Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood-retinal barrier

Several retinal and choroidal diseases are potentially treatable by intraocular delivery of genes whose products may counter or neutralize abnormal gene expression that occurs as part of the diseases. However, prior to considering a transgene, it is necessary to thoroughly investigate the effects of its expression in normal and diseased eyes. An efficient way to do this is to combine tissue-specific promoters with inducible promoter systems in transgenic mice. In this study, we used this approach to evaluate the effects of ectopic expression of angiopoietin-1 (Ang1) in normal eyes and those with ocular neovascularization. Adult mice with induced expression of Ang1 ubiquitously, or specifically in the retina, appeared normal and had no identifiable changes in retinal or choroidal blood vessels or in retinal function as assessed by electroretinography. Increased expression of Ang1 in eyes with severe retinal ischemia or in eyes with rupture of Bruch's membrane significantly suppressed the development of retinal or choroidal neovascularization, respectively. This inhibition of ocular neovascularization is particularly interesting and noteworthy, because overexpression of Ang1 in skin stimulates neovascularization. Ang1 also significantly reduced VEGF-induced retinal vascular permeability. These data suggest that intraocular delivery of ang1 has potential for treatment of ocular neovascularization and macular edema.     

A RANDOMISED,DOUBLE-BLIND,PARALLEL-GROUP COMPARISON OF VENLAFAXINE AND DOTHIEPIN IN GERIATRIC PATIENTS WITH MAJOR DEPRESSION

This randomised, double-blind study conducted at nine sites in the UK and the Netherlands compared the safety and antidepressant efficacy of venlafaxine and dothiepin. Ninety-two geriatric patients (aged 64-87 years) with major depression were randomly assigned to receive either venlafaxine or dothiepin for up to 43 days. The dose of venlafaxine or dothiepin was titrated up to a maximum of 150 mg per day for the first 15 days, and thereafter could range from 50 to 150 mg per day. Adjusted mean scores on the MADRS and the HAM-D decreased significantly (p 0.05) from baseline to the end of the study in both groups. A response to therapy was observed in 60% of patients in the venlafaxine group and 53% of patients in the dothiepin group on the MADRS, and in 60% of patients in both groups on the HAM-D. Suicidal ideation scores on the MADRS were significantly (p=0.042) lower in the venlafaxine group at week 6. Treatment-emergent study events were the primary reason for withdrawal in only 7% of venlafaxine-treated patients and 8% of dothiepin-treated patients. The results confirm the efficacy and tolerability of venlafaxine for treating major depression in the elderly.     

亲体肾及造血干细胞联合移植治疗多发性骨髓瘤并发慢性肾功能衰竭

目的:肾功能不全是多发性骨髓瘤并发肾脏疾病的主要表现且决定其预后,探讨1例多发性骨髓瘤并发慢性肾功能衰竭患者行肾及造血干细胞联合移植的治疗体会。方法:南京中医药大学附属医院于2005-04采用肾及造血干细胞联合移植治疗多发性骨髓瘤并发慢性肾功能衰竭患者1例,男性,46岁,经严格的配型及常规检查,发现其胞兄为适合的亲体供者,经供、受者双方同意,结合病情资料并复习文献,先制订出详细治疗方案,然后行亲体肾及造血干细胞联合移植。结果:①供者术后恢复顺利,术后第7天拆线出院,肾功能正常。②受者肾移植术后第3天,血肌酐降至98.2μmol/L,肌酐清除率为45.7mL/min,肾功能恢复正常;干细胞移植术后第13天,查血红蛋白为54g/L、白细胞为4.0×109L-1、中性粒细胞为1.92×109L-1、血小板为30×109L-1,受者造血功能逐步重建,同时抽血行短片段串联重复的嵌合体监测证实受者造血干细胞基因型为完全供者型,说明受者造血功能和免疫功能重建。结论:肾及造血干细胞联合移植治疗多发性骨髓瘤并发慢性肾功能衰竭是一种可行、有效的方法;供、受者的良好配型是移植进行的必备基本条件;另外,术后初期患者处于完全性免疫缺陷状态,故手术后的消毒、隔离措施和抗感染治疗是移植成功的关键。     

Histamine receptors in the isolated human middle meningeal artery. A comparison with cerebral and temporal arteries

The subtypes of histamine receptors mediating dilatation of human meningeal arteries have been tested in vitro, using "selective" antagonists, and compared with cerebral and temporal arteries previously examined. Dilatory responses were tested after preconstriction with prostaglandin F2 alpha. Both mepyramine and cimetidine caused a parallel shift to the right of the histamine concentration-response curve, suggesting the presence of both H1- and H2-receptors. Combined treatment with mepyramine and cimetidine caused further displacement of the concentration-response curve to the right. Schild analysis indicated pA2 values of 6.3 for cimetidine and 9.8 for mepyramine in situations of near complete blockade of either of the receptors. Both H1- and H2-receptors seem of importance for the histamine-induced dilatation in meningeal arteries and neither appear to dominate. The data considered in conjunction with our previous findings support the finding that experimental histamine-induced headache due to vasodilatation is intracranial of origin.     

Impact of chemotherapy-induced neutropenia on quality of life: a prospective pilot investigation

Purpose In this exploratory, prospective study evaluated quality of life (QoL) changes in patients with diverse cancers during the first cycle of myelosuppressive chemotherapy.Patients and methods Of 80 patients enrolled, 71 were observed during one of five chemotherapy regimens: docetaxel; CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); carboplatin-paclitaxel; carboplatin-docetaxel; and carboplatin-gemcitabine. Complete blood counts were taken weekly. QoL and symptom burden measures were administered at baseline and throughout the cycle, and included SF-36, Cancer Care Monitor (CCM), Hospital Anxiety and Depression Scale (HADS), and Psychosocial Adjustment to Illness Scale (PAIS). Using generalized estimating equations, we modeled the change in each measure from baseline to the end of each week using the following covariates: baseline QoL measure, baseline SF-36 Physical and Mental Health Summary scores, sex, age, cycle week, grade 4 neutropenia any time in the past 7 days (yes/no), and the interaction of the latter two covariates.Results Of the 71 patients observed, 33 developed grade 4 neutropenia during the first 2 weeks. Changes from baseline in SF-36 Bodily Pain, HADS Anxiety, and PAIS Social Environment scores were significantly less favorable (P<0.05) when patients experienced grade 4 neutropenia any time in the past 7 days compared to when they did not (grade 0–3). A similar, but non-significant, trend was also observed for 12 other QoL measures.Conclusion QoL may be adversely affected up to 7 days after patients experience grade 4 (versus grade 0–3) neutropenia. Such findings need to be examined further in studies with adequate statistical power to test a priori hypotheses regarding specific QoL measures.Support for this work was provided by Amgen Inc.Portions of the research were previously presented at: Mayo Clinic Assessing Clinical Significance for QoL Measures in Oncology Research, State-of-the-Science, March 2002, Rochester, MN; the 27th Meeting of the European Society of Medical Oncology, October 2002, Nice, France; and the American Society of Hematology, December 2002, Philadelphia, PA.     

冠状动脉粥样硬化性心脏病患者升主动脉弹性与颈动脉内-中膜厚度的相关性

目的:观察冠状动脉粥样硬化性心脏病(简称冠心病)患者升主动脉弹性与颈动脉内膜-中层厚度及粥样斑块发生的相关性。方法:于2005-08/2006-04选择石河子大学医学院第一附属医院心内科行冠状动脉造影检查患者97例,根据冠状动脉造影结果分为正常对照组41例和冠心病组56例,对两组患者进行超声检查,分别测量升主动脉扩张性D、僵硬度指数β、测量升主动脉前壁收缩期S波以及舒张期E波、A波的速度、颈动脉内膜-中层厚度及粥样斑块发生率。僵硬度指数β=In(收缩压/舒张压)/[(收缩期内径-舒张期内径)/舒张期内径]。动脉扩张性D=2(收缩期内径-舒张期内径)/[舒张期内径(收缩压-舒张压)]×10-3m2/N。结果:纳入患者97例,均进入结果分析。①冠心病组升主动脉扩张性D低于正常对照组,差异有显著性意义[分别为(15.02±9.99)×10-4,(34.75±20.80)×10-3m2/N,P=0.001];僵硬度指数β高于正常对照组(分别为28.20±21.06,15.23±25.32,P=0.001);升主动脉前壁S波和E波速度低于正常对照组[分别为(0.08±0.01),(0.10±0.03)m/s;(0.05±0.01),(0.07±0.02)m/s,P=0.001];颈动脉内膜-中层厚度和颈动脉斑块发生率高于正常对照组[分别为(0.90±0.15),(0.66±0.09)mm;41.03%,5.88%,P=0.001]。②升主动脉前壁S波速度与扩张性呈正相关(r=0.43,P=0.003),与僵硬度指数呈负相关(r=-0.47,P=0.002)。升主动脉前壁E波速度与扩张性呈正相关(r=0.47,P=0.002),与僵硬度指数无相关性。升主动脉前壁A波速度与扩张性和僵硬度指数均无相关性。③升主动脉扩张性D与颈动脉内膜-中层厚度呈负相关(r=-0.49,P=0.004),而僵硬度指数β与内膜-中层厚度则呈正相关(r=0.46,P=0.003)。S波速度与内膜-中层厚度无相关性(r=-0.26,P=0.15)。结论:冠心病患者升主动脉弹性降低即动脉扩张性降低、僵硬度指数升高、升主动脉前壁S波速度下降,颈动脉内膜-中层厚度增厚及粥样斑块发生率增高,将这些参数结合可作为冠心病很有价值的预测指标。     

AGTR1基因A10208G位点多态性与宁夏地区2型糖尿病与健康人的相关性

目的:糖尿病与心血管疾病可能存在着共同的遗传基础,AT1基因可能是心血管疾病与糖尿病共同的候选基因,人类编码AT1受体基因是AGTR1基因。分析2型糖尿病与健康者AGTR1基因A10208G位点多态性与胰岛素抵抗和β细胞功能之间的关系。方法:选择2005-03/2007-03于银川市第一人民医院内分泌科住院新诊断的2型糖尿病患者127例,符合1999年WHO糖尿病诊断标准,男68例,女59例,平均(54.86 11.05)岁,伴有腹型肥胖的2型精尿病患者105例,不伴有腹型肥胖的2型糖尿病患者22例,所有患者均自愿参加本实验,实验经医院伦理委员会批准。健康对照组人群来自宁夏地区的健康志愿者224名,男117名,女107名,平均(56.68 11.39)岁。所有对象均无血缘关系,且两组人群在性别和年龄上均匹配,各项参数之间无统计学意义。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术分析105例伴有肥胖2型糖尿病患者,22例不伴肥胖的2型糖尿病患者及224例健康对照者AGTR1基因A10208G位点多态性,并测定相应生化指标进行分析。结果:351名受试者均进入结果分析。①腹型肥胖糖尿病组AGTR1基因A10208G位点基因型分布和等位基因频率与健康对照组比较有统计学意义(基因型:x~2=10.85,P<0.01;等位基因:x~2=5.57,P<0.05)。②腹型肥胖糖尿病组携G等位基因患者Homa-IR、Homa-β明显高于非腹型肥胖糖尿病组携G等位基因患者(P<0.05)。结论:①AGTR1基因A10208G位点多态性与2型糖尿病存在相关性,尤其是伴有腹型肥胖的2型糖尿病患者。②AGTR1基因A10208G位点A→G的突变可能参与胰岛素抵抗和胰岛β细胞分泌功能损伤。     

Psychopathology in individuals with post-traumatic headaches and other pain types

In this study, the psychological functioning of patients with chronic post-traumatic headache (PTH), chronic combination headache and chronic low back pain without headache, whose time of onset was similar, and a matched group of controls was investigated. The Symptom Checklist 90-Revised (SCL-90-R), State-Trait Anger Expression Inventory (STAXI), State-Trait Anxiety Inventory, Form Y (STAI-Y), and Beck Depression Inventory (BDI) were used to assess the degree of psychopathology. A MANOVA test indicated highly significant differences between groups. In general, the pain groups fell along a continuum with PTH subjects demonstrating the highest elevations, back pain subjects demonstrating the next highest elevations, and combination subjects demonstrating fewer elevations. A cluster analysis indicated that findings were best classified into four clusters, but no one pain diagnosis predominated in any cluster. Eighty-nine percent of controls were assigned to clusters 1 or 2, which revealed essentially normal scores on all tests. It is suggested that while chronic pain patients demonstrate more psychopathology than non-pain controls, a variety of coping styles exists within each pain group independent of diagnostic categorization.     

Identification of functional domains and evolution of Tc1-like transposable elements.

Tc1-like transposable elements from teleost fish have been phylogenetically examined to determine the mechanisms involved in their evolution and conserved domains of function. We identified two new functional domains in these elements. The first is a bipartite nuclear localization signal, indicating that transposons can take advantage of the transport machinery of host cells for nuclear uptake of their transposases. The second is a novel combination of a paired domain-related protein motif juxtaposed to a leucine zipper-like domain located in the putative DNA-binding regions of the transposases. This domain coexists with a special inverted repeat structure in certain transposons in such phylogenetically distant hosts as fish and insects. Our data indicate that reassortment of functional domains and horizontal transmission between species are involved in the formation and spread of new types of transposable elements.