptoms of VBAO patients. Severe VBAO symptoms were associated with poor outcomes while non-specific and vestibular symptoms were indicators of a favourable outcome.
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Arteriopatías Oclusivas , Procedimientos Endovasculares , Accidente Cerebrovascular , Insuficiencia Vertebrobasilar , Arteriopatías Oclusivas/complicaciones , Arterias , Procedimientos Endovasculares/efectos adversos , Humanos , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/cirugía , Trombectomía , Resultado del Tratamiento , Insuficiencia Vertebrobasilar/diagnóstico por imagen , Insuficiencia Vertebrobasilar/cirugíaRESUMEN
BACKGROUND: Renal impairment (RI) is associated with worse outcomes in the treatment of intravenous thrombolysis and emergent endovascular treatment (EVT) in anterior circulation stroke. The objective of this study was to investigate the association of RI with short-term and long-term outcomes in patients with vertebrobasilar artery occlusions (VBAO) who received EVT. METHODS: Consecutive patients with VBAO receiving EVT involving 21 stroke centers were retrospectively included. Multivariate regression analyses were used to evaluate the association of RI with mortality and symptomatic intracranial hemorrhage (sICH) during the hospital stay, and also mortality, favorable functional outcome (modified Rankin Scale (mRS) score of 0-3), and functional improvement (shift in mRS score) at 3 months and 1 year follow-up. The association between RI and the risk of recurrent stroke was evaluated with multivariate competing-risk regression analyses. RESULTS: After adjustment for potential confounders, RI was independently associated with sICH (OR 3.30, 95% CI 1.55 to 7.18), as well as mortality (OR 2.54, 95% CI 1.47 to 4.38; OR 3.07, 95% CI 1.72 to 8.08), favorable functional outcome (OR 0.33, 95% CI 0.17 to 0.66; OR 0.25, 95% CI 0.12 to 0.51), and functional improvement (OR 0.45, 95% CI 0.28 to 0.74; OR 0.35, 95% CI 0.21 to 0.60) at 3 months and 1 year follow-up, respectively, but RI was not associated with in-hospital mortality. Additionally, there was no significant association between RI and recurrent stroke within 1 year. CONCLUSIONS: Our findings suggest that RI is associated with a higher risk of sICH in hospital and a decrease in survival, favorable functional outcome, and functional improvement at 90 days and 1 year follow-up. TRIAL REGISTRATION NUMBER: URL: http://www.chictr.org.cn/; Unique identifier: ChiCTR2000033211.
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Arteriopatías Oclusivas , Procedimientos Endovasculares , Accidente Cerebrovascular , Arterias , Procedimientos Endovasculares/efectos adversos , Humanos , Hemorragias Intracraneales , Estudios Retrospectivos , Accidente Cerebrovascular/terapia , Trombectomía , Resultado del TratamientoRESUMEN
Hemorrhagic transformation (HT) is a major complication of ischemic stroke and further deteriorates neurological outcomes. Bradykinin 1 receptor (B1R) has been proven to mediate vasculo-toxicity in various experimental models. However, its role in the development of HT after stroke remains unclear. We detected the B1R expression in brain tissues with or without HT in a rat model of cerebral ischemia/reperfusion (I/R) with type 1 diabetes, showing higher B1R expression in the hemorrhagic areas than the ischemic tissues. Then, B1R agonist or antagonist was administrated intravenously just before reperfusion to investigate its effect on HT and the underlying molecular mechanism. Administration of low (300 nmol/kg) or high (1 µmol/kg) dose of B1R antagonist mitigated hemorrhage, improved neurobehavioral deficits, and preserved blood-brain-barrier (BBB) integrity after reperfusion for 8 h whereas the 300 nmol/kg of B1R agonist aggravated these outcomes, though only the high does of B1R antagonist affected the infarction volume. Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was increased by B1R activation but decreased by B1R inhibition, which mediated B1R toxicity on BBB disruption and ischemia-related HT. Furthermore, B1R activation facilitated the mRNA and protein expressions of MMP-9 in the hemorrhagic tissues, and these increases were blocked by both ERK inhibitor U0126 and NF-κB inhibitor PDTC. U0126 also remarkably decreased the B1R-induced NF-κB/p65 activation. We concluded that upregulated B1R may contribute to early HT after I/R in type 1 diabetic rats via ERK1/2/NF-κB/MMP-9 pathway. B1R inhibition could be an encouraging therapeutic strategy to withstand HT after ischemic stroke in diabetic patients.
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Hemorragia Cerebral/metabolismo , Receptor de Bradiquinina B1/metabolismo , Accidente Cerebrovascular/patología , Animales , Hemorragia Cerebral/patología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1 , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiología , Accidente Cerebrovascular/metabolismoRESUMEN
Functional connectivity (FC) between the subthalamic nucleus (STN) and the sensorimotor cortex is increased in off-medication patients with Parkinson's disease (PD). However, the status of FC between STN and sensorimotor cortex in on-medication PD patients remains unclear. In this study, resting state functional magnetic resonance imaging was employed on 31 patients with PD under medication and 31 healthy controls. Two-sample t-test was used to study the change in FC pattern of the STN, the FC strength of the bilateral STN was correlated with overall motor symptoms, while unilateral STN was correlated with offside motor symptoms. Both bilateral and right STN showed increased FC with the right sensorimotor cortex, whereas only right STN FC was correlated with left-body rigidity scores in all PD patients. An additional subgroup analysis was performed according to the ratio of mean tremor scores and mean postural instability and gait difficulty (PIGD) scores, only the PIGD subgroup showed the increased FC between right STN and sensorimotor cortex under medication. Increased FC between the STN and the sensorimotor cortex was found, which was related to motor symptom severity in on-medication PD patients. Anti-PD drugs may influence the hyperdirect pathway to alleviate motor symptoms with the more effect on the tremor subtype.
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BACKGROUND AND PURPOSE: Parkinson's disease (PD) patients frequently present visual hallucinations (VHs)·The determinants of VHs in Chinese PD patients remain largely unknown. The aim of this study was to illuminate the prevalence and clinical correlates of VHs in the Chinese population with PD. METHODS: A total of 371 consecutive, idiopathic PD patients were recruited into the study. Patients were categorized as hallucinators and nonhallucinators according to Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: VHs were observed in 72 (19.4%) patients. Among them, 26.4% of the hallucinators experienced minor hallucinations, and 73.6% had complex visual hallucinations. The age, disease duration, percentage of patients using dopamine agonists, UPDRS part III, Hoehn and Yahr (H-Y) stage, and Non-Motor Symptoms Questionnaire (NMS-Quest) score in hallucinators were significantly greater than in nonhallucinators (P<0.05). The Montreal Cognitive Assessment (MOCA) and PD Sleep Scale (PDSS) scores in nonhallucinators were significantly higher than in hallucinators (P<0.05). The Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) scores were not different between the hallucinators and nonhallucinators. The forward binary logistic regression model showed that disease duration, dopamine agonist use, sleep quality, and cognition were associated with VHs in PD patients. CONCLUSIONS: Our results confirm the high prevalence of VHs in patients with PD. The VHs are associated with duration, dopamine agonist use, sleep quality, and cognition, and should trigger further inquiry by neurologists.
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Alucinaciones/epidemiología , Alucinaciones/etiología , Enfermedad de Parkinson/complicaciones , Anciano , Pueblo Asiatico , Distribución de Chi-Cuadrado , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Prevalencia , Escalas de Valoración Psiquiátrica , Estudios Retrospectivos , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
In-stent restenosis (ISR) following intracranial artery stenting affects long-term clinical outcome. This randomized controlled trial sought to identify the long-term efficacy of exogenous tissue kallikrein (TK) for preventing ISR after intracranial stenting of symptomatic middle cerebral artery (MCA) atherosclerotic stenosis.Sixty-one patients successfully treated with intracranial stenting for symptomatic MCA M1 segment stenosis (>70%) were enrolled and randomized into 2 groups: control group and TK group. Patients in the TK group received human urinary kallidinogenase for 7 days, followed by maintenance therapy of pancreatic kallikrein for 6 months. The primary end point was angiographically verified ISR at 6 months, and secondary end points included vascular events and death within 12 months. Endogenous TK plasma concentrations of patients were measured before stenting and at the 6-month follow-up time-point.Patients in the TK group had lower occurrence rates of ISR and vascular events than patients in the control group. There was no difference in endogenous TK levels in plasma at 6 months postoperatively between the TK and control groups. Further subgroup analysis revealed that patients without ISR had higher endogenous TK levels at baseline and lower concentrations at 6 months postoperatively compared with patients who underwent ISR.Exogenous TK is effective for the prevention of ISR after intracranial stenting.
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Arteriosclerosis Intracraneal/prevención & control , Arteriosclerosis Intracraneal/cirugía , Arteria Cerebral Media , Stents , Calicreínas de Tejido/uso terapéutico , Constricción Patológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Effective treatments against restenosis after percutaneous transluminal angioplasty and stenting are largely lacking. Human tissue kallikrein gene transfer has been shown to be able to attenuate neointima formation induced by balloon catheter. As a tissue kallikrein in vivo, human urinary kininogenase (HUK) is widely used to prevent ischemia-reperfusion injury. However, the effects of HUK on neointima formation have not been explored. We therefore investigated whether HUK could alleviate balloon catheter-induced intimal hyperplasia in rabbits fed with high-fat diets. METHODS: The effects of HUK on neointima and atherosclerosis formation were analyzed by hematoxylin-eosin staining and immunohistochemical staining in balloon-injured carotid arteries of rabbits. Local inflammatory response was evaluated by detecting the gene expression of tumor necrosis factor α and interleukin 1ß with real-time quantitative polymerase chain reaction plus the invasion of macrophages with immunohistochemical staining. Western blotting was employed to investigate the effects of HUK on activities of endothelial nitric oxide synthase (eNOS), transforming growth factor ß1 (TGF-ß1), and Smad signaling pathway. The long-term effect of HUK on intimal hyperplasia of the injured carotid artery was assessed by angiography. RESULTS: Quantitative image analysis showed that intravenous administration of HUK for 14 days significantly decreased the intimal areas and intima area/media area ratios (day 14, 54% decrease in intimal area and 58% decrease in intima area/media area ratios; day 28, 63% and 85%). Significant decreases were also noted in macrophage foam cell-positive area after 7-day or 14-day administration of HUK (day 7, 69% decrease in intimal area and 78% decrease in media area; day 14, 79% and 60%; day 28, 68% and 44%). Actin staining for smooth muscle cells in neointima at 2 months showed similar results (vascular smooth muscle cell-positive area of neointima, 28.21% ± 5.58% vs 43.78% ± 8.36%; P < .05). Real-time quantitative polymerase chain reaction or Western blot analysis showed that HUK reduced expression of tumor necrosis factor α, interleukin 1ß, TGF-ß1, and p-Smad2/3 but increased the expression of p-eNOS. Angiography analysis showed that 14-day administration of HUK significantly decreased the degree of stenosis (26.8% ± 7.1% vs 47.9% ± 5.7%; P < .01) at 2 months after balloon injury. CONCLUSIONS: Our results indicate that HUK is able to attenuate atherosclerosis formation and to inhibit intimal hyperplasia by downregulating TGF-ß1 expression and Smad2/3 phosphorylation, upregulating eNOS activity. HUK may be a potential therapeutic agent to prevent stenosis after vascular injury.
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Angioplastia de Balón/efectos adversos , Arterias Carótidas/efectos de los fármacos , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Estenosis Carotídea/prevención & control , Calicreínas/farmacología , Neointima , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Orina/química , Administración Intravenosa , Angiografía de Substracción Digital , Animales , Arterias Carótidas/enzimología , Arterias Carótidas/patología , Traumatismos de las Arterias Carótidas/enzimología , Traumatismos de las Arterias Carótidas/genética , Traumatismos de las Arterias Carótidas/patología , Estenosis Carotídea/enzimología , Estenosis Carotídea/genética , Estenosis Carotídea/patología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Esquema de Medicación , Células Espumosas/efectos de los fármacos , Células Espumosas/enzimología , Células Espumosas/patología , Humanos , Hiperplasia , Mediadores de Inflamación/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Calicreínas/administración & dosificación , Calicreínas/orina , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/patología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Conejos , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND AND PURPOSE: The relationship between chronic kidney disease and cerebral small vessel disease (cSVD), especially enlarged perivascular spaces (EPVS), has not been fully understood. This study aimed to investigate the association of chronic kidney disease and EPVS, as well as the total burden of cSVD on magnetic resonance imaging, expressed by the simultaneous presence of multiple markers of cSVD, among patients with first-ever lacunar stroke. METHODS: Four hundred and thirteen consecutive patients were prospectively enrolled. Centrum semiovale and basal ganglia EPVS on T2-weighted magnetic resonance imaging, as well as other imaging markers of cSVD, including lacune, white matter lesions, and cerebral microbleeds, were rated using validated scales. Chronic kidney disease was defined as either reduced estimated glomerular filtration rate or the presence of proteinuria. RESULTS: After adjustments for potential confounders by logistic regression, proteinuria and impaired estimated glomerular filtration rate were correlated with the severity of EPVS in both centrum semiovale (odds ratio [OR] 2.59; 95% confidence interval [CI] 1.19-5.64 and OR 2.37; 95% CI 1.19-4.73) and basal ganglia (OR 5.12; 95% CI 2.70-12.10 and OR 4.17; 95% CI 2.08-8.37). A similar association was also found between proteinuria and low estimated glomerular filtration rate levels and the comprehensive cSVD burden (OR 2.13; 95% CI 1.10-4.14 and OR 5.59; 95% CI 2.58-12.08). CONCLUSIONS: Proteinuria and impaired estimated glomerular filtration rate are associated with increasing EPVS severity and, furthermore, accumulated magnetic resonance imaging burden of cSVD in patients with first-ever acute lacunar stroke.
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Ganglios Basales/patología , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Imagen por Resonancia Magnética , Insuficiencia Renal Crónica/diagnóstico , Accidente Vascular Cerebral Lacunar/diagnóstico , Anciano , Ganglios Basales/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/epidemiología , Enfermedades de los Pequeños Vasos Cerebrales/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/metabolismo , Accidente Vascular Cerebral Lacunar/epidemiología , Accidente Vascular Cerebral Lacunar/metabolismoRESUMEN
BACKGROUND: This study was designed to examine a novel role of COX-2/PGE2 signaling as a regulator of PTPRJ expression in endothelial cells. METHODS: A bioinformatics analysis of a whole genome array was carried out to search for regulators of PTPRJ expression in endothelial cells. PTPRJ expression was also measured in endothelial cells derived from a balloon injury-induced neointimal hyperplasia model in male New Zealand Rabbits. Changes in PTPRJ expression in HUVEC cells was examined by RT-PCR and western blotting after transfection of COX-2 plasmids or treatment with varying concentrations of a COX-2 inhibitor. RESULTS: A significant correlation was identified between COX-2 and PTPRJ in GSE39264 (Pearson correlation coefficient â=â -0.87; n = 22; P < 0.01, two-tailed). PTPRJ expression was reduced during the progression of neointimal hyperplasia after balloon injury, which correlated with an increase in COX-2 expression. In HUVECs, after transfection with 1 µg/ml, 0.5 µg/ml, or 0.25 µg/ml COX-2 plasmids, PTPRJ protein expression was reduced to 0.60- (± 0.08), 0.75- (± 0.09), and 0.88- (± 0.04) fold, respectively, while mRNA expression was reduced to 0.15- (± 0.03), 0.26- (± 0.05), and 0.47- (± 0.09) fold, respectively. After treatment of HUVECs with 10 µmol/L or 20 µmol/L celecoxib, the reduction in PTPRJ expression induced by COX-2 over-expression was not only rescued but in fact increased by 2.05-fold (± 0.28) and 3.34-fold (± 0.37), respectively, compared with control. CONCLUSIONS: Our results suggest that COX-2/PGE2 signaling may function as a negative regulator of PTPRJ expression in endothelial cells both in vivo and vitro.
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Ciclooxigenasa 2/metabolismo , Células Endoteliales/metabolismo , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/metabolismo , Animales , Celecoxib , Células Cultivadas , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Animales de Enfermedad , Células Endoteliales/citología , Regulación de la Expresión Génica/efectos de los fármacos , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hiperplasia/metabolismo , Hiperplasia/patología , Masculino , Pirazoles/farmacología , ARN Mensajero/metabolismo , Conejos , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Sulfonamidas/farmacologíaRESUMEN
Vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of ischemic stroke. However, accumulating evidence demonstrated that VEGF could exacerbate blood-brain barrier (BBB) disruption after ischemic stroke. This study was designed to investigate the underlying mechanisms. In the present study, a transient (90 min) middle cerebral artery occlusion (MCAO) model was performed to induce ischemic stroke in mice. VEGF was administered intracerebroventricularly 3h after reperfusion. A gene expression microarray was utilized to investigate the differentially expressed genes among the sham, MCAO, and VEGF groups. A total of 3381 mRNAs were significantly altered by cerebral ischemia when compared with the sham group, and 15 of them were changed in the VEGF group when compared with the MCAO group. Among the 15 genes, orosomucoid (Orm) 1 was most sharply changed, and this gene has previously been reported to maintain the permeability of microvessels and integrity of the BBB. Results of the microarray showed that the expression of Orm1 increased after cerebral ischemia, whereas it decreased in response to VEGF, which was confirmed by real-time quantitative PCR, western blotting, immunohistochemistry, and immunofluorescence. The bioinformatics analysis indicated two NF-κB binding sites on the Orm1 promoter, and a super-shift assay verified that NF-κB could bind the Orm1 promoter. Results of the electrophoretic mobility shift assay (EMSA) revealed that VEGF inhibited the DNA-binding activity of NF-κB/p65. Furthermore, the elevated expression and activation of key members in the canonical NF-κB pathway induced by cerebral ischemia were also inhibited by VEGF treatment. In conclusion, this study demonstrated that decreasing the Orm1 expression via inhibition of the NF-κB pathway could be a possible mechanism involved in the aggravation of BBB disruption after stroke by VEGF.
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Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Infarto de la Arteria Cerebral Media/patología , Orosomucoide/metabolismo , Factor A de Crecimiento Endotelial Vascular/efectos adversos , Animales , Edema Encefálico/etiología , Infarto Encefálico/diagnóstico , Infarto Encefálico/etiología , Recuento de Células , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Infarto de la Arteria Cerebral Media/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Orosomucoide/genética , Unión Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Traumatic brain injury (TBI) is a considerable cause of mild cognitive impairment and dementia. Intranasal administration of nerve growth factor (NGF) has previously been found to improve cognitive function after TBI, but the mechanism remains unclear. This study aimed to investigate the effects of intranasal NGF on the tau hyperphosphorylation following TBI. A modified Feeney's weight-drop model was used to induce TBI. Rats were randomly divided into control group, TBI group, TBI+NGF group, TBI+PDTC group and TBI+IL-1ra group. Rats in TBI+NGF group were administered with NGF (5 µg/d) for 3d before surgery. Hyperphosphorylated tau protein was remarkable in the peri-contusional cortex area with TBI. Both western blotting and immunostaining results displayed intranasal pretreatment of NGF significantly reduced tau phosphorylation. To evaluate the underlying mechanism, the levels of glycogen synthase kinase 3ß (GSK-3ß), interleukin-1ß (IL-1ß), and the DNA binding activity of nuclear factor-κB (NF-κB) were assayed. NGF markedly inhibited GSK-3ß. NGF also reduced TBI-induced elevation of IL-1ß and NF-κB DNA binding activity. Furthermore, PDTC and IL-1ra were injected to prove a potential signaling pathway among NF-κB, IL-1ß and GSK-3ß. Taken together, these findings demonstrated that intranasal NGF could effectively attenuate the hyperphosphorylation of tau after TBI, which might involve an integrated signaling pathway related to NF-κB.
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Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/patología , Encéfalo/efectos de los fármacos , Factor de Crecimiento Nervioso/administración & dosificación , Proteínas tau/metabolismo , Administración Intranasal , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilación/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Proteínas tau/genéticaRESUMEN
BACKGROUND AND PURPOSE: S100B and its scavenger, soluble receptor for advanced glycation end products (sRAGE), participate in various acute and chronic brain disorders. However, their impact on hemorrhage-prone small vessel disease represented by cerebral microbleeds (CMBs) is unclear. The purpose of this study was to investigate the relationship of CMBs with plasma S100B and sRAGE. METHODS: A cohort of 147 consecutive patients with first-ever acute lacunar stroke was prospectively enrolled. We collected demographic, clinical, and laboratory data, including plasma levels of S100B and sRAGE, and presence and number of CMBs using susceptibility-weighted imaging (SWI). Associations between plasma S100B, sRAGE levels and the presence, number, and location of CMBs were determined. RESULTS: CMBs were present in 58 patients (39.5%). Each 1SD-increase in S100B and sRAGE levels was significantly associated with presence of CMBs (adjusted odds ratio [OR], 3.06; 95% confidence interval [CI], 1.81-5.17 and adjusted OR, 0.29; 95% CI, 0.16-0.53; respectively) and number of CMBs (adjusted relative risk [RR], 4.07; 95% CI, 3.60-5.65 for S100B and RR 0.34; 95% CI, 0.25-0.46 for sRAGE). When stratified by location, plasma S100B and sRAGE levels were similarly associated with presence of deep CMBs (adjusted OR, 3.65; 95% CI, 1.99-6.69 and adjusted OR, 0.23; 95% CI, 0.12-0.46; respectively), but not with strictly lobar CMBs. CONCLUSIONS: Higher levels of S100B and lower levels of sRAGE are independently associated with presence and number of CMBs in patients with first-ever acute lacunar stroke, particularly in those with deep CMBs.
Asunto(s)
Hemorragia Cerebral/sangre , Hemorragia Cerebral/complicaciones , Receptores Inmunológicos/sangre , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Accidente Vascular Cerebral Lacunar/sangre , Accidente Vascular Cerebral Lacunar/complicaciones , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Receptor para Productos Finales de Glicación Avanzada , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
RATIONALE: Many recent studies suggest that the kallikrein-kinin system play a protective role in the impairment of vascular smooth muscle cells and vascular endothelial cell. AIMS: The study aims to determine whether tissue kallikrein is efficacy for preventing the long-term in-stent restenosis after stenting of symptomatic atherosclerotic stenosis of the middle cerebral artery M1 segment. DESIGN: This is a Phase II, randomized, single-blinded, controlled trial. In line with SAMMPRIS stenting indications, patients (n = 90) with the symptomatic the middle cerebral artery M1 segment stenosis ≥ 70% and successfully treated with stent will be enrolled. Eligible patients will be randomized using computer generated numbers, and allocated to receive tissue kallikrein treatment or not. Patients in tissue kallikrein treatment group will be prescribed with intravenous infusion of tissue kallikrein (0.15 PNAU/d, dissolved in 100 ml saline) for 7 days after stenting and then oral administration of pancreatic kallikrein enteric-coated tablet (240 U, 3/d) to the end of study. As the foundation treatment, all the enrolled patients will receive aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage. STUDY OUTCOMES: Patients will be evaluated at 1, 6 and 12 months after stenting. The primary outcomes are the in-stent restenosis rate, new stroke or aggravation of the previous ischemic stroke ipsilateral to the severe stenotic artery. Secondary outcomes include stroke of other artery territories, myocardial infarction and vascular death. Modification of stroke knowledge, exercise and diet habit, smoking cessation and available laboratory data will also be recorded. CONCLUSION: As our pilot study, tissue kallikrein would be expected to prevent the long-term in-stent restenosis after stenting of the symptomatic middle cerebral artery dramatically.
Asunto(s)
Infarto de la Arteria Cerebral Media/cirugía , Arteriosclerosis Intracraneal/inducido químicamente , Arteriosclerosis Intracraneal/prevención & control , Stents/efectos adversos , Calicreínas de Tejido/uso terapéutico , Adulto , Angiografía de Substracción Digital , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Método Simple Ciego , Factores de TiempoRESUMEN
Intraluminal suture middle cerebral artery occlusion (MCAO) model is the most frequently used model for ischemic stroke. However, the success rate of this model is variable among different research studies. This study aimed to investigate the effect of postischemic temperature on the success rate. A total of 100 C57BL/6 mice were randomized into two groups: control group (n=50), body temperature was allowed to self-regulate after MCAO; temperature-controlled group (n=50), mice were kept warm in an incubator for 12 h after MCAO. The body temperature of animals was measured before, during, and for 12 h after MCAO. Neurological deficits and infarct volumes were measured at 24 h after MCAO. There was significant difference (P<0.05) of the body temperature between the two groups from 0.5 h to 3.5 h post ischemia. Moreover, there was obvious difference between the success rates of the two groups (control group: 52%, temperature-controlled group: 84%, P<0.05). In the successful models, infarct volume was significantly (P<0.05) higher in temperature-controlled group (53.44%±9.83%, n=42) than control group (45.63%±10.24%, n=26). There was significant difference of the modified neurological severity scores (P<0.05), left adhesive tests (P<0.05) between the two groups. Our data demonstrated that postischemic warming contributed to the success of mouse MCAO model.