基于系统生物学整合技术挖掘结直肠癌形成中的核心通路和驱动基因

目的 探索结直肠癌(Colorectal carcinoma, CRC)形成中的核心通路和关键基因;方法 利用Meta分析技术从以往5项CRC发生相关转录组学研究中筛选癌及癌旁差异表达基因;ComBat方法合并5项研究的癌组织基因表达谱数据,针对上述差异表达基因用PCIT软件进行共表达网络构建;CFinder软件揭示该共表达网络中存在的核心亚网络,并用Gather软件确定主要核心亚网络所富集的生物学功能;以重要核心亚网络（或通路）为重点,联合节点基因在CRC中的表达变化方向和相应染色体区域扩增或缺失的信息,发现亚网络功能形成中的候选驱动基因。结果 Meta分析转录组学研究共发现差异表达基因2073个,其中在5项研究中癌组织一致上调1174个,一致下调899个,这些基因在CRC样本中形成的共表达网络包括798个基因节点和1462条边,存在22个核心亚网络;最大的核心亚网络由77个基因和436条边组成,功能涉及细胞周期和增殖信号调控,UBE2C、MYBL2、FAM83D、AURKA、TPX2等11个基因被预测为该信号功能的驱动基因。结论 细胞周期和增殖信号通路是结直肠癌发生中的核心通路,UBE2C和AURKA等11个基因是该核心通路的驱动基因。     

Cigarette smoking and risk of primary intracerebral haemorrhage

From September 1985 to December 1989 a total of 158 patients had primary intracerebral haemorrhage in the population of 116000 in the Jyväskylä Region, Central Finland. All had the diagnosis confirmed by either computerised tomography or necropsy, and information on cigarette smoking habits was available in 155 patients, 20% of whom were current cigarette smokers. One control was selected for each of the 155 patients matched on sex, age, and residence from the census of Central Finland. The odds ratio of primary intracerebral haemorrhage of current cigarette smokers compared with current non-smokers was estimated on basis of the number of discordant pairs as 1.4 (95% confidence interval 0.7 to 2.8). Adjustment for hypertension or diabetes did not change this estimate. Our data did not show evidence of an positive association of cigarette smoking and risk of primary intracerebral haemorrhage. This assumption was strenghtened when the results of previous studies and the present study were pooled giving an odds ratio of 1.0 (95% confidence interval 0.8 to 1.3).     

HIPDM single photon emission computed tomography brain imaging in partial onset secondarily generalized tonic-clonic seizures

HIPDM-Single photon emission computed tomography brain imaging was performed during interictal and ictal stages in three patients with complex partial seizures and secondarily generalized tonic-clonic seizures. In all three patients, interictal studies demonstrated decreased regional cerebral perfusion (rCP) and ictal studies showed increased rCP in the epileptogenic region. The demonstration of focal hyperperfusion by SPECT performed during secondarily generalized tonic-clonic seizures suggests that rCP in the epileptic focus remains higher than in other cerebral regions during immediate postictal stages, even in secondarily generalized seizures.     

小胶质细胞活化在脑缺血耐受中的双重作用

目的 观察局灶性缺血预处理对小胶质细胞活化的影响,探讨小胶质细胞在内源性神经保护机制中的作用.方法 48只SD大鼠按随机数字表法分为空白对照组(SS+SS)、缺血预处理组(IPC+SS)、假手术+缺血组(SS+MCAO)、缺血预处理+再缺血组(IPC+MCAO),每组各12只.运用TTC染色、组织化学染色、透射电镜和图像方法分析比较各组大鼠梗死灶体积、超微结构及小胶质细胞活化的变化.结果 与SS+MCAO组相比,IPC+MCAO组脑梗死灶体积明显缩小,比较差异有统计学意义(P＜0.05),超微结构改变较轻.IPC+MCAO组及SS+MCAO组的小胶质细胞活化水平均较IPC+SS组增高,但二者相比,IPC+MCAO组明显低于SS+MCAO组,比较差异有统计学意义(P＜0.05).结论 小胶质细胞活化在脑缺血耐受中具有双重作用,其介导的轻微炎性过程可能是局灶性缺血预处理启动内源性神经保护的重要分子机制.     

Thrombolysis safety and effectiveness in acute ischemic stroke patients with pre-morbid disability

IntroductionRecombinant tissue plasminogen activator (rt-PA) is the first-line therapy demonstrated to be safe and effective in acute ischemic stroke. People with pre-existing severe dementia or physical disability are usually excluded from rt-PA. The aim of our study was to investigate rt-PA safety and effectiveness in acute stroke with pre-existing disability (mRS ≥ 2).MethodsThe study encompassed 35 acute ischemic stroke patients with mRS ≥ 2 treated with rt-PA. In order to assess the differences in clinical outcome in three disability groups (mRS = 2; 3; 4/5), the following parameters were evaluated: intracerebral hemorrhage, mortality, NIHSS, ΔNIHSS and mRS.ResultsBaseline-NIHSS and age were not significantly different among groups. Mortality was higher in the pre-morbid mRS 4/5 group (44%) than in the pre-morbid mRS 2 (16.7%) and mRS 3 groups (21.4%). In survived patients, median ΔNIHSS% was higher in the mRS 2 and 3 groups (-63.3% and −92.3%, respectively) than in the mRS 4/5 group (−9.1%). The 247 rt-PA treated subjects with mRS < 2 in the same period showed lower mortality rate (4.7%), lower sICH (5%), lower mRS at discharge (median 1; range 0–6) and similar ΔNIHSS% (−75%).ConclusionPatients with mRS 2 and 3 may benefit from rt-PA with a moderate risk of sICH and mortality.     

Nicardipine Associated Risk of Short-Term Mortality in Critically Ill Patients with Ischemic Stroke

Background: Hypertensive emergency is commonly associated with acute ischemic stroke and can be a predictor of poor outcome in these patients. Nicardipine and labetalol are commonly administered for the treatment of acute hypertension following stroke. Yet, data are lacking on the safety of these agents in this setting. Objective: This study aimed to determine all-cause in-hospital mortality, medication-related hypotensive episodes, development of hospital acquired infections and hospital length of stay between nicardipine and labetalol use for the management of hypertension after acute ischemic stroke. Methods: This retrospective study used a prospective database of individuals admitted to the neurointensive care unit at a university-based hospital over 39 months. Patients with confirmed ischemic strokes were included in this analysis. Data were recorded for administration of nicardipine and labetalol following acute stroke. Results: A total of 244 patients with acute ischemic stroke were included in this analysis (mean age, 64.3 ± 15 years; 52.2% males). Nicardipine use after acute ischemic stroke was associated with an increased risk of 30-day mortality (odds ratio [OR]: 4.6, 95% confidence interval [CI] 1.3-15.7; P = .02). A single episode of hypotension in the first 72hours of admission was also significantly associated with mortality (OR 4.35 [95% CI 1.2-14.9]; P = .02). Conclusions: Nicardipine was associated with an increased risk of short-term mortality after acute ischemic stroke. This may have been due to hypotension, tachycardia, or pulmonary edema which were not apparent in our study. Further studies are required to elucidate the cause of this association.     

血小板减少合并缺血性卒中的诊治进展

在临床中，如果免疫性血小板减少（immune thrombocytopenia，ITP）、肝素诱发的血小板减少 （heparin-induced thrombocytopenia，HIT）、血栓性血小板减少性紫癜（thrombotic thrombocytopenic purpura， TTP）等血小板减少疾病患者合并缺血性卒中，其治疗存在矛盾。本文对血小板减少的病因机制及血小 板减少合并急性缺血性卒中时静脉溶栓、机械取栓及抗血小板治疗等方面的研究进展进行了综述。     

西安地区伴心房颤动老年急性缺血性卒中患者临床特征及1年预后分析

目的 探讨西安地区伴心房颤动老年急性缺血性卒中（acute ischemic stroke,AIS）患者临床特征及1 年预后情况。 方法 通过西安卒中数据库平台,收集西安市4所三级甲等医院2015年1-12月连续入院的老年AIS （年龄≥65岁）患者的临床资料,比较分析伴心房颤动老年AIS患者的临床特征;登记随访1年的结局 事件（包括卒中复发、死亡和预后不良）,通过多因素Logi sti c回归分析,探讨西安地区伴心房颤动老 年AIS患者1年不良预后的独立危险因素。 结果 研究最终纳入老年AIS患者1239例,其中伴心房颤动者133例（10.7%）。与不伴心房颤动组相比, 伴心房颤动老年AIS患者的年龄大（[ 77.7±6.3）岁 vs（74.0±6.1）岁,P=0.019]、出院mRS评分高（2.0 分 vs 1.0分,P <0.001）、出院NIHSS评分≥14分比例高（16.5% vs 3.1%,P <0.001）、合并肺炎患者比例 高（21.1% vs 5.8%,P <0.001）、入院48 h不能行走的患者比例高（63.0% vs 36.1%,P <0.001）、空腹 血糖水平高[（6.3±3.0）mmol/L vs（5.8±2.0）mmol/L,P =0.037]、LDL-C水平低[（2.4±0.7）mmol/L vs （2.5±0.8）mmol/L,P =0.031]。伴心房颤动老年AIS患者1年卒中复发率高（15.8% vs 5.9%,P =0.020）、 死亡率高（32.3% vs 9.2%,P <0.001）、预后不良率高（51.9% vs 25.9%,P <0.001）。校正相关混杂 因素后,多因素Logistic回归分析显示,心房颤动是老年AIS患者1年死亡风险的独立影响因素（OR 2.45, 95%CI 1.26～4.78,P =0.008）,但不是1年卒中复发和预后不良的独立影响因素（P >0.05）。 结论 相比不伴心房颤动组,西安地区伴心房颤动老年AIS患者年龄更大、卒中所致残障及神经功 能缺损更重、合并肺炎和入院48 h不能行走的患者比例较高;伴心房颤动老年AIS患者1年死亡风险显 著升高。     

Filling the gaps on stroke research: Focus on inflammation and immunity

For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19.We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.     

The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice

PurposeCerebral ischemia induces a profound neuro-inflammatory response, but the underlying molecular mechanisms are poorly understood. Inflammasomes (NLRP1, NLRP3, NLRC4, AIM2) are intracellular multi-protein complexes which can induce sets of pro-inflammatory cyto- and chemokines, and thereby guide inflammation. We, here, assessed the functional role of NLRP3 in ischemia/reperfusion (I/R) injury in a mouse model of transient cerebral ischemia.MethodsIschemic stroke was induced in C57Bl/6 mice by 60 min transient middle cerebral artery occlusion (tMCAO) and 3, 7 or 23 h of reperfusion, a paradigm of I/R injury. The expression patterns of inflammasomes in the ischemic hemispheres were evaluated by semiquantitative real-time PCR and Western Blot analysis accompanied by protein localization using immunocytochemistry. Finally, animals were treated with the inflammasome inhibitors Sulforaphane, Genipin, MCC950 or vehicle, directly before or upon recanalization after tMCAO. Stroke outcome was assessed, including infarct size and functional deficits, local inflammatory response, neuronal survival as well as blood–brain barrier function on day 1 after tMCAO.ResultsAfter tMCAO the relative gene expression levels of NLRP3 increased 20-30x within 1 day in the ischemic hemisphere which translated into an increased expression of NLRP3 in neurons. Accordingly, the gene expression levels of the NLRP3-modulator, Bruton’s Tyrosine Kinase (BTK), and the NLRP3-inducible cytokine IL-1β significantly rose. Lesser or non-significant changes were seen for the other inflammasomes. Application of inflammasome inhibitors covering all inflammasomes or specifically NLRP3 significantly reduced infarct volumes when given before or after tMCAO and was accompanied by clear evidence for reduced activation of caspase 1. This stroke attenuating effect coincided with less immune cell infiltration in the ischemic hemisphere and preservation of the blood–brain barrier integrity.ConclusionsOur data show that induction of the NLRP3 inflammasome in neurons drives neuroinflammation in acute ischemic stroke. Early blockade of NLRP3 protects from I/R injury by mitigating inflammation and stabilizing the blood–brain barrier.