Induction of ischemic tolerance as a promising treatment against diabetic retinopathy

Diabetic retinopathy is a leading cause of acquired blindness, and it is the most common ischemic disorder of the retina. Available treatments are not very effective. Efforts to inhibit diabetic reti- nopathy have focused either on highly specific therapeutic approaches for pharmacologic targets or using genetic approaches to change expression of certain enzymes. However, it might be wise to choose innovative treatment modalities that act by multiple potential mechanisms. The resis- tance to ischemic injury, or ischemic tolerance, can be transiently induced by prior exposure to a non-injurious preconditioning stimulus. A complete functional and histologic protection against retinal ischemic damage can be achieved by previous preconditioning with non-damaging isch- emia. In this review, we will discuss evidence that supports that ischemic conditioning could help avert the dreaded consequences that results from retinal diabetic damage.     

Exosomes containing miR-451a is involved in the protective effect of cerebral ischemic preconditioning against cerebral ischemia and reperfusion injury

AimTo study the role of exosomes in the protective effect of cerebral ischemic preconditioning (cerebral‐IPC) against cerebral I/R injury.MethodMouse models of cerebral‐IPC and MCAO/R were established as described previously, and their behavioral, pathological, and proteomic changes were analyzed. Neuro‐2a subjected to OGD/R were treated with exosomes isolated from the plasma of sham‐operated and cerebral‐IPC mice. The differentially expressed miRNAs between exosomes derived from sham‐operated (S‐exosomes) and preconditioned (IPC‐exosomes) mice were identified through miRNA array, and their targets were identified through database search. The control and OGD/R cells were treated with the IPC‐exosomes, miRNA mimic or target protein inhibitor, and their viability, oxidative, stress and apoptosis rates were measured. The activated pathways were identified by analyzing the levels of relevant proteins.ResultsCerebral‐IPC mitigated the cerebral injury following ischemia and reperfusion, and increased the number of plasma exosomes. IPC‐exosomes increased the survival of Neuro‐2a cells after OGD/R. The miR‐451a targeting Rac1 was upregulated in the IPC‐exosomes relative to S‐exosomes. The miR‐451a mimic and the Rac1 inhibitor NSC23766 reversed OGD/R‐mediated activation of Rac1 and its downstream pathways.ConclusionCerebral‐IPC ameliorated cerebral I/R injury by inducing the release of exosomes containing miR‐451a.     

Neurobrucellosis as an exceptional cause of transient ischemic attacks

We report a series of four cases presented with transient ischemic attacks (TIA) or ischemic stroke as the predominant manifestation of neurobrucellosis (NB). Three of the patients were 20-28 years of age, and one patient was 53 years old. They all used to consume unpasteurized milk or its products. Two patients had systemic brucellosis in the past and received antibiotic treatment. Other causes of TIA including cardiac embolism, hypercoagulability, vascular malformations, systemic vasculitis, and infective endocarditis were excluded. NB was diagnosed with serological tests or cultures for Brucella in the cerebrospinal fluid. None of the patients had any further TIA after the initiation of specific treatment. NB should always be sought in young patients with TIA or ischemic stroke, especially if they have no risk factors for stroke and live in an endemic area for brucellosis, even if they do not have other systemic signs of brucellosis.     

A review of remote ischemic conditioning as a potential strategy for neural repair poststroke

Ischemic stroke is one of the major disabling health-care problem and multiple different approaches are needed to enhance rehabilitation, in which neural repair is the structural basement. Remote ischemic conditioning (RIC) is a strategy to trigger endogenous protect. RIC has been reported to play neuroprotective role in acute stage of stroke, but the effect of RIC on repair process remaining unclear. Several studies have discovered some overlapped mechanisms RIC and neural repair performs. This review provides a hypothesis that RIC is a potential therapeutic strategy on stroke rehabilitation by evaluating the existing evidence and puts forward some remaining questions to clarify and future researches to be performed in the field.     

15-脂氧化酶及其mRNA在局灶性脑缺血预处理大鼠中作用机制的探讨

目的　观察局灶性脑缺血预处理对大鼠脑 15 -脂氧化酶 (15 - L O)表达及其 m RNA(15 - L O m RNA)转录的影响 ,探讨两者在诱导脑缺血耐受中的意义。方法　线栓法制备大鼠局灶性脑预缺血 -缺血再灌注模型 (PC-MCAO)及局灶性单纯脑缺血再灌注模型 (MCAO) ,各组于不同时程用免疫组化法检测 15 - L O的表达、原位杂交法检测 15 - L O m RNA的表达。结果　 PC- MCAO组较对应时程的 MCAO组 15 - L O m RNA及其蛋白 15 - L O的表达强度显著降低 (P<0 .0 5 )。结论　脑预缺血处理可致 15 - L O及其基因表达下调 ,这可能是局灶性脑缺血预处理诱导脑缺血耐受的机制之一。     

局灶性缺血预处理对脑梗死大鼠神经生长因子表达的影响

目的:研究局灶性缺血预处理对脑梗死大鼠神经生长因子(nerve growthfactor,NGF)表达的影响,探讨缺 血预处理诱导脑缺血耐受机制。方法:SD大鼠随机分为3组。预缺血组和假手术组在大脑中动脉缺血(MCAO)前3天 分别接受10min的预缺血或假手术,MCAO 2h后再灌注22h处死;对照组两次均为假手术,比较各组神经功能评分、梗 死体积及NGF的表达。结果:预缺血组神经功能评分、梗死体积较假手术组减少(P<0．05),NGF表达明显高于其余两 组(P<0．01)。结论:局灶性缺血预处理可诱导脑缺血耐受的产生,其作用机制可能与NGF的表达改变有关。     

短暂性脑缺血发作对脑缺血耐受的影响

目的 探讨短暂性脑缺血发作（TIA）在脑缺血耐受方面的临床意义。方法 选择30例TIA后72h内发生脑梗死的患者为试验组（TIA组）,并随机选择30例无TIA史的脑梗死患者作对照组。结果 TIA组和脑梗死组在脑梗死体积、治疗前与治疗后15d,30d,90d的欧洲卒中量表（ESS）评分方面存在统计学差异（8.2 ml vs 10.6 ml;62±22 vs 58±24;70±28 vs 66±32;80±20 vs 76±24;82±18 vs 77±23; P均<0.05）。结论 TIA后发生脑梗死对减轻脑细胞损伤有一定临床意义。     

高龄老年人症状性颈动脉狭窄与颈动脉内膜切除术(附3例临床报告)

目的　探讨高龄老年人症状性颈动脉狭窄的诊断、狭窄程度与颈动脉内膜切除术的有效性。方法　回顾追踪 3例高龄老年人颈动脉内膜切除术前后临床缺血发作症状、颈动脉超声、头颅及颈部磁共振血管造影的变化。结果　 2例患者经颈动脉内膜切除术后 2、5年内缺血发作缓解 ,颈动脉检查狭窄消失 ,1例患者术后 1个月切除部位形成血栓再次出现狭窄。结论　老年人症状性高度颈动脉狭窄者可从手术中获益。     

缺血预处理诱导脑缺血耐受时间依赖性的实验研究

目的探讨缺血预处理诱导缺血耐受的时间依赖性及可能的机制。方法健康SD大鼠110只,采用随机数字表法分为假手术(SS)+大脑中动脉阻塞(MCAO)组(简称SS组)和缺血预处理(IP)+MCAO组(简称IP组),每组50只,另10只备用。将两组大鼠再随机分为5个亚组(n=10),IP组给予预缺血10 min后分别于6 h、24 h、3 d、7d、14 d后给予大脑中动脉完全阻塞22 h,再灌注2 h;SS组未进行缺血预处理,而单纯暴露颈总动脉处的解剖结构10 min,余步骤同IP组。采用Swanson间接法和Nick&Spot图像采集分析系统计算各组大鼠梗死体积,光镜下观察各组脑组织病理变化,采用免疫组化方法检测大鼠脑组织胶质纤维酸性蛋白(GFAP)、脑源性神经营养因子(BDNF)表达。结果给予10 min的大脑中动脉短暂的缺血预处理能够明显减少24 h、3 d、7 d1、4 d后再次缺血后的梗死体积(P<0.05),而6 h时间点脑梗死体积与SS组比较无统计学差异(P>0.05)。与SS组比较,IP组各时间点GFAP和BNDF阳性表达增多(P<0.05),且间隔3 d、7 d组增多明显(P<0.05),14 d后开始逐渐降低。结论 IP不但能引起神经系统损害,而且能够诱导缺血耐受的产生;IP诱导的缺血耐受对IP后3~7 d发生的再缺血损害保护作用最强。BDNF表达基本与缺血耐受的保护作用时间规律一致,提示BDNF可能是脑缺血耐受的重要机制之一。     

The association between high on-treatment platelet reactivity and early recurrence of ischemic events after minor stroke or TIA

Objectives: To evaluate the role of HTPR in predicting early recurrence of ischemic events in patients with minor ischemic stroke or high-risk TIA.

Methods: From January 2014 to September 2014, a single center continuously enrolled patients with minor ischemic stroke or high-risk TIA and gave them antiplatelet therapy consisting of aspirin with clopidogrel. HTPR was assessed by TEG after 7 days of antiplatelet therapy and detected CYP2C19 genotype. The incidence of recurrent ischemic events was assessed 3 months after onset. The incidence of recurrent ischemic events was compared between the HTPR and NTPR groups with the Kaplan-Meier method, and multivariate Cox proportional hazards models were used to determine the risk factors associated with recurrent ischemic events.

Results: We enrolled 278 eligible patients with minor ischemic stroke or high-risk TIA. Through TEG testing, patients with HTPR were 22.7%, and carriers were not associated with HTPR to ADP by TEG-ADP(%) (p = 0.193). A total of 265 patients completed 3 months of follow-up, and Kaplan-Meier analysis showed that patients with HTPR had a higher percentage of recurrent ischemic events compared with patients with NTPR (p = 0.002). In multivariate Cox proportional hazards models, history of ischemic stroke or TIA (HR 4.45, 95% CI 1.77–11.16, p = 0.001) and HTPR (HR 3.34, 95% CI 1.41–7.91, p = 0.006) was independently associated with recurrent ischemic events.

Discussion: In patients with minor stroke or TIA, the prevalence of HTPR was 22.7%, and HTPR was independently associated with recurrent ischemic events.     

短暂性缺血发作对后续大面积脑梗死预后的影响

目的 观察同侧短暂性缺血发作(TIA)对后继大面积脑梗死的影响.方法 将51例首次发病的大面积脑梗死患者,按照是否预先发生同侧的TIA及发生间隔进行分组,采用欧洲卒中评分方法在治疗前及治疗3周时评价各组患者神经功能缺损程度.结果 发病前4周有TIA发生的脑梗死患者较无TIA发作的脑梗死患者入院时及治疗3周后欧洲脑卒中评分有差异(P<0.05),TIA发生时间小于1周者入院时及3周后评分好于病前2～4周发生TIA者,但仅入院时有统计学意义(P<0.05).结论 脑梗死前发生的同侧TIA可能产生缺血耐受现象,对后继发生的脑梗死起保护作用.     

两次线栓法构建脑缺血耐受模型大鼠血脑屏障通透性改变与基质金属蛋白酶9的表达☆

背景：诸多研究证实,短暂性脑缺血预处理可诱导脑缺血耐受。然而,脑缺血耐受的内源性保护机制尚未明确。 目的：观察脑缺血预处理诱导脑缺血耐受大鼠再灌注不同时间窗血脑屏障通透性改变及基质金属蛋白酶9表达的变化。 方法：将Wistar大鼠随机分为3组,缺血预处理组采用线栓法阻塞大脑中动脉10 min建立局灶性缺血预处理模型,分别在缺血预处理后1,3,7,14,21 d进行再次缺血2 h;模型组不进行缺血预处理,假手术组不阻塞血管。于再灌注22 h进行神经功能检测,采用TTC染色测定脑梗死体积,通过测定渗出血管外的伊文思蓝含量来评价血脑屏障通透性的变化,免疫组织化学和原位杂交法检测基质金属蛋白酶9蛋白及mRNA的表达。 结果与结论：与模型组比较,缺血预处理组1,3,7 d亚组的神经功能评分、脑梗死体积、血脑屏障通透性、脑含水量以及基质金属蛋白酶9蛋白和mRNA表达均明显减小/降低(P < 0.05或P < 0.01),其中以3 d亚组降低最为明显。提示缺血预处理诱导了脑缺血耐受,预缺血诱导的血脑屏障通透性改变以及基质金属蛋白酶9表达减低在脑缺血耐受中发挥重要作用。     

皮质下缺血性血管性认知损害患者注意功能障碍的临床研究

目的:观察皮质下缺血性血管性认知功能损害(SIVCI)患者注意亚型障碍的特征。方法:对30例非痴呆型SIVCI(SIVCIND)患者(SIVCIND组)、15例皮质下缺血性血管性痴呆(SIVD)患者(SIVD组)和15名健康志愿者(对照组)采用计算机上持续操作任务(CPT)、Stroop试验及双任务测试法测试持续注意、选择注意和分散注意功能。结果:与对照组比较,SIVD组CPT反应时延长,漏报率增加(P<0.05);SIVCIND组漏报率与对照组比较显著增加,差异有显著统计学意义(P<0.01)。SIVD患者冲突及中性条件下,反应时与错误率及干扰量均增加;SIVCIND患者Stroop试验冲突条件反应时延长(P<0.01)、双任务法耗时差无明显增加(P>0.05);SIVD患者耗时差增加(P<0.01)。结论:SIVCIND早期主要以持续:注意及选择注意功能损害为主,晚期则持续注意、选择注意和分散注意功能普遍受累。     

急性缺血性脑卒中患者血浆sICAM-1水平的研究

目的 :通过对急性缺血性脑卒中患者血浆中的主要粘附分子之一 ,s ICAM- 1水平的测定 ,以明确细胞粘附分子与急性缺血性脑卒中的关系。方法 :选取 2 4小时内发病的卒中组病人 36例 ,18例年龄相匹配的同期其他住院病人作为对照组。卒中组的危险因素与对照组无显著差异。采用 EL ISA法测定两组研究对象血浆的 s ICAM- 1水平。结果 :血浆 s ICAM- 1水平卒中组明显高于对照组 (P<0 .0 1) ,所有卒中患者发病 7天后的 s ICAM- 1水平显著低于起病时 (P<0 .0 1) ,与对照组相比无显著差别 (P>0 .0 5 )。结论 :研究表明在急性脑缺血性卒中的过程中确实存在着细胞粘附分子的合成上调。     

Near‐infrared diffuse reflectance signals for monitoring spreading depolarizations and progression of the lesion in a male rat focal cerebral ischemia model

In ischemic stroke research, a better understanding of the pathophysiology and development of neuroprotection methods are crucial, for which in vivo imaging to monitor spreading depolarizations (SDs) and evolution of tissue damage is desired. Since these events are accompanied by cellular morphological changes, light‐scattering signals, which are sensitive to cellular and subcellular morphology, can be used for monitoring them. In this study, we performed transcranial imaging of near‐infrared (NIR) diffuse reflectance at ～800 nm, which sensitively reflects light‐scattering change, and examined how NIR reflectance is correlated with simultaneously measured cerebral blood flow (CBF) for a rat middle cerebral artery occlusion (MCAO) model. After MCAO, wavelike NIR reflectance changes indicating occurrence of SDs were generated and propagated around the ischemic core for ～90 min, during which time NIR reflectance increased not only within the ischemic core but also in the peripheral region. The area with increased reflectance expanded with increase in the number of SD occurrences, the correlation coefficient being 0.7686 (n = 5). The area with increased reflectance had become infarcted at 24 hr after MCAO. The infarct region was found to be associated with hypoperfusion or no‐flow response to SD, but hyperemia or hypoperfusion followed by hyperemia response to SD was also observed, and the regional heterogeneity seemed to be connected with the rat cerebrovasculature and hence existence/absence of collateral flow. The results suggest that NIR reflectance signals depicted early evolution of tissue damage, which was not seen by CBF changes, and enabled lesion progression monitoring in the present stroke model.     

缺血性脑卒中/短暂性脑缺血发作患者脑动脉病变分布相关危险因素分析

目的 探讨缺血性脑卒中(ischemic stroke,IS)/短暂性脑缺血发作(transient ischemic attack,TIA)脑动脉病变分布的相关危险因素.方法 对169例IS/TIA患者行颈部及颅内脑血管检查,记录血管病变危险因素如年龄、性别、高血压、糖尿病、长期吸烟、长期饮酒等病史,同时记录实验室、心电图、超声心动图、腹部B超、胸X片等检查结果.确定单变量与不同狭窄模式的相关性采用单变量Logistic回归分析,确定不同颅内外大动脉狭窄模式的独立危险因素采用多元逐步和多变量多项分类Logistic回归分析.结果 高龄、长期吸烟及高低密度脂蛋白(LDL-C)是颅内外大动脉狭窄的独立危险因素,发生颅内外大动脉狭窄的风险分别增加了1.83、6.918、1.656倍;脑卒中史(OR=4.816)、长期吸烟(OR=121.608)、高LDL-C(OR=3.067)是单纯颅内大动脉狭窄的独立危险因素;高龄(OR =2.486)、长期吸烟(OR=25.072)、高LDL-C(OR=5.160)是颅内外大动脉狭窄并存的独立危险因素;而高纤维蛋白原(OR =4.790)是单纯颅外大动脉狭窄的独立危险因素.结论 不同类型颅内外大动脉狭窄病变的独立危险因素不同.     

缺血预处理（IPC）对大鼠局灶性脑梗死后HSP70和FOS表达的影响

目的 :研究缺血预处理 (IPC)对局灶性脑梗死后HSP70和FOS表达的影响 ,探讨IPC的脑保护作用机制。方法 :利用线栓法建立局灶性脑缺血 大脑中动脉闭塞模型 (MCAO)。MCAO 10min作为IPC ,IPC后 48h制作永久性大脑中动脉梗死 (PMCAO)模型。了解IPC对PMCAO后大脑神经功能和脑组织学损害的影响 ,免疫组化法研究PMCAO后 3hFOS表达变化以及 2 4h后HSP 70表达变化。结果 :IPC显著减轻PMCAO后大鼠神经功能损害和组织学损害 ,减少PMCAO后FOS、HSP 70的表达。结论 :IPC对其后PMCAO有明显的保护作用 ,能诱导脑缺血耐受 (IT)的产生 ,脑IT的神经保护作用与脑梗死后HSP 70和FOS表达改变密切相关。