DII4／Notch1在消化道血管发育不良出血患者中的表达以及沙利度胺的干预机制

DII4／Notch1信号通路是肿瘤血管形成、血管发育等领域的研究热点．然而其在消化道血管发育不良（AGD）中的作用机制尚未阐明。沙利度胺常用于治疗AGD所致的消化道出血。目的：探讨DII4／Notch1信号通路在消化道AGD形成中的作用以及沙利度胺的干预机制。方法：收集不明原因反复消化道出血、经胶囊内镜和（或）小肠镜检查确诊为AGD的患者25例和因AGD致消化道出血接受沙利度胺（100mg／d．疗程4个月）治疗者10例,18名健康志愿者作为正常对照。以ELISA法检测血清DII4、Notchl浓度。结果：AGD组血清DII4、Notch1浓度显著高于正常对照组（P〈0．01）,且DII4与Notch1间呈正相关（r=0．900,P〈0．01）。沙利度胺治疗前后,AGD患者的血清DII4、Notch1浓度无明显改变;根据性别和疗效进行分层分析,差异亦无统计学意义。结论：DII4／Notch1信号通路可能参与了消化道AGD的形成．沙利度胺对该信号通路的调节作用不明显．     

沙利度胺治疗血管发育不良所致消化道出血的疗效观察

目的 观察和研究沙利度胺治疗血管发育不良所致消化道出血的临床疗效及其机制.方法 收集2004年11月-2006年12月血管发育不良所致反复发作的消化道出血患者18例,给予沙利度胺片100 mg/d口服,疗程4个月.中位随访时间16.7个月,观察治疗前、后患者临床疗效和血清血管内皮生长因子(vEGF)和肿瘤坏死因子一a(TNF-a)水平变化.结果 患者临床疗效总评分由治疗前的(15.000±3.630)分降至治疗后的(5.330±3.325)分,差异有统计学意义(P＜0.01).随访期间,18例患者平均出血次数为(1.000±1.237)次,输血量为(100.000±240.098)ml,均比治疗前显著减少[(11.220±6.404)次和(1422.220±1556.601)ml,P值均＜0.01];血红蛋白含量为(9.533±2.278)g/ml,比治疗前显著上升[(5.950±1.656)g/ml,P＜0.01].5例患者服药前血清中VEGF浓度为180 pg/ml、TNF-α浓度为58 Pg/ml,治疗后VEGF和TNF-α浓度明显降低(116和34 pg/ml,P值均＜0.01).结论 沙利度胺能明显抑制血管发育不良消化道出血患者的血清VEGF、TNF-α水平,对血管发育不良所致的消化道出血疗效显著.     

沙利度胺治疗小肠血管发育不良所致消化道出血的疗效观察

目的观察沙利度胺治疗小肠血管发育不良所致消化道出血的临床疗效。方法收集2009年1月．2011年10月小肠血管发育不良所致消化道出血患者20例,给予沙利度胺片100mg／d口服,疗程4个月,观察治疗前、后患者临床疗效。结果患者临床疗效总评分由治疗前的（14．56±3．30）分降至治疗后的（5．23±3．25）分,差异有统计学意义（P〈0．01）。随访期间,20例患者平均出血次数为（1．00±1．13）次,输血量为（100．00±230．01）mL,均比治疗前显著减少[（11．12±5．73）次和（1338．22±1451．32）mL,P值均〈0．01）;治疗后血红蛋白含量为（9．41±2．17）g／mL,比治疗前的（5．68±1．60]g／mL）显著上升（P〈O．01]。结论沙利度胺对小肠血管发育不良所致的消化道出血疗效显著,可望成为一种治疗小肠血管发育不良的有效药物。     

缺氧条件下人脐静脉内皮细胞Ang-2、Notch1、Dll4、HIF-1α表达以及沙利度胺对其表达的影响水

背景：沙利度胺治疗胃肠道血管畸形所致的难治性消化道出血安全、有效,而胃肠道血管畸形所致的消化道出血可能与缺氧引起的血管代偿性增生有关。目的：探讨人脐静脉内皮细胞（HUVEC）血管生成素2（Ang-2）、Noteh1、Dll4和缺氧诱导因子（HIF）-1α在缺氧环境中的表达以及沙利度胺的干预机制。方法：HUVEC分别于常氧和缺氧环境下培养。缺氧培养的HUVEC分为溶剂对照组和不同浓度（25、50、100、200μg／mL）沙利度胺组。以Real-time PCR和蛋白质印迹法分别检测Ang-2、Noteh1、Dll4、HIF-1α mRNA和蛋白表达。结果：缺氧条件下Ang-2、Noteh1、Dll4、HIF-1α mRNA和蛋白表达均高于常氧状态,差异有统计学意义（P〈0．05）。沙利度胺可呈浓度依赖性地抑制HUVEC Ang-2、Noteh1、Dll4 mRNA和蛋白表达（P〈0．05）。结论：沙利度胺对Ang-2、Noteh1、Dll4表达的抑制作用可能是其抑制血管生成从而治疗胃肠道血管畸形致消化道出血的机制之一。     

沙立度胺治疗血管发育不良致下消化道出血1例报告

患者女,74岁,2009年9月29日因“便血20余天”入院。患者20d前无明显诱因出现便血,色暗红,每天1次,量约50g,无腹痛、呕血。Hb37g／L。     

沙利度胺对人脐静脉内皮细胞增殖和血管生成的影响

目的 探讨沙利度胺治疗血管发育不良所致消化道出血的机制.方法 体外培养人脐静脉内皮细胞至对数生长期,分为空白对照组、溶剂对照组(二甲基亚砜)和不同浓度(10、20、40、60、80、100μg/ml)沙利度胺组,根据加或不加成纤维细胞生长因子(bFGF,10 ng/ml),共分为16组.刺激72 h后,MTT法检测细胞增殖情况,酶联免疫吸附法和实时定量PCR法测定血管内皮生长因子(VEGF)、肿瘤坏死因子-α(TNF-α)表达.结果 加或不加bFGF刺激,中、高浓度(≥40/μg/ml)沙利度胺均能抑制人脐静脉内皮细胞增殖.未加bFGF刺激时.20μg/ml沙利度胺能明显抑制VEGF表达.加bFGF刺激时,10 μg/ml沙利度胺即能明显抑制VEGF表达.未检出TNF-α表达.结论 体外实验中,沙利度胺能抑制人脐静脉内皮细胞增殖和VEGF表达,从而抑制血管生成,达到治疗血管发育不良所致消化道出血的目的 .     

沙利度胺的药理特点及其在溃疡性结肠炎中的作用

沙利度胺被认为具有免疫调节和抗血管生成作用,已被用于治疗多种免疫性疾病和血管增生性疾病。肠道黏膜免疫反应异常和血管生成异常在溃疡性结肠炎(UC)的发病机制中起重要作用。因此,沙利度胺对UC可能具有有益的治疗作用。此文结合近年来的文献资料对沙利度胺的药理特点及其在UC中的作用作一综述。     

肠道血管畸形出血患者低氧诱导因子-1和血管生成素-2表达及沙利度胺的干预研究

目的 探讨低氧诱导因子(HIF)-1及血管生成素(Ang)-2在血管畸形所致反复消化道出血中的表达及沙利度胺的干预作用.方法 筛选25例因反复消化道出血经胶囊内镜或小肠镜检查诊断为血管畸形者和18名无严重器质性疾病的正常对照者.另选取10例接受沙利度胺治疗(每日4次,每次25 mg,疗程4个月)并至少随访1年的血管畸形者.分别留取血标本,采用酶联免疫吸附试验(ELISA)检测血管畸形组与正常对照组以及沙利度胺治疗前后血清HIF-1及Ang-2的表达差异.结果 血管畸形组血清HIF-1及Ang-2表达量[分别为(113.84±26.66)和(652.11±140.39)ng/ml]均明显高于正常对照组[分别为(43.28±17.30)和(265.60±53.88)ng/ml,P值均=0.000],且二者表达显著相关(r=0.700,P=0.000).沙利度胺治疗前后HIF-1及Ang-2表达差异无统计学意义(P值分别=0.498和0.136).8例沙利度胺治疗有效者治疗后Ang-2表达量降低了(113.80±73.60)ng/ml(P=0.003).结论 HIF-1及Ang-2可能与血管畸形的形成有关,沙利度胺对血清Ang-2的抑制程度能预知其疗效或预后.

Abstract：

Objective To study the expressions of hypoxia inducible factor (HIF)-1 and angiopoietin (Ang)-2 in repeated gastrointestinal bleeding due to vascular malformation, and the efficacy of treatment with thalidomide. Methods Twenty-five patients with repeated gastrointestinal bleeding due to vascular malformation confirmed by capsule endoscopy or enteroscopy were collected and 18 subjects without severe diseases were served as controls. Ten patients with gastrointestinal vascular malformation, who received 25 mg of thalidomide 4 times daily for 4 months and were followed up for at least one year, were also enrolled. The serum samples from all participauts were detected for expressions of HIF-1 and Ang-2 using enzyme-linked immunosorbent assay (ELISA).The expressions of HIF-1 and Ang-2 were compared between angiodysplasia group and control group.The expressions of HIF-1 and Ang-2 were comparatively evaluated before and after treatment with thalidomide in treatment group. Results The expressions of HIF-1 and Ang-2 in vascular malformation group [( 113. 84 ± 26. 66 ) ng/ml and ( 652. 11 ± 140. 39) ng/ml, respectively] were significantly higher than that of control group [(43.28±17.30) ng/ml and (265.60±53.88) ng/ml,respectively, P=0. 000]. The expression of HIF-1 was positively associated with that of Ang-2. (r=0. 700, P= 0. 000). There was no difference in expressions of HIF-1 and Ang-2 before and after treatment with thalidomide (P=0. 498 and =0. 136, respectively). However, significant reduction of Ang-2 [(113. 80±73. 60) ng/ml(P=0. 003)] was found in 8 effectively treated patients after thalidomide treatment. Conclusions HIF-1 and Ang-2 might play an important role in the formation of vascular malformation. The extent of Ang-2 reduction after thalidomide treatment may be helpful in evaluating its efficacy or prognosis.     

血管新生抑制剂沙利度胺在多发性骨髓瘤治疗中的作用和地位

多发性骨髓瘤(MM)是骨髓浆细胞克隆性增殖的恶性肿瘤,好发于老年人,发病年龄多在50 ～ 70岁.近20年来随着我国人口老龄化,MM的发病率正逐年上升.迄今为止,MM仍被认为是一种不能治愈的恶性血液病,其治疗经历了几个重要的阶段.上世纪60年代美法仑(melphalan)的出现使骨髓瘤患者的生存期由7个月提高到21 ～ 30个月;80年代联合化疗方案如M2方案、VAD方案以及之后自体造血干细胞移植都使骨髓瘤的疗效得以提高;随着对发病机制的深入研究,治疗骨髓瘤的新靶点和新方法相继出现,进入到新药时代后骨髓瘤的治疗有了质的飞跃.     

Jagged1/Notch在消化道肿瘤及其血管形成中的作用

Jagged1是哺乳动物细胞膜上Notch受体的主要配体之一,其介导的Notch信号通路的活化和抑制参与多种消化道肿瘤的发生、发展.最新研究发现,Jagged1在肿瘤血管形成中起着重要作用,为肿瘤治疗提供了潜在的靶点.     

不明原因消化道出血的DSA和介入治疗

背景：不明原因消化道出血的诊断和治疗是临床的一大难题．数字减影血管造影（DSA）对不明原因消化道出血的诊断具有独到的优势。目的：探讨DSA和介入治疗对不明原因消化道出血的诊断和治疗价值。方法：对2008年9月～2010年10月哈尔滨医科大学附属第四医院收治的82例不明原因消化道出血患者行DSA．发现可疑病变行动脉栓塞或药物灌注等介入治疗。结果：DSA阳性者64例,诊断率78．0％,其中小肠出血58例,术后吻合口出血6例。22例患者表现为造影剂外溢的出血直接征象,42例表现为间接征象;26例（40．6％）患者的出血原因为小肠肿瘤,18例为憩室（28．1％）。17例患者（16例动脉栓塞、1例药物灌注）接受介入治疗,取得良好的疗效。结论：DSA能明确不明原因消化道出血的部位和病因。并能对部分患者行介入治疗．具有较高的诊断和治疗价值。     

Upper Gastrointestinal Bleeding in Patients with CKD

Background and objectives

Patients with CKD receiving maintenance dialysis are at risk for upper gastrointestinal bleeding. However, the risk of upper gastrointestinal bleeding in patients with early CKD who are not receiving dialysis is unknown. The hypothesis was that their risk of upper gastrointestinal bleeding is negatively linked to renal function. To test this hypothesis, the association between eGFR and risk of upper gastrointestinal bleeding in patients with stages 3–5 CKD who were not receiving dialysis was analyzed.

Design, setting, participants, & measurements

Patients with stages 3–5 CKD in the CKD program from 2003 to 2009 were enrolled and prospectively followed until December of 2012 to monitor the development of upper gastrointestinal bleeding. The risk of upper gastrointestinal bleeding was analyzed using competing-risks regression with time-varying covariates.

Results

In total, 2968 patients with stages 3–5 CKD who were not receiving dialysis were followed for a median of 1.9 years. The incidence of upper gastrointestinal bleeding per 100 patient-years was 3.7 (95% confidence interval, 3.5 to 3.9) in patients with stage 3 CKD, 5.0 (95% confidence interval, 4.8 to 5.3) in patients with stage 4 CKD, and 13.9 (95% confidence interval, 13.1 to 14.8) in patients with stage 5 CKD. Higher eGFR was associated with a lower risk of upper gastrointestinal bleeding (P=0.03), with a subdistribution hazard ratio of 0.93 (95% confidence interval, 0.87 to 0.99) for every 5 ml/min per 1.73 m² higher eGFR. A history of upper gastrointestinal bleeding (P<0.001) and lower serum albumin (P=0.004) were independently associated with higher upper gastrointestinal bleeding risk.

Conclusions

In patients with CKD who are not receiving dialysis, lower renal function is associated with higher risk for upper gastrointestinal bleeding. The risk is higher in patients with previous upper gastrointestinal bleeding history and low serum albumin.     

Massive Lower Gastrointestinal Bleeding in Patients with Typhoid Fever

The classical approach to management of intestinal hemorrhage due to typhoid ulceration has been conservative. In. however, the event of massive, persistent and life-threatening hemorrhage not responding to conservative measures, early surgical intervention is life-saving, controls typhoid toxemia rapidly and presents no special difficulties. A right hemicolectomy is recommended. Four such patients treated by us with bowel resection have had an uneventful recovery.     

The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity

Genetic studies have shown that ubiquitination and endocytosis of the Drosophila ligand Delta in signal-sending cells are required for activation of Notch signaling, but how these events promote Notch activation remains poorly understood. Here, we show that an ubiquitination-defective mutant of the murine Delta-homologue Dll1 is endocytosed but, in contrast to the wild-type Dll1, is unable to subsequently recycle back to the cell surface or to bind Notch1 efficiently. These results demonstrate that ubiquitination, although not required for endocytosis, is essential for Dll1 recycling and that recycling is required to acquire affinity for the receptor. On the other hand, a chimeric molecule encompassing the extracellular domain of Dll1 and the transmembrane/intracellular domain of Dll3, which contains no lysine, is endocytosed, recycled, and interacts with Notch1 but is unable to induce transendocytosis of the extracellular region of Notch1 or to signal. These observations suggest that the chimera uses an ubiquitination-independent signal to recycle, allowing it to acquire affinity for Notch1. Our results support the idea that ligand recycling determines its competence to bind efficiently to the receptor but that this is insufficient to allow it to perform transendocytosis, an event required for activation of Notch signaling. Finally, the present study indicates that Dll1 partially localizes to lipid microdomains, whereas both ubiquitination-defective Dll1 and the Dll1-3 chimera are excluded from these compartments, suggesting that these microdomains provide the environment necessary for Dll1 to activate Notch signaling.     

非静脉曲张性急性上消化道出血血清胃泌素检测及其临床意义

目的:了解非静脉曲张性急性上消化道出血血清胃泌素变化及其临床意义。方法:A组:急性非静脉曲张性上消化道出血34例;B组:活动期消化性溃疡29例;C组:慢性胃炎30例。采用放免法检测血清胃泌素。结果:A组血清胄泌素为97.94±22.75ng/L,95％可信限(95％CI)为92.08～103.80ng/L;B组胃泌素52.31±9.94ng/L,95％CI 48.70～55.94ng/L;C组胃泌素35.15±11.95ng/L,95％ CI 30.88～39.42ng/L。A组胃泌素显著高于B、C组(P<0.01),B组胃泌素也明显高于C组(P<0.05)。结论:胃泌素增多与消化道出血相关。