缺血性卒中免疫学研究进展

缺血性卒中的病理生理学过程是复杂的、多因素(遗传因素和免疫因素等)参与的免疫炎症反应过程,具有多相性特点,既包括促炎症反应,又包括抗炎症反应,且炎性因子和炎性细胞的表达变化及其效应呈时间依赖性,从而发挥神经损伤或神经保护作用.本文综述缺血性卒中相关免疫学研究进展.     

Large animal ischemic stroke models: replicating human stroke pathophysiology

The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions.Although promising therapeutics have been identified using these animal models,with most undergoing significant testing in rodent models,the vast majority of these interventions have failed in human clinical trials.This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models.Large animal models such as non-human primates,sheep,pigs,and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline.The objective of this review is to highlight key characteristics that potentially make these gyrencephalic,large animal ischemic stroke models more predictive by comparing pathophysiological responses,tissue-level changes,and model limitations.     

缺血性脑卒中的超早期血管再通方法

随着缺血性脑卒中的日益高发和发病年龄的日趋年轻化,对超早期患者给予积极有效的血管再通治疗以恢复血流供应,对于脑卒中的治疗及后期功能康复均具有至关重要的意义。目前应用于临床的血管再通方法主要包括静脉溶栓、动脉溶栓、机械性再通和桥接治疗等。本文介绍了国际公认的缺血性脑卒中超早期临床血管再通方法,并针对缺血性脑卒中超早期血管再通方法应用中存在的一些争议热点进行讨论。     

Advances in treatment of acute ischemic stroke

Stroke carries a severe toll in terms of loss of life and disability for patients and their families. Until 10 years ago, physicians, and in particular neurologists, had a conservative, nonaggresive approach to this devastating disease. The advent of thrombolytic therapy not only proved that acute ischemic stroke is treatable, but also that early reperfusion can dramatically change the outcome of acute stroke patients. As a result of these trials, intravenous (IV) tissue plasminogen activator (t-PA) has been approved for treatment of acute ischemic stroke within 3 hours after symptom onset in the United States, Canada, Australia, and the European Union. The near future is extremely promising. Imaging modalities, such as diffusion- and perfusion-weighted images, as well as CT perfusion and CT angiography, to better select patients for treatment are now routinely performed in most academic medical centers. Novel IV and intra-arterial (IA) agents have been developed and tested. Emerging therapies will soon be available to increase the therapeutic windows for thrombolysis both by better screening patients using MRI or CT and by new IV and IA treatments. Several multicenter controlled trials in both imaging-guided decisions and therapeutic agents are either completed or being performed. We review data on advancement in imaging and treatment of acute ischemic stroke, in particular focusing on pharmacologic and mechanical IA thrombolysis.     

Advances in treatment of acute ischemic stroke

Stroke carries a severe toll in terms of loss of life and disability for patients and their families. Until 10 years ago, physicians, and in particular neurologists, had a conservative, non-aggressive approach to this devastating disease. The advent of thrombolytic therapy not only proved that acute ischemic stroke is treatable, but also that early reperfusion can dramatically change the outcome of acute stroke patients. As a result of these trials, intravenous (IV) tissue plasminogen activator (t-PA) has been approved for treatment of acute ischemic stroke within 3 hours after symptom onset in the United States, Canada, Australia, and the European Union. The near future is extremely promising. Imaging modalities, such as diffusion- and perfusion-weighted images, as well as CT perfusion and CT angiography, to better select patients for treatment are now routinely performed in most academic medical centers. Novel IV and intra-arterial (IA) agents have been developed and tested. Emerging therapies will soon be available to increase the therapeutic windows for thrombolysis both by better screening patients using MRI or CT and by new IV and IA treatments. Several multicenter controlled trials in both imaging-guided decisions and therapeutic agents are either completed or being performed. We review data on advancement in imaging and treatment of acute ischemic stroke, in particular focusing on pharmacologic and mechanical IA thrombolysis.     

急性缺血性卒中影像学研究进展

在我国,随着生活水平的不断提高、工作节奏的加快,以及高血压、糖尿病患者的增多,脑血管病的发病率呈现逐年上升趋势。根据2008年公布的第3次全国死因调查结果,我国居民前5位死因依次为脑血管病、恶性肿瘤、呼吸系统疾病、心脏病,以及损伤和中毒。以13亿人口计,全国每年新发病例约为250万例,死于脑血管病者超过150万例,幸存者600～700万例,病残率高达75%。更为严重的     

长链非编码RNA在缺血性脑卒中的研究进展

缺血性脑卒中是目前影响人类健康,威胁人类生命的主要疾病之一,目前该病已受到越 来越多的关注。长链非编码 RNA（lncRNA）作为基因组中的调节基因具有非常复杂的生物学功能,可以 参与多种细胞生物活动环节,包括染色质重塑、mRNA 可变性剪接、mRNA 降解和蛋白质的翻译等。目 前已发现诸多 lncRNA 在肿瘤、心血管疾病及神经退行性疾病的发生和发展等过程中发挥重要作用,但 是有关 lncRNA 与缺血性脑血管病的研究还很有限。现就 lncRNA 与缺血性卒中的研究进展作一综述。     

Recent advances in pathophysiology and treatment of acute ischemic stroke]

The pathophysiology of ischemic neuronal cell damage has been studied extensively. Intracellular calcium ions, excitatory amino acids, nitric oxide, oxygen free radicals, proteolysis, apoptosis, and so on play important roles. There are also gene expressions following cerebral ischemia, such as the immediately early gene, heat shock protein, cytokines, adhesion molecule, and growth factor, etc. In vessels of the ischemic brain, activation of platelets, leukocytes, the coagulation cascade, and fibrin generation occur and aggravate the cerebral microcirculatory disturbance. Treatment of acute ischemic stroke must be based on the clinical type (atherothrombotic, lacunar or cardioembolic) and the time after onset. Fibrinolysis by tissue plasminogen activator (intravenous administration) is approved in the USA for patients with cerebral infarction within 3 hours after onset. Efficacy of anticoagulant therapy using heparin was not verified by the International Stroke Trial (IST). In Japan selective anti-thrombin agent (argatroban) is used in patients with atherothrombotic cerebral infarction within 48 hours after onset. Results of IST and Chinese Acute Stroke Trial (CAST) showed aspirin within 48 hours after onset of cerebral infarction reduced recurrence of ischemic stroke during the acute stage and death within 6 months.     

Advances in revascularization for acute ischemic stroke treatment

Intravenous thrombolysis with recombinant tissue plasminogen activator is the established treatment for acute ischemic stroke patients presenting within 3 h after stroke onset. In a significant number of patients, however, intravenous thrombolysis with recombinant tissue plasminogen activator remains ineffective. New thrombolytic agents, such as reteplase, tenecteplase or desmoteplase, offer pharmacokinetic and dynamic advantages over recombinant tissue plasminogen activator and have been or are currently being tested for safety and efficacy in clinical trials. Endovascular revascularization is an evolving treatment option enabling mechanical clot disruption or extraction in combination with thrombolysis. Several new endovascular devices have been successfully tested for safety in acute ischemic stroke patients and are now being tested for efficacy in larger clinical trials. Continued innovation and refinement of endovascular technology and techniques is expected to increase technical success with a minimal procedure-related morbidity in the treatment of acute ischemic stroke.     

Effects of vascular endothelial growth factor in ischemic stroke

Vascular endothelial growth factor (VEGF) is a pleiotropic growth factor that is crucially involved in neurovascular remodeling in the ischemic brain. VEGF promotes angiogenesis, protects ischemic neurons from injury, has potent anti‐inflammatory actions, and promotes brain plasticity, in addition to enhancing the recruitment and proliferation of neural precursor cells. These broad actions make VEGF interesting as a model molecule that allows understanding endogenous responses of the brain to injuries. However, several studies indicate that the route and timing of VEGF administration are crucial for the effects of VEGF on ischemic brain tissue. Hence, systemic VEGF delivery in the very acute stroke phase may exacerbate brain damage because of the promotion of blood–brain barrier breakdown that inevitably accompanies vascular growth. Future studies aimed at the promotion of neurovascular remodeling in ischemic stroke should carefully take into consideration pleiotropic actions of angiogenic growth factors beyond vascular growth. © 2012 Wiley Periodicals, Inc.     

Traditional Chinese medicine for vascular protection in ischemic stroke

Although new drugs and intervention strategies have emerged from recent studies of neuroprotection, compared with haemodynamic and hemorheologic factors, knowledge of vascular factors of ischemic stroke is rather limited. In practical terms, any strategy shown to reduce the incidence of fatal and nonfatal vascular events can be termed ＂vascular protection＂, including anti-thrombotic and anti-hypertensive therapies, as well as agents that directly benefit vascular endothelium. Vascular events include myocardial infarction, stroke, and claudication. Factors involved in these events include statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. In traditional Chinese medicine, the principles of ＂activating blood circulation to remove stasis＂, ＂tonifying the kidney and replenishing the essence＂, ＂dispelling pathogenic wind and removing obstruction from the meridians＂, and ＂warming Yang and promoting water metabolism＂ are possibly related to vascular protection. However, more evidence is needed to correlate these positive effects with vascular protection.     

Advances and challenges in treatment and prevention of ischemic stroke

We review recent advances in the treatment and prevention of acute ischemic stroke, including the current state of endovascular therapy, in light of 5 randomized controlled trials published this past year. Although no benefit of endovascular therapy over intravenous (IV) recombinant tissue plasminogen activator (rt‐PA) has been demonstrated, endovascular therapy is an appropriate treatment for acute ischemic stroke patients within the t‐PA window who are ineligible for IV t‐PA but have a large vascular occlusion. These trials reveal promises and current limitations of endovascular therapy, and comparison of reperfusion therapies remains an important area of research. One common theme is the strong association between a faster time to reperfusion, improved outcome, and reduced mortality. Primary and secondary stroke prevention trials emphasize the importance of aggressive management of medical risk factors as part of any preventative strategy. New oral anticoagulants, for example, offer cost‐effective risk reduction in patients with atrial fibrillation, and may represent an opportunity for those with cryptogenic stroke. We highlight areas of unmet need and promising research in stroke, including the need to deliver proven therapies to more patients, and the need to recruit patients into clinical trials that better define the role of endovascular and other stroke therapies. Finally, improvement in strategies to recover speech, cognition, and motor function has the potential to benefit far more stroke patients than any acute stroke therapy, and represents the greatest opportunity for research in the coming century. Ann Neurol 2013;74:363–372     

Polymorphisms and vascular cognitive impairment after ischemic stroke

Environmental and genetic factors may both affect the risk of vascular cognitive impairment developing after a stroke. To identify factors affecting this risk, the cognitive status of 121 patients was examined 3 months after an ischemic stroke. In all patients and in 270 control subjects, 7 polymorphisms reported to affect risk of vascular ischemic disease were genotyped. In 51 patients (42.1%), vascular cognitive impairment resulted, defined by a Mini-Mental State Examination score of less than 24. These patients were older and more likely to be women. Alleles of none of the polymorphisms differed between patients with or without vascular cognitive impairment, except for glutamate-cysteine ligase modifier (GCLM) (odds ratio = 2.8, P = .006). When all stroke patients were considered, the GCLM genotype did not affect Mini-Mental State Examination scores. Testing the GCLM genotype in an independent group of stroke patients may determine whether this association with vascular cognitive impairment is genuine.     

Advances in minimally invasive treatment of hemorrhagic and ischemic stroke

正Cerebrovascular diseases,including ischemic and hemorrhagic strokes,affect more than 6 million US adults annually.Strokes cause high rates of morbidity and mortality due to the central nervous system’s sensitivity to disruptions in blood flow,and are refractory to traditional surgical interventions.A variety of minimally invasive surgical and endovascular approaches have recently been developed to improve patient outcomes following stroke.     

Relaxin in vascular physiology and pathophysiology: possible implications in ischemic brain disease

The hormone relaxin, known for its action on the female reproductive tract, is also able to act on organs and systems different from the reproductive ones, including the blood vessels, the heart and the brain. Relaxin causes vasodilation in several organs stimulating the biosynthetic pathway of nitric oxide (NO), a potent vasodilator. Relaxin also has a cardioprotective action: it reduces the inflammatory activation of neutrophils and their adhesion to the endothelium, and protects against myocardial injury caused by ischemia and reperfusion (I-R) in experimental animal models of myocardial infarction. Its mechanisms of action chiefly depend on the hormone's vasodilatory and anti-inflammatory properties. Recently, an additional form of relaxin has been discovered in the brain, where it has been postulated to act locally as a neurotransmitter. Relaxin, acting mainly on circumventricular organs, stimulates water drinking and vasopressin release and appears to be involved in the regulation of behavioural processes. Based on its properties on the cardiovascular system, it is possible to hypothesise that relaxin could regulate the vascular tone in the central nervous system and, going a step further, could protect the brain from IR-induced damage, possibly by an NO-mediated mechanism. This latter possibility is supported by the observation that relaxin is able to up regulate the endogenous production of NO in several target cells, as NO, at appropriate levels, is known to be involved in the protection against neural pathophysiological processes such as I-R-induced injury.     

Hyperglycemia in acute ischemic stroke: a vascular perspective.

Admission hyperglycemia complicates approximately one-third of acute ischemic strokes and is associated with a worse clinical outcome. Both human and animal studies have showed that hyperglycemia is particularly detrimental in ischemia/reperfusion. Decreased reperfusion blood flow has been observed after middle cerebral artery occlusion in acutely hyperglycemic animals, suggesting the vasculature as an important site of hyperglycemic reperfusion injury. This paper reviews biochemical and molecular pathways in the vasculature that are rapidly affected by hyperglycemia and concludes that these changes result in a pro-vasoconstrictive, pro-thrombotic and pro-inflammatory phenotype that renders the vasculature vulnerable to reperfusion injury. Understanding these pathways should lead to the development of rational therapies that reduce hyperglycemic reperfusion injury and thus improve outcome in this large subset of acute ischemic stroke patients.     

急性缺血性脑卒中血管内治疗的临床研究进展

急性缺血性脑卒中发病率和致残率高,及早恢复血流有助于改善患者的预后,机械取栓因其时间窗相对宽以及血管再通率高而备受关注。机械取栓在医疗器械上经历了从MERCI取栓系统到Solitaire FR支架、Revive SE取栓器、3D支架取栓器和Penumbra系统等的改进,取栓成功率和90 d良好预后率（改良Ranking评分低于2分）逐渐得到提高。对取栓治疗失败的补救措施进行研究。而且对特殊人群（醒后卒中、儿童、高龄、妊娠）脑卒中的取栓应用也有成功使用的研究报道。总之,机械取栓能够有效开通急性闭塞的脑部大血管,从而及时恢复急性缺血脑组织的血液供应,达到改善急性缺血性脑卒中患者预后的效果。随着取栓医疗器械和技术的不断进步,效果越来越好。