New players in old amyloid precursor protein-processing pathways

The amyloid precursor protein (APP) gives rise to beta-amyloid peptides, which are the main constituents of senile plaques in brains of Alzheimer's disease (AD) patients. The generation of beta-amyloid peptides requires the enzymatic activity of the beta-site APP-cleaving enzyme 1 (BACE1). BACE1 is primarily expressed by neurons and increased BACE1 protein concentrations and enzymatic activities have been reported in the brains of AD patients. However, there is accumulating evidence that, in addition to neurons, reactive astrocytes are capable of expressing BACE1 and, therefore, may contribute to beta-amyloid plaque formation. This suggests that conditions accompanied by chronic astrocyte activation may contribute to developing AD. Non-amyloidogenic processing of the APP can be stimulated by phorbol esters (PEs) and by intracellular diacylglycerol (DAG) generation. This led to the hypothesis that classical and novel protein kinase Cs (PKCs), which are activated by DAG/PEs, regulate APP processing. However, in addition to PKCs, there are other DAG/PE receptors present in neurons which may participate in the modulation of APP processing. Munc13-1, a presynaptic protein with an essential role in synaptic vesicle priming, represents such an alternative target of the DAG second messenger pathway. Using Munc13-1 knock-out mice and human neuroblastoma cells transfected with wild-type and mutant Munc13-1 constructs it was demonstrated that Munc13-1 acts independently of and in parallel with PKC to modulate APP metabolism. Therefore, agonists specific for the Munc13-1 C1-domain or small molecules mimicking the function of the endogenous Munc13-1 activator RIM1 may prove useful to shift APP processing towards the non-amyloidogenic pathway.     

环氧合酶-2及其选择性抑制剂塞来昔布对结肠癌肝转移瘤VEGF、FGF-2影响的实验研究

目的 :研究环氧化酶 2及其选择性抑制剂塞来昔布和血管生成因子VEGF、FGF 2间的关系 ,从而探讨环氧化酶 2对结肠癌肝转移瘤血管形成的影响。方法 :以细胞培养法建立稳定的结肠癌细胞株HT 2 9和HCT 116 ,利用脾切除法建立结肠癌肝转移动物模型 ,免疫组化检测结肠癌肝转移瘤VEGF、FGF 2蛋白表达。结果 :结肠癌肝脏转移率 ,HT 2 9组、HCT 116组、塞来昔布组分别为 83 33%、16 6 7%、33 33%。肝脏转移瘤VEGF、FGF 2的表达 ,HT 2 9组与HCT 116组、塞来昔布组比较均表达增强 ,有显著统计学意义 (P <0 0 1～ 0 0 5 ) ;塞来昔布组与HCT 116组比较无显著性差异 (P >0 0 5 )。结论 :环氧合酶 2与结肠癌肝转移瘤血管生成密切相关 ,其高表达促进了结肠癌肝转移瘤新生血管生成。其机制可能是上调促血管生成因子VEGF、FGF 2的表达     

高频灰阶超声鉴别良恶性胸肌淋巴结

目的:评价灰阶超声在鉴别良、恶性胸肌淋巴结中的应用价值.材料和方法:研究对象为43枚乳癌患者的胸肌淋巴结,其中16枚为转移性胸肌淋巴结、27枚为非转移性胸肌淋巴结;另有19枚乳腺良性病变患者的胸肌淋巴结和22枚正常者的胸肌淋巴结作为对照组.使用仪器为HDI-3000型彩色多普勒超声诊断仪,配备5～12MHz宽频控头.运用超声测量胸肌淋巴结的长径、轮廓形态、长径-厚度比、髓皮质厚度比,作为鉴别良、恶性胸肌淋巴结的参数,比较良、恶性胸肌淋巴结在形态学上差异.结果:良、恶性胸肌淋巴结的长径、轮廓形态、髓皮质厚度比无显著性差异;恶性淋巴结长径-厚度比(1.7±0.4)明显低于良性淋巴结(2.0±0.5),P＜0.05.结论:灰阶超声在鉴别良、恶性胸肌淋巴结中具有一定的应用价值.     

8-硝基白杨素的合成及其抗肿瘤作用

目的　探讨 8-硝基白杨素的抗肿瘤活性。方法　荷Lewis肺癌雄性小鼠 5 0只 ,随机分为5组 (NS对照组 ,环磷酰胺组 ,低、中、高剂量 8-硝基白杨素组 ) ,每组 1 0只 ,均采用腹腔注射给药。末次给药 2 4h后 ,颈椎脱位处死小鼠 ,观察各组瘤重减轻情况及转移结节数。结果　低、中、高剂量 8-硝基白杨素均能明显抑制肿瘤的生长和肿瘤转移结节的数 (阳性药对照组和各处理组与对照组相比 ,P均<0 .0 1 ) ,高剂量 ( 5 0mg kg) 8-硝基白杨素与 1 0 0mg kg的环磷酰胺的抗肿瘤作用相当 (P >0 .0 5 )。结论　 8-硝基白杨素作为一种新黄酮衍生物 ,具有良好的抗肿瘤作用。     

急性传染性非典型肺炎的影像表现

目的探讨急性传染性非典型肺炎(SARS)的X线表现及变化规律.方法回顾性分析临床诊断SARS的61例患者,对发病后的一系列胸片和CT影像进行统计分析.结果患者以发热为最早起病症状,88.5%患者在起病1周内肺部出现肺局灶性斑片状模糊影,并迅速扩大.2周内病变达高峰,有57.4%患者两肺大部分肺野受累,病情重.83.6%患者在5周内肺部阴影逐渐消散.在恢复期16例CT扫描中,有13例显示肺部遗留纤维化病灶.有6例患者合并感染,病期延长,4例死亡.结论SARS早期出现肺部炎性改变,发展迅速,大部分两肺受累,重症比例高,易致肺纤维化.     

糖基化终末产物对大鼠肾系膜细胞纤溶酶原激活物抑制物-1表达韵影响

目的：观察糖基化终末产物（AGEs）对大鼠肾系膜细胞纤溶酶原激活物抑制物-1（PAI-1）表达的影响及其与细胞外基质（ECM）成分含量的关系。方法：体外培养正常大鼠肾系膜细胞，分别用糖化牛血清白蛋白（AGEs）及未经糖化的牛血清白蛋白（BSA）处理，以常规培养的肾系膜细胞作为对照，检测不同时间、不同浓度AGEs对纤维连接蛋白（FN）、Ⅳ型胶原、PAI-1表达的影响。MTT法检测AGEs对系膜细胞增殖的作用，ELISA测定条件培养基中FN、Ⅳ型胶原及PAI-1蛋白含量，逆转录聚合酶链式反应（RT—PCR）检测系膜细胞PAI-1 mRNA的表达。结果：与相应浓度的BSA比较，AGEs（0—200mg／L）对系膜细胞增殖无明显影响，但可不同程度地刺激系膜细胞FN、Ⅳ型胶原、PAI-1蛋白的产生。RT—PCR检测显示，给予AGEs（100mg／L）的系膜细胞PAI-1 mRNA的表达明显增加（P〈0．01）。结论：AGEs促进系膜细胞PAI—1的表达，提示AGEs通过上调PAI-1的表达而减少细胞外基质降解，可能是糖尿病肾病细胞外基质积聚的原因之一。     

A Synergistic Effect Between PG490-88 and Tacrolimus Prolongs Renal Allograft Survival in Monkeys

This study was undertaken to determine if PG490-88 and tacrolimus (Tac) act synergistically to prevent renal allograft rejection in monkeys and to explore possible mechanisms of synergy between these agents. MHC-mismatched renal allografts were transplanted into cynomolgus monkeys after bilateral nephrectomy. Recipients were divided into the following groups: (i) no treatment; (ii) PG490-88 (0.03 mg/kg); (iii) Tac (1 mg/kg); (iv) PG490-88 (0.01 mg/kg) + Tac (1 mg/kg) and (v) PG490-88 (0.03 mg/kg) + Tac (1 mg/kg). Through synergy PG490-88 and Tac inhibited anti-CD3/PMA-induced T-cell proliferation and IFN-gamma expression in vitro. Tac monotherapy only marginally prolonged survival (27 +/- 3.2 days), while the combination of PG490-88 and Tac significantly prolonged graft survival to a median of 99 days (PG490-88 at 0.03 mg) and 38.5 days (PG490-88 at 0.01 mg/kg). Prolonged survival correlated with inhibited IgM production as well as reduced T-cell infiltration, IL-2 protein expression and NF-AT/NF-kappaB activity. We conclude that PG490-88 and a subtherapeutic dose of Tac significantly prolong renal allograft survival in monkeys through the synergistic inhibition of T-cell activation and a decrease in IFN-gamma production and NF-AT/NF-kappaB activity.     

Bax，Bcl-2在非小细胞肺癌中的表达相关性研究

目的 研究Bax，Bel-2在人类非小细胞肺癌中的表达及其相关性。方法 应用免疫组织化学（S—P法）检测80例非小细胞肺癌组织标本和40例肺良性病变组织中Bax，Bcl-2的表达水平。结果 ①非小细胞肺癌组织中Bax，Bel-2表达水平分别为63．8％，51．2％，二者表达均与组织学类型无关；②Bax，Bel-2在非小细胞肺癌中表达呈负相关。结论 Bax，Bel-2共同参与细胞凋亡，促进非小细胞肺癌的发生发展。     

心脏移植急性排斥反应与CD8+CD28+T细胞钙离子浓度变化的相关性研究

目的：探讨CD8^＋CD28^＋T细胞钙离子浓度的变化与心脏移植急性排斥反应（AR）的相关关系。方法：用流式细胞仪检测正常SD大鼠组（T0组）、同种心脏移植组（T1）（Wistar→SD大鼠）术后第1、3、5、7天CD8^＋CD28^＋T细胞内钙离子浓度的变化，分析CD8^＋CD28^＋T细胞内钙离子浓度的变化与心脏移植AR程度的相关关系。结果：CD8^＋CD28^＋T细胞内钙离子浓度升高与AR严重程度成正相关，相关系数为0．469，相关具有显著性（P〈0．05）。结论：心脏移植后CD8^＋CD28^＋T细胞内钙离子浓度显著升高，其升高程度与AR严重程度成正相关。     

吗丁啉联合四磨汤治疗新生儿胃食管反流的临床观察

目的观察吗丁啉联合四磨汤治疗新生儿胃食管反流(GER)的效果。方法经食管钡剂造影诊断明确的68例新生儿胃食管反流者随机分为治疗组34例,对照组34例,治疗组在喂奶前20~30分钟口服或鼻饲吗丁啉(0.3 mg/Kg.次),q8h,并合用四磨汤(1m l/Kg.次),每日3次,对照组仅服用吗丁啉,疗程均为5天。结果治疗组显效26例,有效5例,无效3例,有效率88.2%。对照组显效17例,有效7例,无效10例,有效率70.6%。两组比较结果差异有统计学意义,2χ=4.66,P<0.05。结论吗丁啉联合四磨汤治疗新生儿胃食管反流效果明显,无毒副作用,且有利于生长发育。