P糖蛋白在难治性癫痫耐药机制中作用的研究进展

难治性癫痫的耐药机制一直是研究的焦点.近年来,通过对脑组织P糖蛋白及其他耐药相关蛋白的研究发现,无论是在动物还是临床患者身上,难治性癫痫试验均存在P糖蛋白表达量增高现象;而且癫痫发作还会引起P糖蛋白表达部位增加,一定程度上促进了难治性癫痫的耐药机制阐明.基于此原理,人们对P糖蛋白抑制剂进行研究,为将来解决难治性癫痫的新药研发起到促进作用.文中综述癫痫耐药机制、多药耐药转运体学说、P糖蛋白的特征以及在癫痫耐药中的作用机制研究进展,并展望P糖蛋白抑制剂治疗难治性癫痫的前景.     

难治性癫痫患者致痫灶中CX43的表达

目的探讨由CX43组成的缝隙连接在难治性癫痫患者致痫灶脑组织中的表达,为难治性癫痫的临床研究及治疗提供新的思路。方法以24例行手术治疗的难治性癫痫患者为实验组,6例脑外伤急诊手术患者为对照组,采集其手术切除的致痫灶脑组织,应用免疫组织化学方法,观察CX43的表达并与对照组进行比较。结果免疫组织化学方法检测显示实验组CX43的表达高于对照组(P<0.001)。结论难治性癫痫患者致痫灶脑组织中CX43表达增高,提示CX43所形成的缝隙连接参与癫痫活动,可能在癫痫的发生、发展中发挥重要的作用。     

TRPC6在结节性硬化症癫痫患者皮层脑组织中的表达

目的 研究瞬时受体电位通道蛋白C6 (TRPC6)在结节性硬化症(TSC)癫痫患者皮层脑组织的表达与分布,探讨TRPC6通道参与结节性硬化致痫的可能机制.方法 收集手术切除并经病理检测证实是TSC癫痫患者的皮层脑组织标本18例,与7例正常对照皮层脑组织比较,通过采用Western blot、免疫组化、免疫荧光双标,检测TRPC6在正常脑组织与TSC病理标本中的表达分布情况.结果 Western blot蛋白检测结果显示,在TSC和对照大脑皮质(CTX) TRPC6均在相应的分子量94KDa处有特异性蛋白条带,与CTX比较,TSC组TRPC6条带与内参GAPDH条带灰度值之比显著增高(P＜0.05);免疫组化及免疫荧光双标结果显示,TRPC6在TSC病灶中免疫强度明显增高,且特异性高表达于皮层损伤区致痫灶中的异构神经元.包括特征性的巨形细胞(GCs)、异形神经元(DNs).结论 TRPC6在结节性硬化症患者致痫皮层脑组织中表达异常增高,特异性的细胞分布模式可能与癫痫发病密切相关.     

难治性癫痫致病灶术前定位EEG联合fMRI检查的临床评价

目的:探讨分析同步EEG联合fMRI检查对难治性癫痫致痫灶定位的意义。方法:予17例难治性癫痫术前同步EEG联合FMRI检查。分析当EEG出现痫样放电时的fMRI检查数据,这时脑组织血氧水平依赖信号会因痫样放电产生改变并呈现于MRI图像上,以确定致痫灶。将深部电极EEG及脑皮质电极术中确定的位置与该位置进行比较,以评价该位置确定的准确性。结果:10例患者同步EEG联合fMRI检查与术中致痫灶的范围和位置无差别;7例患者同步EEG联合fMRI检查确定的致痫灶中心位置与术中确定的位置一致,但是范围不够准确,较后者稍大。术后14例发作控制,3例虽未完全控制,发作率明显降低。结论:EEG联合fMRI检查对难治性癫痫致痫灶定位准确且无创伤,可用作术前定位。     

胃癌患者P-糖蛋白与P53蛋白表达及临床意义

目的 研究胃癌患者P-糖蛋白与P53蛋白的表达及相互关系。方法 应用免疫组织化学方法对30例胃癌患者P-糖蛋白与P53蛋白表达进行检测。结果 发现P-糖蛋白表达阳性者占60％;P53蛋白表达阳性者占40％;两者的表达相互关联。结论 结果显示P53蛋白与胃癌患者的多药耐药相关。     

胃癌与大肠癌患者P53蛋白与P-糖蛋白表达异同及临床意义

目的研究胃癌与大肠癌患者P53蛋白与P-糖蛋白的表达异同与临床意义.方法应用免疫组织化学方法对49例胃癌患者与50例大肠癌患者P53蛋白与P-糖蛋白表达进行检测.结果发现在胃肠癌患者中,P53蛋白阳性表达者占41%,P-糖蛋白阳性表达者占63%,两者的表达有相互关联,在大肠癌患者中P53蛋白阳性表达者占52%,P-糖蛋白阳性表达者占5 0%,两者表达亦正相关.而胃癌患者与大肠癌患者在P53蛋白与P-糖蛋白表达结果分析相类似.结论结果显示在胃癌和大肠癌患者中P53蛋白表达与患者的多药耐药相关.     

海人酸致痫大鼠中多药耐药相关蛋白1和主穹窿蛋白的表达及作用

目的:探讨多药耐药相关蛋白1(MRP1)和主穹窿蛋白(MVP)在难治性癫痫中的耐药机制.方法:用免疫组化法检测海人酸(KA)致痫大鼠海马组织中MRP1和MVP的表达,应用SPSS17.0软件进行统计分析.结果:KA组的MRP1和MVP的表达均比对照组明显增高(P<0.01).KA组的MRP1和MVP的表达相似,随时间段...     

正电子发射断层扫描与视频脑电图在难治性癫痫致痫灶的术前定位研究

<正>对药物难治性癫痫常进行癫痫外科术前评估,如能准确定位的局灶性癫痫考虑手术治疗,否则继续进行药物治疗或其他疗法。目前,术前致痫灶定位的方法是结合临床发作症状学、各种脑电图检查、神经影像学及脑磁图(MEG)等结果综合评估定位,术前准确的癫痫灶定位和大脑功能区评价与手术方式的选择及疗效密切相关。视频脑     

前列地尔对局灶性脑缺血大鼠脑组织p53的影响

目的:从脑组织p53的表达变化的角度来探讨前列地尔对大鼠局灶性脑缺血的防治机制及其量效关系。方法:采用大脑中动脉闭塞方法建立局灶性脑缺血动物模型,观察低、中、高剂量前列地尔对局灶性脑缺血大鼠大脑皮质p53表达的影响。结果:前列地尔各组大鼠脑组织p53表达平均灰度分别为115.75±11.38、140.13±11.38、156.21±10.05,均高于缺血对照组97.91±10.01。结论:前列地尔防治大鼠局灶性脑缺血损伤的机制可能与抑制脑组织p53表达有关,且以高剂量效果较好。     

视频脑电图与发作期SPECT对痫灶定位的比较分析

目的：比较视频脑电图与发作期SPECT对痫灶定位的临床效果。方法比较分析我院收治的62例难治性癫痫患者VEEG和SPECT检查结果。结果两组局灶性病灶、一侧多灶和双侧病灶比较,差异具有显著性（P＜0.05）;本组62例患者VEEG与SPECT发作期检查结果吻合率较高（74.19%）。结论癫痫病患者发作期VEEG与SPECT检查结果一致性较高,联合应用能够准确定位痫灶,为诊断和治疗提供准确依据。     

磁共振波谱分析及皮层脑电图在难治性癫痫手术中的定位意义

目的 探讨磁共振波谱分析结合皮层脑电图在手术治疗难治性癫痫定位癫痫灶的意义.方法 对16例难治性癫痫患者,根据其临床发作类型、体征、磁共振波谱分析、皮层脑电图定位癫痫灶,同时对癫痫灶进行手术干预.结果 随诊6个月～5年.根据1996年Engel疗效分级标准评测:Ⅰ级为10例、Ⅱ级为2例、Ⅲ级为3例、Ⅳ级为1例.Ⅰ级、Ⅱ级12例为临床治愈,Ⅲ级3例为好转,治愈率为75％,治愈好转率为93.8％.结论 磁共振波谱分析可在癫痫外科术前评估中发挥重要作用,结合皮层脑电图可提高致痫灶定位的准确率,提高手术的效果.     

膀胱移行细胞癌P-糖蛋白与Survivin、Fas表达及其相关性研究

目的：探讨膀胱移行细胞癌中P-糖蛋白（P-GP）与Survivin、Fas表达的相互关系及其与膀胱癌生物学行为之间的相关性。方法：应用免疫组织化学方法检测64例膀胱移行细胞癌和12例正常膀胱黏膜中P-GP、Survivin、Fas的表达。结果：膀胱移行细胞癌中P-GP、Survivin的表达阳性率高于正常黏膜，与膀胱癌的分级有关（P〈0．01）；而Fas在膀胱正常黏膜中表达高于移行细胞癌，差异有统计学意义（P〈0．01）。复发性膀胱癌P—GP的阳性表达率高于初发膀胱癌（P〈0．01）。膀胱移行细胞癌P—GP、Survivin的表达与Fas呈负相关，而P—GP与Survivin表达无关。结论：膀胱移行细胞癌的多药耐药P-GP与Fas的表达密切相关，与Survivin的表达无关。本研究为采用MDR逆转剂或Fas干扰剂以增加膀胱移行细胞癌的化疗敏感性提供实验依据。     

颞叶癫痫的手术治疗(附26例报告)

目的提高药物难治性癫痫的致痫灶精确定位和外科治疗水平。方法对26例颞叶癫痫患者应用长程视频脑电进行术前监测定位和皮层电极、深部电极进行术中定位;采用显微外科技术进行病灶+颞叶切除或颞叶+海马杏仁核切除。结果26例患者根据脑电图,18例患者根据MRI检查定位了致痫灶。术后无病死和严重并发症,服用抗癫痫药物减少;随访6～18个月,1级16例,2级6例,3级4例。结论长程视频脑电图和MRI检查是定位癫痫灶可靠的检查方法。应用显微外科技术可减少并发症,取得较好的治疗效果。     

Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats

Aim:

To investigate the changes of expression and function of P-glycoprotein (P-GP) in cerebral cortex, hippocampus, liver, intestinal mucosa and kidney of streptozocin-induced diabetic rats.

Methods:

Diabetic rats were prepared via a single dose of streptozocin (65 mg/kg, ip). Abcb1/P-GP mRNA and protein expression levels in tissues were evaluated using quantitative real time polymerase chain reaction (QRT-PCR) analysis and Western blot, respectively. P-GP function was investigated via measuring tissue-to-plasma concentration ratios and body fluid excretion percentages of rhodamine 123.

Results:

In 5- and 8-week diabetic rats, Abcb1a mRNA levels were significantly decreased in cerebral cortices and intestinal mucosa, but dramatically increased in hippocampus and kidney. In liver, the level was increased in 5-week diabetic rats, and decreased in 8-week diabetic rats. Abcb1b mRNA levels were increased in cerebral cortex, hippocampus and kidney, but reduced in liver and intestinal mucosa in the diabetic rats. Western blot results were in accordance with the alterations of Abcb1a mRNA levels in most tissues examined. P-GP activity was markedly decreased in most tissues of diabetic rats, except kidney tissues.

Conclusion:

Alterations in the expression and function of Abcb1/P-GP under diabetic conditions are tissue specific, Abcb1 specific and diabetic duration-dependent.     

难治性癫痫的耐药机理

癫痫是一种常见病，但约30％为难治型，一些证据表明多种药物转运蛋白如P—糖蛋白(P—GP)和多种药物抗结合蛋白(MRP)在癫痫脑组织中过量表达，从而减少了抗癫痫药物进入癫痫神经元的量，这一假设可能是产生癫痫抗药性的原因之一，这方面有待进一步研究。     

难治性癫痫患者的苯妥英钠血药浓度监测及用药分析

本文对38例服用苯妥英钠的难治性癫痫患者进行血药浓度监测和用药分析.结果38例中,中毒人数为21例,用药不足人数7例.提示难治性癫痫患者与苯妥英钠的用药水平有关,临床应用苯妥英钠应个体化,每位患者的治疗剂量不能只凭经验用药,必须进行血药浓度监测.     

乙肝核心抗体IgM在癫痫持续状态中的相关作用

目的探讨乙肝病毒核心抗体（HBcIgM）及其它伴随因素在癫痫持续状态中的作用。方法采取21例癫痫持续状态与32例非持续状态癫痫病人的血液行乙肝两对半定量及电解质检测，同时头颅CT、脑电图辅助定位、定性检查，并行病史和一般情况调查。结果癫痫持续状态组病人乙肝两对半检测HBcIgM大于5U者较癫痫非持续状态组显著增高（P〈0．05），血清钾增高，年龄偏小也较对照组差异有显著意义（P〈0．05）。结论HBclgM的大量复制及高血钾与低龄癫痫持续状态的发病可能有关。     

Insulin therapy restores impaired function and expression of P-glycoprotein in blood-brain barrier of experimental diabetes

We aimed to investigate effects of insulin on function and expression of P-glycoprotein (P-GP) in the blood-brain barrier of streptozotocin (STZ)-induced diabetic rats. Brain-to-plasma concentration ratio of vincristine (VCR) in rats was used as an indicator of in vivo function of P-GP. Western blot and quantitative real time-polymerase chain reaction were used to determine protein levels of P-GP and its mdr1a/mdr1b mRNA levels, respectively, in cerebral cortex of rats. In vitro effects of insulin on function and expression of P-GP in primarily cultured rat brain microvessel endothelial cells (rBMECs) were evaluated using rhodamine 123 (Rho123) uptakes and Western blot, respectively. The results showed that 3- and 5-week insulin treatment alleviated the impaired efflux function, expression and mdr1a/mdr1b mRNA levels of P-GP in cerebral cortex of diabetic rats. The 3- and 5-week insulin treatments also significantly enhanced P-GP levels and mdr1a/mdr1b mRNA levels in the cerebral cortex of normal rats. Addition of insulin to the insulin-deficient diabetic rat serum normalized the impaired function and expression of P-GP in rBMECs cultured in diabetic rat serum. When incubated with normal culture medium containing different levels of insulin, the rBMECs exhibited the enhanced P-GP levels and the reduced Rho123 uptake in a concentration-dependent manner. So we may conclude that appropriate level of insulin plays an important role in maintaining the normal function of BBB through regulating the function and expression of P-GP in the diabetic and normal rats.     

拉莫三嗪对难治性癫痫的治疗作用

目的：评价拉莫三嗪对难治性癫痫的治疗作用和安全性。方法：难治性癫痫病人７６例治疗前３ｍｏ开始填写发作的逐日志，完成后随机分成单盲、安慰剂对照（ｎ＝４４）与双盲、交叉、安慰剂对照（ｎ＝３２）２组，保持原用抗痫药不变，按５０～４００ｍｇ／ｄ（未用丙戊酸者）或２５～２００ｍｇ／ｄ（用丙戊酸者），ｑｏｄ，ｑｎ或ｂｉｄ加用拉莫三嗪，对照组用同等剂量的维生素Ｃ，３ｍｏ为一个疗程。结果：拉莫三嗪有效率为５６％，不良反应较轻。结论：拉莫三嗪治疗难治性癫痫是有效和安全的。     

Development of a refractory gastro-oesophageal reflux score using an administrative claims database

Aliment Pharmacol Ther 2011; 34: 555–567

Summary

Background Approximately one‐third of gastro‐oesophageal reflux disease (GERD) patients demonstrate refractory symptoms following treatment with proton pump inhibitor (PPI) therapy. Aim To develop a refractory GERD score that can be applied to predict patients’ healthcare utilisation. Methods We enrolled adults (≥18 years) with a diagnosis of GERD. Refractory GERD was evaluated on an 8‐point scale where 1 point was given for each of the following criteria: doubling, addition, or switching of GERD medication dose, receipt of a GERD‐related endoscopic procedure or surgery, or ≥3 GERD‐related outpatient visits. Refractory GERD was defined as the presence of two or more points. Results A total of 135 139 GERD patients (44% male) were analysed with a mean (±s.d.) age of 52.9 ± 15 years. The mean overall refractory GERD score was 1.12 ± 1.2 (range 0–8 on an 8‐point scale); 31% of patients had refractory GERD with a mean score of 2.56 ± 0.82. Among patients with refractory GERD, 31% doubled their GERD medication, 28% added a new GERD medication, 60% switched GERD medications, 54% had a GERD‐related procedure and 1% had a GERD‐related surgery. Patients with refractory GERD were more likely to be female (59% vs. 55%, P < 0.001) and had a higher co‐morbidity score (0.78 vs. 0.56, P < 0.001). The overall mean costs for refractory patients during the study period were significantly higher compared with treatment‐responsive patients ($18 088 ± $36 220 vs. $11 044 ± $22 955, P < 0.001). Conclusions Refractory GERD was present in approximately one‐third of the GERD patients. We created a GERD refractory score that could define need for increased anti‐reflux therapy and predict higher healthcare resource utilisation.