Association of pretreatment ASPECTS scores with tPA-induced arterial recanalization in acute middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: The Alberta Stroke Program Early CT-Score (ASPECTS) assesses early ischemic changes within the middle cerebral artery (MCA) and predicts poor outcome and increased risk for thrombolysis-related symptomatic ICH. We evaluated the potential relationship between pretreatment ASPECTS and tPA-induced recanalization in patients with MCA occlusions. SUBJECTS & METHODS: Consecutive patients with acute ischemic stroke due to MCA occlusion were treated with standard IV-tPA and assessed with transcranial Doppler (TCD) for arterial recanalization. Early recanalization was determined with previously validated Thrombolysis in Brain Ischemia (TIBI) flow-grading system at 120 minutes after tPA-bolus. All pretreatment CT-scans were prospectively scored by trained investigators blinded to TCD findings. Functional outcome at 3 months was evaluated using the modified Rankin Scale (mRS). RESULTS: IV-tPA was administered in 192 patients (mean age 68 +/- 14 years, median NIHSS-score 17). Patients with complete recanalization (n= 51) had higher median pretreatment ASPECTS (10, interquartile range 2) than patients with incomplete or absent recanalization (n= 141; median ASPECTS 9, interquartile range 3, P= .034 Mann-Whitney U-test). An ASPECTS < or =6 was documented in 4% and 17% of patients with present and absent recanalization, respectively (P= .019). Pretreatment ASPECTS was associated with complete recanalization (OR per 1-point increase: 1.54; 95% CI 1.06-2.22, P= .023) after adjustment for baseline characteristics, risk factors, NIHSS-score, pretreatment TIBI grades and site of arterial occlusion on baseline TCD. Complete recanalization (OR: 33.97, 95% CI 5.95-185.99, P < .001) and higher ASPECTS (OR per 1-point increase: 1.91; 95% CI 1.17-3.14, P= .010) were independent predictors of good functional outcome (mRS 0-2). CONCLUSIONS: Higher pretreatment ASPECT-scores are associated with a greater chance of complete recanalization and favorable long-term outcome in tPA-treated patients with acute MCA occlusion.     

慢性肾小球肾炎患者血浆纤溶酶原激活物及其受体和纤溶酶原激活物抑制剂的变化与干预研究

目的探讨慢性肾小球肾炎血浆纤溶酶原激活物及其受体和纤溶酶原激活物抑制剂(PAI-1)的变化意义,血管紧张素转换酶抑制剂(ACEI)治疗的干预影响。方法测定78例慢性肾小球肾炎患者的血浆组织型纤溶酶原激活物(tPA)、尿激酶型纤溶酶原激活物(uPA)及其受体(uPAR)和PAI-1的水平,与健康成年人43人作对照;并观察经ACEI治疗8周后各项指标的改变。结果78例患者血浆uPAR水平明显高于对照组(P<0.05),PAI-1水平显著高于对照组(P<0.01)。予以ACEI(福辛普利)10～20mg/d治疗8周后,ACEI治疗组患者PAI-1水平较常规治疗组患者明显下降(P<0.05)。结论慢性肾小球肾炎患者血浆PAI-1水平明显升高,细胞外基质(ECM)的转化受到抑制;ACEI治疗可降低PAI-1水平,促进ECM的转归,延缓肾脏纤维化。     

慢性肝炎患者血浆vWF及其前肽与纤溶系统测定的临床意义

目的:探讨肝炎患者血浆vWFpp,vWF,tPA,PAI1及DDimer含量及临床意义.方法:利用ELISA法对肝炎组及对照组血浆vWFpp,vWF,tPA,PAI1及DDimer含量进行测定.结果:肝炎组血浆vWFpp(1.54±1.83)mg/L与对照组(0.43±0.09)mg/L有显著差异,P<0.01;vWF(60.30±99.81)mg/L与对照组(11.27±5.34)mg/L有显著差异(P<0.01);tPA(27.87±14.05)μg/L与对照组(16.70±7.13)μg/L有显著差异(P<0.01);PAI1(43.22±13.53)μg/L与对照组(63.37±6.63)μg/L有显著差异(P<0.01);DDimer(1.02±1.36)mg/L含量与对照组(0.60±0.67)mg/L有显著差异(P<0.01).vWFpp含量与vWF,DDime间具有显著的相关性(P<0.01);tPA含量与PAI1含量间亦具有显著的相关性(P<0.05).其他测定项间无显著的相关性.结论:慢性肝炎患者的血液vWFpp,vWF,D二聚体、tPA及PAI1水平能通过不同途径反映肝病时机体的凝血与纤溶系统的状态,且对于病情的判断和预后具有重要意义.     

Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis

Mesenchymal stem cells or multipotent stromal cells (MSCs) have initially captured attention in the scientific world because of their differentiation potential into osteoblasts, chondroblasts and adipocytes and possible transdifferentiation into neurons, glial cells and endothelial cells. This broad plasticity was originally hypothesized as the key mechanism of their demonstrated efficacy in numerous animal models of disease as well as in clinical settings. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly caused by the multitude of bioactive molecules secreted by these remarkable cells. Numerous angiogenic factors, growth factors and cytokines have been discovered in the MSC secretome, all have been demonstrated to alter endothelial cell behavior in vitro and induce angiogenesis in vivo. As a consequence, MSCs have been widely explored as a promising treatment strategy in disorders caused by insufficient angiogenesis such as chronic wounds, stroke and myocardial infarction. In this review, we will summarize into detail the angiogenic factors found in the MSC secretome and their therapeutic mode of action in pathologies caused by limited blood vessel formation. Also the application of MSC as a vehicle to deliver drugs and/or genes in (anti-)angiogenesis will be discussed. Furthermore, the literature describing MSC transdifferentiation into endothelial cells will be evaluated critically.     

In vivo optical imaging correlates with improvement of cerebral ischemia treated by intravenous bone marrow stromal cells (BMSCs) and edaravone

Abstract

Objective:

Recent studies show that modern in vivo optical imaging can detect matrix metallopeptidase (MMP) activation in the ischemic brain. In this study, we analyze the protective effects of bone marrow stromal cells (BMSCs) and edaravone (EDA) against tissue plasminogen activator (tPA) risk in the ischemic brain with in vivo optical fluorescence MMP imaging.

Methods:

At 48 hours after 60 minutes of transient middle cerebral artery occlusion (tMCAO) with tPA, C57BL/6J mice were subjected to motor function analysis, in vivo and ex vivo optical imaging for MMP activation, gelatin zymography, and double immunofluorescent analyses with or without intravenous BMSC transplantation and the intravenous free radical scavenger EDA.

Results:

In vivo fluorescent signals for MMP were detected over the heads of living mice 48 hours after tMCAO; the strongest were in the tPA group, which were reduced by BMSC or EDA treatment. These in vivo data were confirmed by ex vivo fluorescence imaging. While massive intracerebral hemorrhages were observed in the ischemic hemispheres of the tPA group, only slight hemorrhages were found in the tPA/BMSC, tPA/EDA, and EDA groups. Gelatin zymography showed the strongest MMP-9 activation in the tPA group after tMCAO, which was reduced by BMSC or EDA treatment.

Conclusion:

The present study provides a correlation between in vivo optical imaging of MMP activation and the improvement of ischemic brain damage caused by tPA after tMCAO and treated by BMSC and EDA.     

Role and mechanism of tissue plasminogen activator in venous wall fibrosis remodeling after deep venous thrombosis via the glycogen synthase kinase-3 beta signaling pathway

Background

Deep venous thrombosis (DVT) confers vein wall injury associated with fibrosis and extracellular matrix turnover. The activation of vascular smooth muscle cells (VSMCs) and phenotypic switching are postulated to be the significant contributing factors in the evolution of the pathogenic processes. This study investigated the effect of tissue plasminogen activator (tPA) on the phenotypic switching and collagen deposition of VSMCs, as well as related signaling pathway that leads to this activation.

Materials and methods

The model of stasis-induced DVT was established by ligation of the femoral vein. VSMCs transfected with the plasmid vector carrying a rat recombinant tPA gene with an enhanced green fluorescent protein (EGFP) tag (AdtPA-EGFP). Fibrotic change, expression of collagen type I, the cell number of media, and intimal thickness score were evaluated; the comparisons were made among the AdtPA-EGFP–transfected group, an empty vector (AdNull-EGFP) transfected group, and a phosphate-buffered saline perfused group in vivo. tPA induced VSMCs phenotypic switching and collagen deposition in vitro. The related signaling pathway molecules and the cell cycle progression were also investigated by western blot and flow cytometry.

Results

In the AdtPA-EGFP stasis DVT model, early vein wall collagenolysis and deposition occurred more remarkable. Histological studies showed that the expression of vein wall collagen type I protein, cell number of media, and intimal thickness score was significantly increased (P < 0.05). In primary culture VSMCs, sustained stimulation with tPA induced collagen type I upregulation and triggered sequential signaling events involving Akt, extracellular signal–regulated kinases 1/2 (ERK1/2), glycogen synthase kinase-3 (GSK3)-β phosphorylation, and cyclin D1 induction. Blockade of phosphatidylinositol 3-kinase-Akt and ERK1/2 activation suppressed tPA-induced GSK3β phosphorylation, cyclin D1 expression, and the deposition of collagen type I.

Conclusions

tPA was a profibrotic factor that potentiated the phenotypic switching and the deposition of collagen in VSMC. The effect of tPA on VSMCs involved activation of Akt and ERK1/2 pathways and inhibition of GSK3β activity, which could promote a switch of the synthetic phenotype in VSMCs and lead to the remodeling of vascular injury.