急性脑梗死患者GPIba和ADAM17表达及其与中医证型的关系
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摘要
第一部分动脉粥样硬化性血栓性脑梗死患者急性期GPIba和ADAM17的表达
     目的:
     探讨动脉粥样硬化性血栓性脑梗死患者急性期GPIba和ADAM17的表达,以及GPIba脱落和AD AM17的关系。
     方法:
     306例急性期动脉粥样硬化性血栓性脑梗死病人作为观察组,230例健康人作为对照组,他们在年龄、性别、种族、高血压、糖尿病史方面统计学无明显差异。分别通过流式细胞学、蛋白质印迹、酶联免疫吸附法检测了血小板膜上GPIba、 ADAM17和血浆中的糖盏蛋白(GC)。
     结果:
     与对照组相比,动脉粥样硬化血栓性脑梗死患者急性期GPIba的表达明显下降(P=0.000, P<0.01),ADAM17的表达升高(P=0.000,P<0.01),血浆中糖盏蛋白的含量增高,但没有统计学意义(P=0.699,P>0.05)。相关分析显示动脉粥样硬化性血栓性脑梗死患者急性期GPIba与GC没有相关性(r=0.095,P>0.05), GPIba与NIHSS有负相关(r=-0.514,P<0.01)。
     结论:
     ADAM17可能是动脉粥样硬化性血栓性脑梗死的危险因素,GPIba可以作为中风严重程度的一个指标。
     第二部分缺血性中风中经络患者凝血指标与中医证型的关系
     目的:
     观察缺血性中风(中经络)患者不同中医证型与凝血指标的关系,为缺血性中风的预防和治疗提供客观依据。
     方法:
     306例缺血性中风中经络患者根据《中风病辨证诊断标准》分为五型:风痰瘀阻型、风火上扰型、痰热腑实型、阴虚风动型、气虚血瘀型。230例来自于社区没有中风证据的人作为对照组。抽血检测GPIbα、ADAM17、血小板计数(PLT)、平均血小板体积(MPV)、血小板分布宽度(PDW)、凝血功能和同型半胱氨酸,并比较各证型患者凝血指标的水平及其相关性。
     结果:
     (1)缺血性中风中经络病人辨证属风痰瘀阻型102人,占33.33%;风火上扰型68人,占22.22%;痰热腑实型51人,占16.67%;阴虚风动型45人,占14.71%;气虚血瘀型40人,占13.07%。
     (2)306例病人中,男性147例,占48%,女性159例,占52%,平均年龄为63.30士10.76岁。缺血性中风不同证型之间性别比较,经X2检验差异无显著性(X2=2.758,P>0.05);各组间年龄经F检验差异无显著性(F=0.227,P=0.923,P>0.05)。
     (3)各证型之间GPIba经F检验差异有显著性(F=3.737,P=0.006,P<0.01),经LSD法两两比较:气虚血瘀型与风痰瘀阻型、风火上扰型有明显差异(P=0.011,P<0.05; P=0.001, P<0.01),阴虚风动型与风火上扰型有明显差异(P=0.009,P<0.01)。各证型之间ADAM17的表达无显著性差异(F=1.008,P=0.403,P>0.05)。
     (4)各证型间Hcy经F检验有显著性差异(F=4.613,P=0.001,P<0.01)。风痰瘀阻型与风火上扰型、气虚血瘀型比较有统计学意义(P=0.026,P=0.017,P均<0.05);风痰瘀阻型与阴虚风动型比较差异有显著性(P=0.000,P<0.01),风痰瘀阻型与痰热腑实型无明显差异(P=0.051,P>0.05)。
     (5)各证型间MPV经F检验差异有显著性(F=2.503,P=0.042,P<0.05),风痰瘀阻型与风火上扰型、阴虚风动型比较有统计学差异(P=0.01,P=0.015,P均<0.05)。各组间PDW经F检验差异有显著性(F=2.515,P=0.042,P<0.05),风痰瘀阻型与风火上扰型、阴虚风动型比较有统计学差异(P=0.01,P=0.02,P均<0.05),风痰瘀阻型、痰热腑实型与气虚血瘀型比较无统计学意义(P=0.62,P=6.02,P均>0.05)。
     (6)各证型间PLT、PT、TT、APTT、INR经F检验差异无显著性(P均>0.05)。各组间Fib经F检验有显著性差异(F=14.143,P=0.000,P<0.01),风痰瘀阻型与痰热腑实型、阴虚风动型有显著性差异(P=0.000,P=0.000,P均<0.01);气虚血瘀型与痰热腑实型、阴虚风动型有显著性差异(P=0.000,P=0.000,P均<0.01);而风痰瘀阻型、风火上扰型和气虚血瘀型之间无明显差异(P=0.169,P=0.748,P=0.167,P均>0.05)。
     (7)各证型间D-二聚体经F检验差异有显著性(F=2.962,P=0.02,P<0.05),风痰瘀阻型与风火上扰型、痰热腑实型、阴虚风动型比较有统计学意义(P=0.022,P<0.05;P=0.047,P<0.05; P=0.005, P<0.01);阴虚风动型与气虚血瘀型比较有统计学意义(P=0.038,P<0.05)。
     (8)缺血性中风中经络患者GPIbα与纤维蛋白原呈明显负相关(r=-0.249,P=0.000,P<0.01)。缺血性中风中经络患者纤维蛋白原和D-二聚体呈正相关(r=0.151,P=0.008,P<0.01)。
     结论:
     (1)风痰瘀阻型可能是缺血性中风中经络的主要证型。
     (2)缺血性中风中经络的证型与年龄、性别、AD AM17, PT、TT、APTT、INR无明显关系,与GPIbα、同型半胱氨酸、D-二聚体、纤维蛋白原、MPV、PDW有关。
     (3)风火上扰、风痰瘀阻型GPIbα最高;风痰瘀阻型Hcy最高;风痰瘀阻型MPV、 PDW最高;风痰瘀阻型、风火上扰型、气虚血瘀型纤维蛋白原较高;风痰瘀阻型与气虚血瘀型D-二聚体变化最明显。说明风痰瘀阻、痰热腑实、气虚血瘀证与凝血指标的关系密切。
     (4)缺血性中风中经络患者GPIbα与纤维蛋白原呈明显负相关,纤维蛋白原和D-二聚体呈正相关。
Part One:Changes in platelet GPIba and AD AM17in the acute stage of atherosclerotic ischemic stroke
     Objective:
     Glycoprotein (GP)Iba ectodomain shedding has important implications for thrombosis and hemostasis. A disintegrin and metalloproteinase17(ADAM17) was identified to play an essential role in agonist induced GPIba shedding. The relationship of GPIba shedding and ADAM17in the acute stage of atherosclerotic ischemic stroke (AIS) patients has not been thoroughly studied.
     Methods:
     306patients and230controls matched for age, sex, race, history of hypertension and diabetes mellitus were enrolled in the study. GPIba, ADAM17, glycocalicin (GC) were detected by flow cytometry, western blotting and enzyme-linked immunosorbent assay (ELISA) respectively.
     Results:
     Compared with the control group, the expression of GPIba in acute ischemic stroke patients were significantly lower (P=0.000, P<0.01). The amount of plasma glycocalicin and AD AM17were higher than those in control group (P=0.699, P=0.000), and AD AM17showed significant difference. Pearson's analysis showed glycocalicin had no correlation with GPIba in AIS patients (r=0.095, P>0.05). GPIba and NIHSS had negative correlation (r=-0.514,P<0.01).
     Conclusion:
     Our findings indicate that ADAM17may be a risk factor in AIS patients and the expression of GPIba can serve as a measure for stroke severity.
     Part Two:Study on the relationship between levels of coagulation markers and TCM syndrome differentiation in ischemic stroke
     Objective:
     To observe the relationship between levels of coagulation markers and TCM syndrome differentiation in ischemic stroke and provide theoretical basis for prevention and cure methods on stroke.
     Methods:
     306cases of ischemic stroke (merdian stroke) were divided into five types: wind-phlegm blocking collateral type、upward invading of wind-fire type、phlegm-heat with blocked intestines type、wind syndrome due to yin-deficiency type and blood stagnancy due to qi-deficiency type.230cases of healthy people were chosen as control. GPIbα、AD AM17、PLT、MPV、PDW、 coagulation function and homocysteine(Hcy) were detected by drawing blood and analysed according to different TCM syndrome type.
     Results:
     (1)Among306patients with ischemic stroke(merdian stroke),33.33%patients were wind-phlegm blocking collateral type,22.22%patients were upward invading of wind-fire type,16.67%patients were phlegm-heat with blocked intestines type,14.71%patients were wind syndrome due to yin-deficiency type and13.07%patients were blood stagnancy due to qi-deficiency type.
     (2) Among those patients,there were147males(48%) and159females(52%).The average age was63.30±10.76years. There were no significant difference among different TCM syndrome types in sex(X2=2.758, P>0.05)and age(F=0.227, P=0.923, P>0.05).
     (3) GPIba showed significant difference among five types (F=3.737, P=0.006, P<0.01).There were significant difference between blood stagnancy due to qi-deficiency type and wind-phlegm blocking collateral type (P=0.011, P<0.05)、upward invading of wind-fire type (P=0.001, P<0.01).GPIba of wind syndrome due to yin-deficiency type showed significant difference compared to that of upward invading of wind-fire type(P=0.009, P<0.01).ADAM17showed no significant difference among different types (F=1.008, P=0.403, P>0.05)
     (4) There were statistical difference in Hcy among different types(F=4.613, P=0.001, P<0.01).There were significant difference between wind-phlegm blocking collateral type and upward invading of wind-fire type、blood stagnancy due to qi-deficiency type、wind syndrome due to yin-deficiency type (P=0.026, P=0.017, P=0.000, P<0.05).Hcy of phlegm-heat with blocked intestines type showed no significant difference compared with that of wind-phlegm blocking collateral type (P=0.051, P>0.05).
     (5) There were significant difference among different types in MPV (F=2.503, P=0.042, P<0.05).Wind-phlegm blocking collateral type showed significant difference compared to upward invading of wind-fire type and wind syndrome due to yin-deficiency type (P=0.01, P=0.015, P<0.05). There were significant difference among different types in PDW (F=2.515, P=0.042, P<0.05). Wind-phlegm blocking collateral type showed significant difference compared to upward invading of wind-fire type and wind syndrome due to yin-deficiency type (P=0.01, P=0.02, P<0.05).There were no significant difference among wind-phlegm blocking collateral type、blood stagnancy due to qi-deficiency type and phlegm-heat with blocked intestines type (P>0.05)
     (6) There were no statistical difference among five types in PLT、PT、TT、APTT and INR (P>0.05).Fibrinogen among five types showed significant difference(F=14.143,P=0.000, P<0.01).There were significant difference between wind-phlegm blocking collateral type、 upward invading of wind-fire type、blood stagnancy due to qi-deficiency type and phlegm-heat with blocked intestines type、wind syndrome due to yin-deficiency type (P<0.01).There were no statistical difference among wind-phlegm blocking collateral type%upward invading of wind-fire type and blood stagnancy due to qi-deficiency (P=0.169, P=0.748, P=0.167,P>0.05)
     (7) There were significant difference in D-dimer among five types (F=2.962, P=0.02, P<0.05). Wind-phlegm blocking collateral type had significant difference compared to upward invading of wind-fire type、phlegm-heat with blocked intestines type and wind syndrome due to yin-deficiency type (P=0.022, P<0.05; P=0.047, P<0.05; P=0.005, P<0.01).Wind syndrome due to yin-deficiency type showed statistical difference compared to blood stagnancy due to qi-deficiency type (P=0.038, P<0.05)
     (8) In ischemic stroke(meridian stroke),there were negative correlation between GPIb∝and fibrinogen (r=-0.249, P=0.000, P<0.01). Fibrinogen bore positive correlation with D-dimer(r=0.151, P=0.008, P<0.01)
     Conclusions:
     (1) In ischemic stroke(meridian stroke), the dominant TCM syndrome type is wind-phlegm blocking collateral type.
     (2) TCM syndrome type of ischemic stroke(meridian stroke)shows no significant relationship with age、sex、AD AM17、PT、TT、APTT and INR,while has relationship with GPIb∝、Hcy、D-dimer、Fibrinogen、MPV and PDW.
     (3) The expression of GPIba in upward invading of wind-fire type and wind-phlegm blocking collateral type are higer than other types. The amount of Hcy is the highest in wind-phlegm blocking collateral type.MPV and PDW were high in wind-phlegm blocking collateral type. The amount of fibrinogen were high in wind-phlegm blocking collateral type、upward invading of wind-fire type and blood stagnancy due to qi-deficiency type.Changes of D-dimer in both wind-phlegm blocking collateral type and blood stagnancy due to qi-deficiency type were the most significant.In summary,there were close relationship between levels of coagulation markers and wind-phlegm blocking collateral type、phlegm-heat with blocked intestines type and blood stagnancy due to qi-deficiency type.
     (4)In ischemic stroke(meridian stroke), there is negative correlation between GPIbaand fibrinogen. Fibrinogen bears positive correlation with D-dimer.
引文
[1]O'Donnell MJ,Xavier D,Liu L,et al.Risk factors for ischemic and intracerebral haemorrhagic stroke in 22 countries(the INTERSTROKE study):a case-control study [J].Lancet,2010,376(9735):112-123.
    [2]Qian J, Liu J, Liu L, et al. Risk factors and prevention of stroke in the Chinese population[J]. Journal of Stroke and Cerebrao-vascular Diseases,2010,2(8):1-6.
    [3]中华医学会神经学脑血管病学组缺血性脑卒中二级预防指南撰写组.中国缺血性脑卒中和短暂性脑缺血发作二级预防指南2010[J].中华神经科杂志,2010,43(2):154-160.
    [4]吴江,贾建平,崔丽英,等.神经病学(第一版).人民卫生出版社.2005.153-158.
    [5]饶明俐主编.中国脑血管病防治指南[M].北京:人民卫生出版社,2007:1-2;30-32.
    [6]Bamford J, Sandercock P, Dennis MS, et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet,1991,337 (8756):1521-1526.
    [7]Adams H P Jr, Bendixen B H, Kappelle L J, et al.Classification of subtype of acute ischemic stroke[J]. Stroke,1993,24(1):35-41.
    [8]Hajat C,Coshall C,Rudd A Qet al.The inter-and intraobserver reliabilities of a new classification system for ischaemic stroke:the South London Stroke Register[J].J Neurol Sci,2001,190(1/2):79-85.
    [9]Ay H, Furie KL, Singhal A,et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol.2005,58(5):688-97.
    [10]HanSW, Kim SH, Lee J Y, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism [J]. Eur Neurol,2007,57(2):96-102.
    [11]Amarenco P, Bogousslavsky J, Caplan LR,et al.New approach to stroke subtyping:the A-S-C-O(phenotypic) classification of stroke.Cerebrovasc Dis,2009,27(5):502-508.
    [12]Gao S, Wang YJ, Xu AD, et al. Chinese ischemic stroke subclassification [J]. Front Neurol,2011,2(1):1-5.
    [13]Bogousslavsky J,Regli F.Centrum ovale infarcts:subcortical infarction in the superficial territory of the middle cerebral artery [J].Neurology,1992,42(10):1992-1998.
    [14]Bladin C F,Chambers B R. Clinical features,pathogenesis,and computed tomographic characteristics of internal watershed infarction[J].Stroke,1993,24(12):1925-1932.
    [15]陈望春,万慧.缺血性脑卒中分型的临床应用及意义.南昌大学学报(医学版),2011,51(1):93-98.
    [16]史宝林,张勇,武艳华,等.脑梗死的遗传流行病学研究.中华流行病学杂志,2003,24(8):719-721.
    [17]Gunarathne A, Patel J V, et al.Ischemic stroke in South Asians:a review of the epidemiology, pathophysiology, and ethnicity-related clinical features [J]. Stroke, 2009,40 (6):415-423.
    [18]Lammintausta A, Lentonen A, et al. Stroke morbidity in Swedish- and Finnish-speaking populations of Turku, Finland [J]. Scand Cardiovasc J,2009,43 (2): 117-122.
    [19]Deleu D, Hamad A A, et al. Ethnic variations in risk factor profile, pattern and recurrence of non-cardioembolic ischemic stroke [J]. Arch Med Res,2006,37 (5): 655-662.
    [20]Trimble B, Morgenstern LB, et al. Stroke in minorities [J]. Neurol Clin,2008, 26 (4):1177-1190.
    [21]Grover SA, Coupal PM, Hu XP. Identifying adults at increasing risk of coronary disease.How well do the current cholesterol guidelines work. JAMA,1995,274 (10):801-806.
    [22]Popper H,Sadikovie S,Sander K,et al.Embolic signals in unselected stroke patients:Prevalence and diagnostic benefit[J].Stroke,2006,37:2039-2043.
    [23]Shimizu M,Kohara S,Yamamoto M,et al.Significant relationship between platelet activation and intra-media thickness of the carotid artery in patients with ischemic cerebrovascular disease[J].Thromb Res,2006,117:647-652.
    [24]伞勇智,李峰,杨鸣,等.凝血机制新进展及脑梗死抗凝治疗的展望.中华脑血管病杂志(电子版),2012,6(2):96-102.
    [25]McCabe DJ, Harrison P, Mackie IJ, et al. Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischemic stroke or transient ischemic attack. Br JH aematol,2004,125:77-78.
    [26]Ozaki Y, Asazuma N, Suzuki-Inoue K, et al. Platelet GPIb-IX-V-dependent signaling. J Thromb Haemost,2005,3(8):1745-1751.
    [27]张奇志.血小板膜糖蛋白GPIbaKozak基因多态性与缺血性脑血管病的相关性研究.青岛大学图书馆,2005:27-28.
    [28]Robert K. Andrews, Denuja Karunakaran, Elizabeth E. Gardiner,et al.Platelet Receptor Proteolysis A Mechanism for Downregulating Platelet Reactivity. Arteriosclerosis, Thrombosis, and Vascular Biology,2007,27:1511.
    [29]Brill A, Chauhan AK, Canault M, Walsh MT, Bergmeier W, Wagner DD. Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion. Cardiovasc Res,2009,84:137-144.
    [30]Merten M,Thiagarajan P.P-selectin expression on platelets determinessize and stability of platelets aggregates[J].Circulation,2000,102(16):1931-1936.
    [31]AY C, JUNGBAUER L V, KAIDER A, et al. P- selectin gene haplotypes modulate soluble P-selectin concentra-tions and contribute to the risk of venous thromboem-bolism [J]. Thromb Haemost,2008,995:899-904.
    [32]Htun P,Fateh-Moghadam S,Tonnrdl B,et al.Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ischemic[J].Stroke,2006,37:2283-2287.
    [33]Li J M, Podolsky RS, Rohrer MJ, et al. Adhesion of activated platelets to venous endothelial cells is mediated via GP Ⅱb/Ⅲa [J]. J Surg Res,1996,61(2):543-548.
    [34]Meng XQ, Liao XP, Long ZG. The expressions of PAC-1 and CD62p in the acute stage of cerebral infarction [J].Foreign Med Sci-Cerebrovasc Dis,2005,13(11):860.
    [35]Wang WY, Wu YC, Wu CC. Prevention of platelet glycoprotein Ⅱb Ⅲa activation by 3,4-methylenedioxy-beta-nitrostyrene, a novel tyrosine kinase inhibitor [J].Mol Pharmacol,2006,70(4):1380-1389.
    [36]中华全国中医学会.中风病中医诊断与疗效评定标准.中国医药学报,1986,(2):56.
    [37]国家中医院管理局脑病急症协作组.中风病中医诊断与疗效评定标准(试行)[J]北京中医药大学学报,1996,19(1):55-56.
    [38]程率芳,郦永平.脑梗塞辨证分型之现状.甘肃中医,2005,18(3):6-7.
    [39]卢爱丽,黄亮,黄燕.缺血中风急性期中医证候与脑动脉血流速度的相关性探讨[J].辽宁中医杂志,2007,34(9):1188-1190.
    [40]廖慧玲,陈光伟,尹思源.缺血性中风证型与血管内皮细胞分泌功能关系的研究.辽宁中医杂志,2010,37(12):2281-2283.
    [41]李保东,巩尊科.中风证型与血栓素、前列环素关系的探讨.中国医药学报,2004,19(12):751.
    [42]Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors,2001:systematic analysis of population health data. Lancet,2006, 367(9524):1747-1757.
    [43]尹玲.脑梗死患者血小板四项参数的检测及临床意义.临床医学,2010,30(2):52.
    [44]Stoll G, Kleinschnitz C, Nieswandt B. The role of glycoprotein Ibalpha and von Willebrand factor interaction in stroke development. Hamostaseologie,2010,30(3): 136-138.
    [45]Bergmeier W, Piffath CL, Cheng G, et al. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates GPIbalpha shedding from platelets in vitro and in vivo. Circ Res,2004,95(7):677-683.
    [46]White, M.M. Jennings, L.K. Platelet protocols. Research and Clinical Laboratory Procedures, San Diego:Academic Press,1999.
    [47]Zhang Y,Zhao Y, Lu S,et al. A High-Throughput Biotin-Avidin-ELISA for Studying Expression of Platelet Membrane Glycoproteins and Its Clinical Application. Tohoku Exp Med,2010,222(1):83-88.
    [48]M.Gawaz,H.Langer, A.E.May.Platelets in inflmation and atherogenesis.J Clin Invest,2005,115:3378-3384.
    [49]G.Hollopeter,H.M.Jantzen,D.Vincent,et al.Identification of the platelet ADP receptor targeted by antithrombotic drugs.Nature,2001,409:202-207.
    [50]F.D.Kolodgie,H.K.Gold,A.P.Burke,et al.Intraplaque hemorrhage and progression of coronary atheroma.N Engl J Med,2003,349:2316-2325.
    [51]del Zoppo GJ. The role of platelets in ischemic stroke. Neurology,1998,51(3 suppl 3):S9-14.
    [52]Tokuue J, Hayashi J, Hata Y, et al. Enhanced platelet Aggregability under high shear stress after treadmill exercise in patients with effort angina. Thromb Haemost, 1996,75(5):833-837.
    [53]Sonoda A, Murata M, Ito D, et al. Association Between Platelet Glycoprotein Ib Genotype and Ischemic Cerebrovascular Disease. Stroke,2000,31(2):493-497.
    [54]Q.Long,X.Y.Xu,K.V.Ramnarine,et al.Numerical investigation of physiologically realistic pulsatileflow through arterialstenosis, J Biomech,2001,34:1229-1242.
    [55]J.R.O'Brien.Shear-induced platelet aggregation. Lancet,1990,335:711-713.
    [56]Maguire JM, Thakkinstian A, Sturm J, et al. Polymorphisms in platelet glycoprotein lbalpha and factor VII and risk of ischemic stroke:a meta-analysis. Stroke,2008,39(6):1710-1716.
    [57]Elvers M, Stegner D, Hagedorn I et al. Impaired αⅡbβ3 integrin activation and shear-dependent thrombus formation in mice lacking phospolipase Dl.Sci Signal,2010,3(103):ral.
    [58]Han Y, Wang Z, Zhu M, et al.Study of platelet membrane glycoproteins and its fibrinogen binding reaction in patients with cerebral infarction and diabetes mellitus. Zhonghua Xue Ye Xue Za Zhi(Chinese),2000,21(3):129-131.
    [59]Alan D. Flow cytometry:a clinical test of platelet function [J]. J Blood,1996,87(12): 4925-4936.
    [60]Nurden P.Bidirectional trafficking of membrane glyocoprotein followingplatelet activation in suspension.Thromb Haemost,1997,78:1305-1315.
    [61]Baurand A, Eckly A, Hechler B, et al. Differential regulation and relocalization of the platelet P2Y receptors after activation:a way to avoid loss of hemostatic properties? Mol Pharmacol,2005,67(3):721-733.
    [62]Garcia BA, Smalley DM, Cho H,et al. The platelet microparticle proteome. J Proteome Res,2005,4(5):1516-1521.
    [63]Dai K, Yan R, Li S, et al. Prolonged inhibition of protein kinase A results in metalloproteinase-dependent platelet GPIba shedding. Thromb Res,2009,124(1): 101-109.
    [64]Aktas B, Pozgajova M, Bergmeier W, et al.Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE). J Biol Chem,2005,280(48):39716-39722.
    [65]Guido Stoll, Christoph Kleinschnitz, Bernhard Nieswandt. Combating innate inflammation:a new paradigm for acute treatment of stroke? Ann. N.Y. Acad. Sci, 2010,1207:149-154.
    [66]E.Boilard, P.A. Nigrovic, K. Larabee, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science,2010.327(5965):580-583.
    [67]Beer JH, Buchi L, Steiner B. Glycocalicin:a new assay-the normal Plasma levels and its potential usefulness in selected diseases. Blood,1994,83(3):691-702.
    [68]Coller BS, Kalomiris E, Steinberg M, et al. Evidence That Glycocalicin Circulates in Normal Plasma J Clin Invest,1984,73(3):794-799.
    [69]Black RA. Tumor necrosis factor-alpha converting enzyme. Int J Biochem Cell Biol,2002,34:1-5.
    [70]Wang X, Giora Z. Feuerstein, Lin Xu, et al. Inhibition of Tumor Necrosis Factor-a-Converting Enzyme by a Selective Antagonist Protects Brain from Focal Ischemic Injury in Rats. Mol Pharmacol,2004,65(4):890-896.
    [71]Hurtado O, Lizasoain I, Fernandez-TomeP, et al.TACE/ADAM17-TNFa pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate.J Cereb Blood Flow Metab,2002,22(5):576-85.
    [72]Cardenas A, Moro MA, Leza JC, et al.Up-regulation of TACE/ADAM17 after ischemic preconditioning is involved in brain tolerance.J Cere Blood Flow Metab,2002,22(11):1297-302.
    [1]王永炎.中医内科学(第六版).上海科学技术出版社,1994.124-126.
    [2]祝美珍,李志刚.缺血性中风中医辨证分型与ICAM-1和CD62P表达水平的相关性[J].中国中西医结合杂志,2005,25(3):225-227.
    [3]邱昕,王开欣,陈国华.武汉地区900例缺血性脑卒中风痰瘀阻型及气虚血瘀型患者危险因素回顾性分析.中国中西医结合杂志,2011,31(11):1483-1486.
    [4]刘璐,高颖.应用logistic回归模型及重复测量方差分析法探讨缺血性中风证候要素与近期预后的关系.中西医结合学报,2012,10(9):983-989.
    [5]国家中医药管理局脑病急症协作组.中风病诊断与疗效评定标准.北京中医药大学学报,1996.19(1):55-56.
    [6]温学红,杨林,李青.不同中医证型的脑梗死患者血液流变学及血脂指标的比较[J].河北中医,2009,31(3):332-334.
    [7]冯桂贞,林安基,吴仕福,等.急性脑梗死中医辨证分型与同型半胱氨酸、超敏C反应蛋白水平的相关性研究[J].光明中医,2009,24(8):1419-1420.
    [8]朱开瑞.中青年与老年急性脑梗死患者血清同型半胱氨酸水平及与中医血瘀证的相关性研究.福建中医药大学图书馆,2012:17.
    [9]田金洲,时晶,倪敬年.脑梗塞患者颈动脉斑块与血瘀证的相关性研究[J].中华中医药杂志,2007,22(3):149-152.
    [10]邵卫.缺血性脑卒中痰瘀阻络证和肝风上扰证的生物学基础的研究.湖北中医学院图书馆,2008:51-56.
    [11]谌剑飞,关少侠,丁萍,等.中风急症证候研究与问题探讨.中国中西医结合急救杂志,2001,8(3):169-171.
    [12]何婷婷,张允岭,金香兰,等.从脑梗死急性期的方药分析论其证型分布.北京中医药大学学报(中医临床版),2012,19(2):35-37.
    [13]刘军莲,宋剑南.中医血瘀证本质研究概况.辽宁中医杂志,2006,33(9):1091-1093.
    [14]陈永斌.血瘀证与血小板活化关联的研究进展[J].中国中医基础医学杂志,2004,10(11):70.
    [15]张奇志.血小板膜糖蛋白GPIbaKozak基因多态性与缺血性脑血管病的相关性研究.青岛大学图书馆,2005.
    [16]Nurden P.Bidirectional trafficking of membrane glyocoprotein followingplatelet activation in suspension.Thromb Haemost,1997,78:1305-1315.
    [17]Ribba AS,Loisel I,Lavergne JM. Ser968 Thr mutation within the A3 domain of von Willebrand factor, in two related patients lead to a defective binding of vWF to collagen. Thromb Haenost,2001,86(3):848
    [18]Wald DS,law M,morris JK. Homocysteine and cardiovascular disease:evidence on causality from a meta-analysis[J]. BMJ,2002,325(7374):1202.
    [19]Eikelboom JW, Hankey GJ,Anand SS, et al. Association between high homocyst(e)ine and ischemic stroke due to large and small-artery disease but not other etiologic subtypes of ischemicstroke[J]. Stroke,2000,31(5):1069-1075.
    [20]李伟峰,张玲端,等.缺血性中风急性期中医证型特点及与血浆HCY的关系[J].中国中医急症,2009,18(8):1274-1275.
    [21]黄立武,黎桂育,李景玉.急性脑梗死患者血浆同型半胱氨酸与中医证型相关性的临床研究.内蒙古中医药,2012.12:3-4.
    [22]N.Alexandru,D.Popov,A.Georgescu.Platelet dysfunction in vascular patholigies and how can it be treated.Thrombosis Research,2012,129:116-126.
    [23]Wang RT, Li Y, Zhu XY,et al. Increased mean platelet volume is associated with aterial stiffness.Platelets,2011,22(6):447-451.
    [24]Arevalo-Lorido JC, Carretero-G6mez J, Villar-Vaca P. Mean platelet volume predicting carotid atherosclerosis in atherothrombotic ischemic stroke.Ir J Med Sci,2012 Jun;181(2):179-83.
    [25]Balcik OS, Bilen S, Ulusoy EK,et al. Thrombopoietin and mean platelet volume in patients with ischemic stroke. Clin Appl Tnromb Hemost,2013,19(1):92-5.
    [26]Mayda-Domac F, Misirli H, Yilmaz M. Prognostic role of mean platelet volume and platelet count in ischemic and hemorrhagic stroke.J Stroke Cerebrovasc Dis, 2010,19(1):66-72.
    [27]郝迎军,吴强,郝宗娇.急性脑梗死患者血小板参数的临床观察[J].中国实用神经疾病杂志,2009,12(7):68-70.
    [28]唐万兵,李梅笑,李观强,等.血浆纤维蛋白原、IL-17水平与脑梗死病程相关性的研究.中国医药导报,2012,9(17):28-31.
    [29]曾昭贤,陈茜,颜红凤.缺血性脑卒中血清尿酸纤维蛋白原及D-二聚体水平相关性的研究,2010,17(22):68-69.
    [30]刘清林.中风病机之我见.光明中医,2008,23(5):666.
    [1]Choi J, Kermode JC. New therapeutic approaches to combat arterial thrombosis:better drugs for old targets, novel targets, and future prospects. Mol Interv,2011,11:111-23.
    [2]Delzoppo GJ.The role of platelets in isehemic stroke.Neurology,1998,51(3 Suppl 3):S9-514.
    [3]张奇志.血小板膜糖蛋白GPIbaKozak基因多态性与缺血性脑血管病的相关性研究.青岛大学图书馆,2005:27-28.
    [4]Marchese P, Murata M, Mazzucato M, et al. Identification of three tyrosine residues of glycoprotein Iba with distinct roles in von Willebrand factor and a-thrombin binding. J Biol Chem,1995,270:9571-9578.
    [5]Dumas JJ, Kumar R, McDonagh T, et al. Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Iba complex reveals conformation differences with a complex bearing von Willebrand disease mutations. J Biol Chem,2004, 279:23327-2334.
    [6]Dumas JJ, Kumar R, Seehra J, et al. Crystal structure of the GpIbα-thrombin complex essential for platelet aggregation. Science (Washington, DC),2003,301:222-226.
    [7]Sixma JJ, Schiphorst ME, Verweij CL, et al. Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin.Eur J Biochem,1991,196:369-375.
    [8]Claus RA, Bockmeyer CL, Sossdorf M,et al. The balance between von-Willebrand factor and its cleaving protease ADAMTS13:biomarker in systemic inflammation and development of organ failure? Curr Mol Med,2010,10:236-248.
    [9]Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell,1996,84:289-297.
    [10]Ruggeri ZM, De Marco L, Gatti L, et al. Platelets have more than one binding site for von Willebrand factor. J Clin Invest,1983,72:1-12.
    [11]Giannini S, Mezzasoma AM, Leone M, et al. Laboratory diagnosis and monitoring of desmopressin treatment of von Willebrand's disease by flow cytometry. Haematologica,2007,92:1647-1654.
    [12]Girma JP, Takahashi Y, Yoshioka A, et al. Ristocetin and botrocetin involve two distinct domains of von Willebrand factor for binding to platelet membrane glycoproteinⅠb. Thromb Haemost,1990,64:326-332.
    [13]Yamashita A, Furukoji E, Marutsuka K, et al. Increased vascular wall thrombogenicity combined with reduced blood flow promotes occlusive thrombus formation in rabbit femoral artery. Arterioscler Thromb Vasc Biol,2004,24:2420-2424.
    [14]Savage B, Shattil SJ, Ruggeri ZM. Modulation of platelet function through adhesion receptors. A dual role for glycoprotein Ⅱb-Ⅲa (integrin alpha Ⅱb beta 3) mediated by fibrinogen and glycoprotein Ⅰb-von Willebrand factor. J Biol Chem,2003, 267:11300-11306.
    [15]Takahashi M, Yamashita A, Moriguchi-Goto S, et al. Critical role of von Willebrand factor and platelet interaction in venous thromboembolism. Histol Histopathol, 2009,24:1391-1398.
    [16]Esraon, C. T. Inflammation, sepsis, and coagulation. Haematologica,1999,84:254-259.
    [17]Dormann D, Clemetson KJ, Kehrel BE. The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity. Blood,2000,96:2469-78.
    [18]Bouton MC, Thurieau C, Guillin M, et al. Characteristics of the interaction between thrombin exosite 1 and the sequence 269-297 of platelet glycoprotein Ib.Thromb Haemost,1998,80:310-315.
    [19]Lancellotti S, Rutella S, De Filippis V, et al. Fibrinogen-elongated{gamma} Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors. J Biol Chem,2008,283:30193-30204.
    [20]De Cristofaro R, De Filippis V. Interaction of the 268-282 region of glycoproteinⅠb with the heparin-binding site of thrombin inhibits the enzyme activation of factor Ⅷ. Biochem J,2003,373:593-601.
    [21]Zaverio M. Ruggeril, Alessandro Zarpellonl, James R. Robertsl.et al.Unravelling the mechanism and significance of thrombin binding to platelet glycoprotein Ib. Thrombosis and Haemostasis,2010,104(5):894-902.
    [22]Ten Cate H, Bauer KA, Levi M, et al. The activation of factor X and prothrombin by recombinant factor Ⅶa in vivo is mediated by tissue factor. J Clin Invest,1993,92:1207-12.
    [23]Monroe DM, Hoffman M, Olivier JA, et al. Platelet activity of high-dose factor Ⅶa is independent of tissue factor. Br J Haematol,1997,99:542-547.
    [24]Weeterings C, de Groot PG, Adelmeijer J,et al. The glycoprotein Ib-IX-V complex contributes to tissue factor-independent thrombin generation by recombinant factor Ⅶa on the activated platelet surface. Blood,2008,112:3227-3233.
    [25]Weeterings C, de Groot PG,Adelmeijer J,et al. The glycoprotein Ib-IX-V complex contributes to tissue factor independent thrombin generation by recombinant factor Ⅶa on the activated platelet surface. Blood,2008,112:3227-3233.
    [26]Wagner, D. D."New links between inflammation and thrombosis".Arterioscler Thromb Vasc Biol,2005,25(7):1321-1324.
    [27]Baglia FA, Shrimpton CN, Emsley J, et al. Factor XI interacts with the leucine-rich repeats of glycoprotein Iba on the activated platelet. J Biol Chem,2004, 279:49323-49329.
    [28]Bradford HN, Pixley RA, Colman RW. Human factor XII binding to the glycoprotein Ib-IX-V complex inhibits thrombin-induced platelet aggregation. J Biol Chem,2000, 275:22756-22763.
    [29]Simon DI, Chen Z, Xu H, et al. Platelet glycoprotein Iba is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med,2000,192:193-204.
    [30]White TC, Berny MA, Tucker El, et al.Protein C supports platelet binding and activation under flow:role of glycoprotein Ib and apolipoprotein E receptor 2.J Thromb Haemost,2008,6:995-1002.
    [31]Bergmeier W, Piffath CL, Goerge T, et al. The role of platelet adhesion receptor GPIba far exceeds that of its main ligand,von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci U S A,2006,103:16900-16905.
    [32]Williamson D, Pikovski I, Cranmer SL, et al. Interaction between platelet glycoprotein Ibalpha and filamin-1 is essential for glycoprotein Ib/EX receptor anchorage at high shear. J Biol Chem,2002,277:2151-2159.
    [33]Dopheide SM, Maxwell MJ, Jackson SP. Shear-dependent tether formation during platelet translocation on von Willebrand factor. Blood,2002,99:159-167.
    [34]Li S, Wang Z, Liao Y, Zhang W,et al. The glycoprotein Ibalpha-von Willebrand factor interaction induces platelet apoptosis.J Thromb Haemost,2010,8(2):341-350.
    [35]Angiolillo, D. J., M. Ueno, et al. "Basic principles of platelet biology and clinical implications". Circ J,2010,74(4):597-607.
    [36]Nurden, A. T., P. Nurden, et al. "Platelets and wound healing." Front Biosci,2008,13: 3532-3548.
    [37]McEver RP. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost.2001,86:746-756.
    [38]Bennett JS. Structure and function of the platelet integrin αⅡbβ3. J Clin Invest,2005,115:3363-3369.
    [39]Shattil SJ, Newman PJ. Integrins:dynamic scaffolds foradhesion and signaling in platelets[J].Blood,2004,104(6):1606-1615.
    [40]Brass LF, Zhu L, Stalker TJ. Novel therapeutic targets at the platelet vascular interface.Arterioscler Thromb Vasc Biol,2008,28:s43-50.
    [41]Bdguin S, Kumar R,Keularts I,et al.Fibrin-dependent platelet procoagulant activity requires GPIb receptors and von Willebrand factor. Blood,1999,93:564-570.
    [42]Ahmad F, Boulaftali Y, Greene TK, et al. Relative Contribution of STIM1 and CalDAG-GEFI to Calcium-Dependent Platelet Activation and Thrombosis. J Thromb Haemost,2011,9:2077-2086.
    [43]Morrell CN, Maggirwar SB. Recently recognized platelet agonists. Curr Opin Hematol,2011,18:309-314.
    [44]Massberg S, Gawaz M, Gruner S et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med,2003,197:41-49.
    [45]Kleinschnitz C, Pozgajova M, Pham M et al. Targeting platelets in acute experimental stroke:impact of glycoprotein Ib, VI, and Ⅱb/Ⅲa blockade on infarct size, functional outcome, and intracranial bleeding.Circulation,2007,115:2323-2330.
    [46]Kleinschnitz, C., S.F. DeMeyer, T. Schwarz, et al. Deficiency of vonWillebrand factor protectsmice fromischemic stroke. Blood,2009,113:3600-3603
    [47]Zhao, B.Q., A.K. Chauhan, M. Canault, et al. Von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury inexperimental stroke. Blood,2009,114: 3329-3334.
    [48]Marx, I., O.D. Christophe, P.J. Lenting, et al. Altered thrombus formation in von Willebrand factor-deficient mice expressing von Willebrand factor variants with defective binding to collagen or GPⅡbⅢa. Blood,2008,112:603-609.
    [49]DeMeyer, S.F., N.Vandeputte, I. Pareyn, et al. Restoration of plasma vonWillebrand factor deficiency is sufficient to correct thrombus formation after gene therapy by severe von Willebrand disease. Arterioscler. Thromb. Vase. Biol,2008,28:1621-1626.
    [50]De Meyer, S.F., T. Schwarz, H. Deckmyn, et al. Binding of von Willebrand factor to collagen and GPIba, but not GPIIb/IIIa contributes to ischemic stroke in mice. Arterioscler.Thromb. Vase. Biol,2010,30(10):1949-1951.
    [51]Elvers M, Stegner D, Hagedorn I et al. Impaired αⅡbβ3 integrin activation and shear-dependent thrombus formation in mice lacking phospolipase D1. Sci Signal,2010,3(103):ral.
    [52]Stoll G, Kleinschnitz C, Nieswandt B. The role of glycoprotein Ibalpha and von Willebrand factor interaction in stroke development. Hamostaseologie, 2010,30:136-138.
    [53]Ishida F,Furihata K,Ishida K,et al.The largest variant of platelet glcoproteinib alpha has four tandem repeats of 13 amino acids in the macro glycopetide region and a genetic linkage with methionine145.Blood,1995,86:1357-1360.
    [54]Hsieh K,Funk M,Schillinger M,et al.Vienna Stroke Registry.Impact of the platelet glycoprotein Ib alpha kozak polymorphism on the risk of ischemic cerebrovascular events:a case-control study.Blood Coagul Fibrinolysis,2004,15(6):469-473.
    [55]Baker RI,Eikelboom J,Lofthouse E,et al.Platelet glycoprotein Iba kozak polymorphism is associated with an increased risk of ischemic stroke.Blood,2001,98:36-40.
    [56]Renne, T., M. Pozgajova, S. Gruner, et al. Defective thrombus formation in mice lacking coagulation factor XII. J. Exp. Med,2005,202:271-281.
    [57]Hagedorn I, S. Schmidbauer, I. Pleines, et al. Factor Ⅻa inhibitor recombinant human albumin infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation,10,121:1520-1517.
    [58]Muller, F.&T. Renne. Novel roles for factor Ⅻ-driven plasma contact system. Curr Opin. Hematol,2008,15:516-521.
    [59]M.Ueno,M.Kodali,A.Tello-MontoliuandD.J.Angiolillo.Role of platelets and antiplatelet therapy in cardiovascular disease.J Atheroscler Thromb,2011,18:431-432.
    [60]R. Berent, H. Sinzinger."Aspirin-resistance"? A few critical considerations on definition, terminology, diagnosis,clinical value, natural course of atherosclerotic disease, and therapeutic consequences.Vasa,2011,40:429-438.
    [61]G.N. Levine, P.B. Berger, D.J. Cohen, et al. Newer pharmacotherapy in patients undergoing percutaneous coronay interventions:A guide for pharmacists and other health care professionals,Pharmacotherapy,2006,26:1537-1556.
    [62]C. Ombrello, R.C. Block,C.N. Morrell. Our expanding view of platelet functions and its clinical implications. J Cardiovasc Trans Res,2010,3:538-546.
    [63]X. Bosch, J. Marragat, J. Sanchis. Platelet glycoprotein Ib/IIIa blockers during percutaneous coronary intervention and as the initial medical treatment of non-ST segment elevation acute coronary syndromes. Cochrane Database Syst Rev,2010,8(9):CD002130.
    [64]J.C. Gilbert, T. DeFeo-Fraulini, R.M. Hutabarat, et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC 1779 in healthy volunteers,Circulation,2007,116:2678-2686.
    [65]D.A. Morrow, E. Braunwald, M.P. Bonaca,et al. TRA 2P-TIMI 50 Steering Committee and Investigators, Vorapaxar in the secondary prevention of atherothrombotic events. N Eng J Med,2012,366:357-362.
    [66]Huizinga EG, Tsuji S, Romijn RA, et al. Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science,2002,297 (5584):1176-1179.
    [67]Uff S, Clemetson JM, Harrison T, et al. Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation. J Biol Chem,2002,277(38):35657-35663.
    [68]Wu D, Vanhoorelbeke K, Cauwenberghs N, et al. Inhibition of the von Willebrand (VWF)-collagen interaction by an antihuman VWF monoclonal antibody results in abolition of in vivo arterial platelet thrombus formation in baboons. Blood,2002,99(10):3623-3628.
    [69]Yang J, Ji S, Dong N, et al. Engineering and characterization of a chimeric anti-platelet glycoprotein Ibalpha monoclonal antibody and preparation of its Fab fragment. Hybridoma(Larchmt),2010,29(2):125-132.
    [70]Baurand A, Eckly A, Hechler B, et al. Differential regulation and relocalization of the platelet P2Y receptors after activation:a way to avoid loss of hemostatic properties? Mol Pharmacol,2005,67(3):721-733.
    [71]Garcia BA, Smalley DM, Cho H,et al. The platelet microparticle proteome. J Proteome Res,2005,4(5):1516-1521.
    [72]Jin M, Drwal G, Bourgeois T, et al. Distinct proteome features of plasma microparticles.Proteomics,2005,5(7):1940-1952.
    [73]Bergmeier W, Piffath CL, Cheng G, et al. Tumor necrosis factor-alpha-converting enzyme (ADAM 17) mediates GPIbalpha shedding from platelets in vitro and in vivo. Circ Res,2004,95(7):677-683.
    [74]Gardiner EE, Arthur JF, Kahn ML, et al. Regulation of platelet membrane levels of glycoprotein VI by a platelet-derived metalloproteinase. Blood,2004,104 (12):3611-3617.
    [75]Bergmeier W, Rabie T, Strehl A, et al. GPVI down-regulation in murine platelets through metalloproteinase-dependent shedding. Thromb Haemost,2004,91 (5):951-958.
    [76]Koenen RR, Pruessmeyer J, Soehnlein O, et al.Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases. Blood,2009,113(19):4799-4809.
    [77]Black RA. Tumor necrosis factor-alpha converting enzyme. Int J Biochem Cell Biol,2002,34:1-5.
    [78]Johannes SCHL6NDORFF, J. David BECHERER,Carl P. BLOBEL.Intracellular maturation and localization of the tumour necrosis factor a convertase (TACE) Biochem. J,2000,347:131-138.
    [79]Wolfgang Bergmeier, Crystal L. Piffath, Guiying Cheng, et al. Tumor Necrosis Factor-aConverting Enzyme(AD AM17) Mediates GPIba Shedding From Platelets In Vitro and In Vivo. Circulation Research,2004,95:677-683.
    [80]Wang Z, Shi Q, Yan R, et al.The role of calpain in the regulation of ADAM17-dependent GPIbalpha ectodomain shedding. Arch Biochem Biophys,2010, 495(2):136-43.
    [81]Beer JH, Buchi L, Steiner B. Glycocalicin:a new assay-the normal Plasma levels and its potential usefulness in selected diseases. Blood,1994,83:691-702. [82] Born GV, Cross MJ. The aggregation of blood platelets. J Physiol,1963,168:178-195.
    [83]M.A. Kratzer, G.V. Born. Simulation of primary haemostasis in vitro, Haemostasis,1985,15:357-362.
    [84]Spectre G, Brill A, Gural A, et al. A new point-of-care method for monitoring anti-platelet therapy:application of the cone and plate(let) analyzer. Platelets,2005,16:293-299.
    [85]Bellido-Martin L, Chen V, Jasuja R,et al. Imaging fibrin formation and platelet and endothelial cell activation in vivo.Thromb Haemost,2011,105:776-782.

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