• 【槲寄生制剂(伊斯卡多)在三维胶原蛋白基质系统中诱导T淋巴细胞运动的供体依赖性和剂量依赖性变异。】 复制标题 收藏 收藏
    DOI:10.1097/00001813-199704001-00014 复制DOI
    作者列表:Nikolai G,Friedl P,Werner M,Zänker KS
    BACKGROUND & AIMS: :Controlled activation of non-specific and specific immune defence mechanisms can beneficially manipulate the host's ability to attack malignant cells. In this context, migration and tissue distribution of immunocompetent cells may be prerequisites for an efficient immune surveillance. The effect of various non-cytotoxic concentrations of the Viscum album L. (mistletoe) preparation Iscadore QuFrF on the locomotory activity of immunomagnetically isolated human CD4+ and CD8+ T lymphocytes from healthy donors was investigated. Cellular migration was examined within a three-dimensional collagen matrix. Donor-dependent variations in baseline activities of spontaneously locomoting T cells were accompanied by individual response patterns of T cells from different donors in the presence of various concentrations of mistletoe preparation (0.25-2.5 micrograms/ml). Using the three-dimensional collagen matrix assay an induction of locomotory activity was detected in a highly reproducible fashion although the optimal concentration of mistletoe preparation and the time point of maximal response were individual for each donor. Our data suggest that the direct stimulation of T-cell migration by mistletoe components may modulate the system of immune surveillance and recognition in patients under mistletoe therapy.
    背景与目标: :非特异性和特异性免疫防御机制的受控激活可以有益地控制宿主攻击恶性细胞的能力。在这种情况下,免疫活性细胞的迁移和组织分布可能是有效免疫监视的先决条件。研究了Viscum album L.(槲寄生)制剂Iscadore QuFrF的各种非细胞毒性浓度对来自健康供体的免疫磁性分离的人CD4和CD8 T淋巴细胞运动功能的影响。在三维胶原蛋白基质中检查了细胞迁移。在各种浓度的槲寄生制剂(0.25-2.5微克/毫升)存在下,自发性自发性T细胞基线活动的供体依赖性变异伴随着来自不同供体的T细胞的个体反应模式。使用三维胶原蛋白基质测定法,以高度可重复的方式检测了运动活性的诱导,尽管对于每个供体而言,槲寄生制剂的最佳浓度和最大响应的时间点各不相同。我们的数据表明,槲寄生成分直接刺激T细胞迁移可能会调节槲寄生治疗下患者的免疫监视和识别系统。
  • 【社区获得性耐甲氧西林金黄色葡萄球菌对奥沙西林耐药所需的VraS / VraR两组分调节系统。】 复制标题 收藏 收藏
    DOI:10.1111/j.1574-6968.2006.00384.x 复制DOI
    作者列表:Boyle-Vavra S,Yin S,Daum RS
    BACKGROUND & AIMS: :Methicillin/oxacillin (Oxa) resistance in Staphylococcus aureus is primarily mediated by the acquired penicillin-binding protein (PBP2a) encoded by mecA. PBP2a acts together with native PBP2 to mediate oxacillin resistance by contributing complementary transpeptidase and transglycosylase activities, respectively. The VraS/VraR two-component regulatory system is inducible by cell-wall antimicrobials (beta-lactams, glycopeptides) and controls transcriptional induction of many cell-wall genes including pbp2 and itself. We investigated the role of VraS/VraR in the phenotypic expression of oxacillin resistance by inactivating vraS in community-acquired MRSA clinical isolates that lack functional genes encoding the mecA regulatory sequences mecI and mecR1. Inactivation of vraS abrogated oxacillin resistance, and complementation with the vraS operon restored the resistance phenotype. mecA transcription increased in the vraS mutants; however, PBP2a abundance was similar to that of the wild type. Although pbp2 transcription decreased in the vraS mutants, overexpression of the pbp2 operon did not restore resistance. These data demonstrate that although expressions of mecA and pbp2 are required for oxacillin resistance, they are not sufficient. Therefore, the vraS/vraR regulatory system plays a crucial role in allowing MRSA to respond to beta-lactams by regulation of a gene target other than the known effectors of methicillin resistance.
    背景与目标: 金黄色葡萄球菌对甲氧西林/奥沙西林(Oxa)的耐药性主要由mecA编码的获得性青霉素结合蛋白(PBP2a)介导。 PBP2a与天然PBP2共同发挥作用,通过分别贡献互补的转肽酶和转糖基酶活性来介导奥沙西林抗性。 VraS / VraR两组分调节系统可通过细胞壁抗微生物剂(β-内酰胺,糖肽)诱导,并控制包括pbp2及其本身在内的许多细胞壁基因的转录诱导。我们通过灭活社区获得的MRSA临床分离株中的vraS而失活,研究了VraS / VraR在奥沙西林耐药性表型表达中的作用,该分离株缺乏编码mecA调控序列mecI和mecR1的功能基因。 vraS的失活消除了奥沙西林的耐药性,与vraS操纵子的互补恢复了耐药性表型。在vraS突变体中,mecA转录增加;但是,PBP2a的丰度与野生型相似。尽管在vraS突变体中pbp2转录降低,但是pbp2操纵子的过表达不能恢复抗性。这些数据表明,尽管抗mecA和pbp2的表达是奥沙西林耐药性所必需的,但它们还不够。因此,vraS / vraR调节系统在允许MRSA通过调节除已知的甲氧西林抗性效应子以外的基因靶标而对β-内酰胺作出响应中起着至关重要的作用。
  • 【人类前脑神经母细胞对成年大鼠中枢神经系统长轴突通路的改造。】 复制标题 收藏 收藏
    DOI:10.1038/347556a0 复制DOI
    作者列表:Wictorin K,Brundin P,Gustavii B,Lindvall O,Björklund A
    BACKGROUND & AIMS: :The failure of lesioned axons to regenerate over long distances in the mammalian central nervous system (CNS) is not due to an inability of central neurons to regenerate, but rather to the non-permissive nature of the CNS tissue environment. Regenerating CNS axons, which grow well within a peripheral nerve, for example, fail to penetrate mature CNS tissue by more than about 1 mm. Recent evidence indicates that this may be due to inhibitory membrane proteins associated with CNS oligodendrocytes and myelin. We report here that human telencephalic neuroblasts implanted into the excitotoxically lesioned striatum of adult rats can escape or neutralize this inhibitory influence of the adult CNS environment and extend axons along major myelinated fibre tracts for distances of up to approximately 20 mm. The axons were seen to elongate along the paths of the striato-nigral and cortico-spinal tracts to reach the substantia nigra, the pontine nuclei and the cervical spinal cord, which are the normal targets for the striatal and cortical projection neurons likely to be present in these implants.
    背景与目标: :损伤的轴突在哺乳动物中枢神经系统(CNS)中无法长距离再生的原因不是由于中枢神经元无法再生,而是由于CNS组织环境的非许可性质。例如,在周围神经中生长良好的再生中枢神经轴突不能穿透成熟的中枢神经系统组织超过约1毫米。最近的证据表明,这可能是由于与CNS少突胶质细胞和髓磷脂相关的抑制性膜蛋白所致。我们在这里报告说,植入成年大鼠兴奋毒性损伤的纹状体的人类端脑神经母细胞可以逃避或中和成年中枢神经系统环境的这种抑制作用,并沿主要有髓纤维束延伸轴突的距离可达约20 mm。看到轴突沿纹状体-黑色和皮质-脊髓束的路径伸长,到达黑质,桥脑核和颈脊髓,它们是可能存在的纹状体和皮质投射神经元的正常靶标在这些植入物中。
  • 【流域可持续水质管理框架和战略规划系统。】 复制标题 收藏 收藏
    DOI:10.1007/s00267-005-0304-1 复制DOI
    作者列表:Chen CH,Liu WL,Leu HG
    BACKGROUND & AIMS: :In Taiwan, the authorities have spent years working on remedying polluted rivers. Generally, the remediation planning works are divided into two phases. During the first phase, the allowed pollution discharge quantity and abatement quantity of each drainage zone, including the assimilative capacity, are generated based on the total river basin. In the second phase, the abatement action plans for each pollution source in each drainage zone are respectively devised by the related organizations based on the strategies generated during the first phase. However, the effectiveness of linking the two phases is usually poor. Highly integrated performances are not always achieved because the separate two-phase method does not take system and management thinking into consideration in the planning stage. This study pioneers the use of the Managing for Results (MFR) method in planning strategies and action plans for river water quality management. A sustainable management framework is proposed based on the concept and method of MFR, Management Thinking, and System Analysis. The framework, consisting of planning, implementation, and controlling stages, systematically considers the relationships and interactions among four factors: environment, society, economy, and institution, based on the principles of sustainable development. Based on the framework, the Modified Bounded Implicit Enumeration algorithm, which is used as a solving method, is combined with Visual Basic software and MS Excel to develop a computer system for strategy planning. The Shetzu River, located in northern Taiwan, is applied as a case study. According to the theoretical, practical, and regulatory considerations, the result-oriented objectives are defined to first improve the pollution length of the Shetzu River in specific remediation periods to finally meet regulated water quality standards. The objectives are then addressed as some of the constraints for the strategy planning model. The model objective is to pursue the maximum assimilative capacity (environmental phase) subjected to the constraints of water quality standards (institutional phase), social equity (social phase), and proper available technology (economic phase). The pollution quantity abatement and allocation, which are named the top strategies, of each drainage zone for different scenarios can be obtained based on each water quality standard. The middle as well as lower strategies and action plans, which consist of pollution quantity abatement and allocation of each class (domestic, industrial, livestock, and non-point pollution sources) and their individual pollution sources in each drainage zone, are then generated based on the top strategies. The performance indicators and measure plans are proposed based on the action plans to promote the comprehensive effectiveness of river water quality management. The authorities have begun to develop a budget based on the strategies and action plans developed in this study. The analytical results indicate that the objectives, strategies, and action plans developed based on the sustainable management framework and strategy planning system can effectively help the related authorities to fulfill the tasks of water quality management for a river basin.
    背景与目标: :在台湾,当局花费了多年的时间来修复受污染的河流。通常,修复计划工作分为两个阶段。在第一阶段,每个流域的允许污染排放量和减排量(包括同化能力)是基于总流域产生的。在第二阶段,相关组织根据第一阶段产生的策略分别制定每个流域每个污染源的减排行动计划。但是,连接两个阶段的有效性通常很差。由于分离的两阶段方法在计划阶段没有考虑系统和管理思想,因此无法始终实现高度集成的性能。这项研究开创了在河流水质管理的规划策略和行动计划中使用“结果管理”(MFR)方法的方法。基于MFR,管理思想和系统分析的概念和方法,提出了一种可持续的管理框架。该框架由规划,实施和控制阶段组成,根据可持续发展的原则,系统地考虑了四个因素之间的关系和相互作用:环境,社会,经济和制度。在此框架的基础上,将改进的有界隐式枚举算法(作为一种求解方法)与Visual Basic软件和MS Excel相结合,以开发用于战略规划的计算机系统。以台湾北部的神社河为例。根据理论,实践和监管方面的考虑,确定了以结果为导向的目标,即首先在特定的修复时期内改善Shetzu河的污染长度,以最终达到规定的水质标准。然后,将目标作为战略计划模型的一些约束条件加以解决。该模型的目标是在水质标准(机构阶段),社会公平(社会阶段)和适当的可用技术(经济阶段)的约束下,追求最大同化能力(环境阶段)。可以根据每个水质标准获得不同情景下每个流域的污染量减免和分配,这是最重要的策略。然后基于每个流域生成中等和较低的战略和行动计划,其中包括减少污染量和分配每个类别(家庭,工业,牲畜和非点源污染源)及其各自的污染源。在最重要的策略上。根据行动计划提出绩效指标和措施计划,以提高河流水质管理的综合有效性。当局已开始根据本研究制定的策略和行动计划制定预算。分析结果表明,基于可持续管理框架和战略计划系统制定的目标,战略和行动计划可以有效地帮助有关部门完成流域水质管理的任务。
  • 【将CT图像集成到电解剖标测系统中对心房纤颤导管消融的临床结果的影响。】 复制标题 收藏 收藏
    DOI:10.1111/j.1540-8167.2006.00594.x 复制DOI
    作者列表:Kistler PM,Rajappan K,Jahngir M,Earley MJ,Harris S,Abrams D,Gupta D,Liew R,Ellis S,Sporton SC,Schilling RJ
    BACKGROUND & AIMS: BACKGROUND:A detailed appreciation of left atrial/pulmonary vein (LA/PV) anatomy may be important in improving the safety and success of catheter ablation (CA) for atrial fibrillation (AF). OBJECTIVES:The aim of this nonrandomized study was to determine the impact of computerized tomography (CT) image integration into a 3-dimensional (3D) mapping system on the clinical outcome of patients undergoing CA for AF. METHODS:Ninety-four patients (age: 56 +/- 10 years) with AF (paroxysmal 46, persistent 48) underwent wide encirclement of ipsilateral PV pairs using irrigated radiofrequency ablation with the endpoint of electrical isolation. Ablation was guided by 3D mapping alone (electroanatomic 24, noncontact 23) in 47 (3DM group) patients and by CT image integration (Cartomerge) in 47 (CT group). In persistent AF, a combination of linear ablation and targeted ablation of complex fractionated electrograms was also performed. RESULTS:Successful PV electrical isolation did not differ between the two groups. A significant reduction in fluoroscopy times was demonstrated in the CT group (49 +/- 27 minutes vs 3DM group 62 +/- 26 minutes, P = 0.03). Arrhythmia recurrence was reduced in the CT group (32% vs 51% in the 3DM group, P < 0.01). In 30 symptomatic patients (12 CT and 18 3DM), repeat procedures for AF (13 in 3DM and 5 CT, P < or = 0.10) and AT (5 in 3DM and 7 CT, P = NS) were performed. Overall success on 7-day monitor off antiarrhythmic drugs was achieved in 60% in the 3DM group when compared with 83% in the CT group (P < 0.05) at a follow-up of 25 +/- 5 weeks. CONCLUSION:CA for AF guided by CT integration was associated with reduced fluoroscopy times, arrhythmia recurrence, and increased restoration of sinus rhythm. Improved visualization of complex LA geometries might improve the safety and success of CA for AF.
    背景与目标: 背景:详细了解左心房/肺静脉(LA / PV)解剖结构对于提高房颤(AF)导管消融(CA)的安全性和成功率可能很重要。
    目的:这项非随机研究的目的是确定将计算机断层扫描(CT)图像集成到3维(3D)制图系统中对接受CA房颤的患者的临床结局的影响。
    方法:94例房颤(阵发性46例,持续性48例)(年龄56 /-10岁)采用射频消融冲洗并以电隔离为终点,对同侧PV对进行了大包围。 47例(3DM组)患者仅通过3D映射(电解剖学24,非接触式23)进行消融,47例(CT组)通过CT图像积分(Cartomerge)进行消融。在持续性房颤中,还执行了复杂的电描记图的线性消融和靶向消融的组合。
    结果:两组之间成功的PV电气隔离没有差异。在CT组中,荧光检查时间显着减少(49 /-27分钟,而3DM组62 /-26分钟,P = 0.03)。 CT组心律失常复发率降低(3DM组为32%,而51%为P <0.01)。在30例有症状的患者中(12 CT和18 3DM),重复进行AF(3DM和5 CT中13例,P <或= 0.10)和AT(3DM和7 CT中5例,P = NS)的重复手术。在25 /-5周的随访中,3DM组60%的抗心律失常药物获得了总体成功,而CT组为83%(P <0.05)。
    结论:CT整合引导的房颤CA与减少的透视时间,心律失常的复发和窦性心律的恢复增加有关。改善复杂的LA几何图形的可视化可能会提高CA用于AF的安全性和成功性。
  • 【用反向四环素调节的逆转录病毒载体(RTRV)系统控制基因的表达。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6705 复制DOI
    作者列表:Watsuji T,Okamoto Y,Emi N,Katsuoka Y,Hagiwara M
    BACKGROUND & AIMS: :A retroviral vector was constructed with an autoregulatory cassette to allow expression of the gene of interest in response to oral administration of doxycycline (Dox) in vivo. The cassette contains all the components of the reverse tetracycline-regulated (rtTA) system, a drug selectable marker with the internal ribosome entry site and the gene of interest (GFP). FACS analyses showed an induction of GFP-fluorescence of two orders of magnitude in retrovirus-infected 208F cells dependent on the amount of Dox in the medium. Furthermore, oral administration of Dox resulted in GFP expression in transplanted 208F cells in the peritoneal cavity of nude mice. Thus this reverse tetracycline-regulated retroviral vector (RTRV) system simplifies the delivery of controllable genes to cultured and implanted cells. It is hoped that this approach may pave the way to controlled gene expression during a particular window of time in gene therapy applications.
    背景与目标: 逆转录病毒载体用自动调节盒构建,以响应体内口服强力霉素(Dox)来表达目的基因。该盒包含逆四环素调节(rtTA)系统的所有组件,具有内部核糖体进入位点和目的基因(GFP)的药物选择标记。 FACS分析显示,在逆转录病毒感染的208F细胞中,取决于培养基中Dox的量,诱导GFP荧光的数量级为两个数量级。此外,口服Dox导致裸鼠腹膜腔内移植的208F细胞表达GFP。因此,这种反向四环素调节的逆转录病毒载体(RTRV)系统简化了可控基因向培养和植入细胞的传递。希望这种方法可以为基因治疗应用中特定时间段内控制基因表达铺平道路。
  • 7 Tachykinins and the cardiovascular system. 复制标题 收藏 收藏

    【速激肽和心血管系统。】 复制标题 收藏 收藏
    DOI:10.2174/138945006778019291 复制DOI
    作者列表:Walsh DA,F McWilliams D
    BACKGROUND & AIMS: :The tachykinin family of vasoactive peptides comprises the neuropeptides substance P, neurokinin A and neurokinin B, and the newly discovered endokinins and hemokinins. Their cardiovascular effects are predominantly mediated by the family of neurokinin receptors. This review summarises the most recent advances in understanding the effects of tachykinins on the vasculature, and summarises their therapeutic potential. Tachykinins stimulate plasma extravasation, particularly acting through neurokinin-1 receptors in an endothelium-dependent manner. They therefore play prominent roles in tissue oedema and inflammation (called neurogenic inflammation). Pro-inflammatory effects of tachykinins are enhanced by their capacity to stimulate inflammatory cell recruitment, and to initiate angiogenesis. Tachykinins also regulate vascular tone and blood flow, although differences between species and between different vascular beds make this a highly complex area of research. They may relax vessels in some scenarios whilst inducing vasoconstriction in other situations, the state of the endothelium appearing to be of key importance. Tachykinins also modulate blood pressure and heart rate, acting both peripherally, and on the central nervous system. Cardiovascular effects of tachykinins and neurokinin receptors may be important therapeutic targets in diverse disorders such as pulmonary oedema, hypertension, pre-eclampsia, complex regional pain syndrome type 2, stroke and chronic inflammatory diseases such as arthritis. Sophisticated modelling of human disease is required to enable neurokinin receptor antagonists to achieve this therapeutic potential.
    背景与目标: 速激肽的血管活性肽家族包括神经肽物质P,神经激肽A和神经激肽B,以及新发现的内皮激肽和血红素。它们的心血管作用主要由神经激肽受体家族介导。这篇综述总结了了解速激肽对脉管系统的影响的最新进展,并总结了其治疗潜力。速激肽刺激血浆外渗,特别是以内皮依赖性方式通过神经激肽-1受体起作用。因此,它们在组织水肿和炎症(称为神经源性炎症)中起重要作用。速激肽的促炎作用通过其刺激炎性细胞募集和启动血管生成的能力而增强。速激肽还调节血管张力和血流量,尽管物种之间和不同血管床之间的差异使这成为一个高度复杂的研究领域。在某些情况下,它们可能使血管松弛,而在其他情况下,它们会引起血管收缩,内皮的状态似乎是至关重要的。速激肽还调节血压和心率,作用于外周和中枢神经系统。速激肽和神经激肽受体的心血管作用可能是多种疾病(例如肺水肿,高血压,先兆子痫,2型复杂区域性疼痛综合征),中风和慢性炎性疾病(例如关节炎)的重要治疗靶标。要使神经激肽受体拮抗剂能够实现这种治疗潜力,就需要对人类疾病进行复杂的建模。
  • 【肌肉骨骼系统的磁共振成像。第8部分。脊柱,第1节。】 复制标题 收藏 收藏
    DOI:10.1097/00003086-199705000-00037 复制DOI
    作者列表:Gundry CR,Fritts HM
    BACKGROUND & AIMS: Magnetic resonance has assumed a preeminent role in the imaging evaluation of the spine. Owing to its multiplanar capability and superior soft tissue contrast, magnetic resonance imaging is the procedure of choice for a host of spinal disorders including degenerative disc disease, tumor evaluation, trauma, and spinal deformities. It represents the most accurate means of distinguishing between recurrent disc herniation and epidural fibrosis, and it excels at the assessment of many postoperative abnormalities such as infection, adjacent segment disc degeneration, and arachnoiditis. Magnetic resonance imaging is also helpful in the evaluation of numerous diagnostic challenges that are less well resolved by other means. This includes the distinction between disc herniation and epidural hematoma, synovial cyst from nonspecific fibrous thickening of a facet capsule, and the evaluation of numerous other soft tissue abnormalities. Computed tomography, computed tomography myelography, and scintigraphy continue to be useful for numerous specific disorders and in those patients with metal hardware or contraindications to magnetic resonance scanning. Overall, however, magnetic resonance is the imaging procedure preferred for many spinal disorders. This article is the first installment of a 3-part series discussing the role of magnetic resonance imaging of spinal disorders. Section 1 will describe the varying imaging modalities available and their relative advantages and disadvantages. A consideration of magnetic resonance imaging techniques will follow, followed by a discussion of the imaging manifestations of early degenerative disc disease. Section 2 will be devoted to an in depth discussion of specific pathologic processes encountered in patients with degenerative disc disease. Section 3 will end the series with a consideration of postoperative imaging followed by a discussion of spinal deformities, trauma, and neoplasms.

    背景与目标: 磁共振在脊柱的成像评估中发挥了重要作用。由于其多平面能力和出色的软组织对比度,磁共振成像是许多脊柱疾病(包括退行性椎间盘疾病,肿瘤评估,创伤和脊柱畸形)的首选程序。它代表了区分复发性椎间盘突出症和硬膜外纤维化的最准确方法,并且擅长评估许多术后异常,例如感染,邻近节段性椎间盘退变和蛛网膜炎。磁共振成像还有助于评估许多诊断挑战,而这些挑战很难通过其他方式解决。这包括区分椎间盘突出症和硬膜外血肿,小囊囊的非特异性纤维增厚引起的滑膜囊肿,以及许多其他软组织异常的评估。计算机体层摄影术,计算机体层摄影术脊髓造影和闪烁显像术继续对许多特定疾病以及那些具有金属硬件或磁共振扫描禁忌症的患者有用。但是,总的来说,磁共振是许多脊柱疾病首选的成像方法。本文是由三部分组成的系列文章的第一部分,该系列讨论了磁共振成像对脊柱疾病的作用。第1节将描述可用的各种成像方式及其相对优缺点。随后将考虑磁共振成像技术,然后讨论早期退行性椎间盘疾病的成像表现。第2节将专门讨论变性椎间盘疾病患者遇到的特定病理过程。第三部分将在结束本系列文章时考虑术后影像学,然后讨论脊柱畸形,创伤和肿瘤。

  • 【肾对肾素-血管紧张素系统阻滞反应的性别差异。】 复制标题 收藏 收藏
    DOI:10.1681/ASN.2005101095 复制DOI
    作者列表:Miller JA,Cherney DZ,Duncan JA,Lai V,Burns KD,Kennedy CR,Zimpelmann J,Gao W,Cattran DC,Scholey JW
    BACKGROUND & AIMS: :Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n = 15; mean age 27 +/- 2) and women (n = 15; mean age 28 +/- 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.
    背景与目标: :证据表明,肾素-血管紧张素系统(RAS)功能存在性别差异。据推测,妇女对RAS阻滞的反应也可能有所不同。在男性和女性中,检查了在8周内达到的肾血管和外周血流动力学对血管紧张素受体阻滞剂递增剂量的反应以及血管紧张素II(AngII)不敏感的程度。参加研究的是30名年轻健康男性(n = 15;平均年龄27/2)和女性(n = 15;平均年龄28/2),他们在每次研究前均接受钠和蛋白质的控制饮食1周。评估了对依贝沙坦递增剂量的体液,肾脏和全身反应(75 mg,4 wk,然后150 mg,4 wk),以及在2周时对AngII的升压反应(3 ng / kg / min)。间隔。在基线和8周后通过实时PCR方案评估皮肤活检中AngII 1型受体的表达。男性和女性的血压均显着下降。与较低剂量的男性相比,女性的AngII敏感性大大降低,厄贝沙坦在4 wk时未显示升压反应,而在150 mg / d的4 wk时,男性仍表现出升压反应。男性和女性在基线时的受体表达没有差异,但女性8周时显着降低,男性则保持不变。我们的发现表明,与女性相比,男性可能需要更大剂量的血管紧张素受体阻滞剂,并且BP反应不能用作肾微血管系统RAS充分阻断的替代指标。
  • 【细胞质基因表达系统提高了阳离子脂质体介导的体内基因向小鼠脑内转移的效率。】 复制标题 收藏 收藏
    DOI:10.1006/bbrc.1997.6568 复制DOI
    作者列表:Mizuguchi H,Nakagawa T,Morioka Y,Imazu S,Nakanishi M,Kondo T,Hayakawa T,Mayumi T
    BACKGROUND & AIMS: Development of methodologies for gene transfer into the central nervous system (CNS) is important for fundamental research as well as clinical studies for gene therapy. Cationic liposomes (CL) are attractive vectors because of their safety and ease of use. However, to date only low rates of success have been reported. We succeeded in obtaining high transfection efficiencies into the newborn mouse brain in vivo by CL and a cytoplasmic gene expression system based on T7 RNA polymerase and T7 RNA polymerase- and the luciferase-gene with the T7 promoter sequence. This system showed an efficiency rate 2 orders of magnitude higher than the standard system, which used CL and luciferase genes with a Rous sarcoma virus promoter, pRSVL. In addition, in vitro experiments using LLCMK2 cells showed that cytoplasmic gene expression occurred rapidly (within 6 h) after transfection. In contrast, pRSVL required 24-48 h for induction of luciferase expression. Our results suggest that the cytoplasmic gene expression system is useful for gene delivery into the CNS.

    背景与目标: 基因转移到中枢神经系统(CNS)的方法学的发展对于基础研究以及基因治疗的临床研究都很重要。由于阳离子脂质体(CL)的安全性和易用性,它们是有吸引力的载体。然而,迄今为止,仅报道了低成功率。我们成功地通过CL和基于T7 RNA聚合酶和T7 RNA聚合酶以及荧光素酶基因(具有T7启动子序列)的细胞质基因表达系统,成功地在体内获得了新生小鼠大脑的高转染效率。该系统的效率比标准系统高2个数量级,后者使用带有Rous肉瘤病毒启动子pRSVL的CL和荧光素酶基因。此外,使用LLCMK2细胞的体外实验显示,转染后(6小时内)细胞质基因表达迅速发生。相比之下,pRSVL需要24-48小时才能诱导萤光素酶表达。我们的结果表明,胞质基因表达系统可用于将基因传递到中枢神经系统。

  • 【恶臭假单胞菌(Pseudomonas putida)U对D-葡萄糖的分解代谢通过细胞外转化为D-葡萄糖酸和诱导特定的葡萄糖酸盐转运系统而发生。】 复制标题 收藏 收藏
    DOI:10.1099/00221287-143-5-1595 复制DOI
    作者列表:Schleissner C,Reglero A,Luengo JM
    BACKGROUND & AIMS: Pseudomonas putida U does not degrade D-glucose through the glycolytic pathway but requires (i) its oxidation to D-gluconic acid by a peripherally located constitutive glucose dehydrogenase (insensitive to osmotic shock), (ii) accumulation of D-gluconic acid in the extracellular medium, and (iii) the induction of a specific energy-dependent transport system responsible for the uptake of D-gluconic acid. This uptake system showed maximal rates of transport at 30 degrees C in 50 mM potassium phosphate buffer, pH 7.0. Under these conditions the K(m) calculated for D-gluconic acid was 6.7 microM. Furthermore, a different transport system, specific for the uptake of glucose, was also identified. It is active and shows maximal uptake rates at 35 degrees C in 50 mM potassium phosphate buffer, pH 6.0, with a K(m) value of 8.3 microM.

    背景与目标: 恶臭假单胞菌U不会通过糖酵解途径降解D-葡萄糖,但需要(i)通过位于外围的组成型葡萄糖脱氢酶(对渗透压休克不敏感)将其氧化为D-葡萄糖酸,(ii)D-葡萄糖酸在D.葡萄糖中的积累(iii)诱导负责摄取D-葡萄糖酸的特定能量依赖性转运系统。该摄取系统显示了在30 mC,pH 7.0的50 mM磷酸钾缓冲液中的最大运输速率。在这些条件下,D-葡萄糖酸的K(m)计算值为6.7 microM。此外,还发现了一个专门针对葡萄糖吸收的不同转运系统。它是有活性的,在35 m的50 mM磷酸钾缓冲液(pH 6.0)中显示最大吸收速率,K(m)值为8.3 microM。

  • 【淋巴系统及其特异性生长因子,血管内皮生长因子C在前列腺癌的淋巴转移中的作用。】 复制标题 收藏 收藏
    DOI:10.1111/j.1464-410X.2006.06403.x 复制DOI
    作者列表:Trojan L,Rensch F,Voss M,Grobholz R,Weiss C,Jackson DG,Alken P,Michel MS
    BACKGROUND & AIMS: OBJECTIVE:To compare prostate carcinoma, with and with no lymph node metastasis, to benign prostatic hyperplasia (BPH) tissue for lymphatic vessel density (LVD) and the expression of the lymph-endothelial specific growth factor, vascular endothelial growth factor C (VEGF-C), to determine their role in lymphogenic metastasis. PATIENTS, MATERIALS AND METHODS:Lymphatic vessels were stained using lymphatic vessel endothelial hyaluronan receptor 1 and assessed in standard areas. The expression of VEGF-C was assessed by the number of positive epithelial cells. The data were compared with the clinical staging. RESULTS:The lowest LVD was found in tumorous areas as opposed to periphery and nontumorous tissue (P = 0.007; P < 0.001). The highest LVD was in BPH tissue (P < 0.001). There was no correlation with clinical staging. There was more VEGF-C staining in pN1 than in pN0 and in BPH specimens (P = 0.002). CONCLUSION:LVD is not a prognostic variable for the process of lymphogenic metastasis in prostate cancer. VEGF-C is up-regulated in prostate cancer and its correlation with lymph node status suggests a role for the development of lymph node metastasis, e.g. via an increased permeability of lymphatic vessels.
    背景与目标: 目的:比较有无淋巴结转移的前列腺癌与良性前列腺增生(BPH)组织的淋巴管密度(LVD)以及淋巴内皮特异性生长因子,血管内皮生长因子C(VEGF- C),确定其在淋巴转移中的作用。
    患者,材料和方法:使用淋巴管内皮透明质酸受体1对淋巴管进行染色,并在标准区域进行评估。通过阳性上皮细胞的数量评估VEGF-C的表达。将数据与临床分期进行比较。
    结果:与周围和非肿瘤组织相比,在肿瘤区域发现的LVD最低(P = 0.007; P <0.001)。 LVD最高的是BPH组织(P <0.001)。与临床分期无关。 pN1和BPH标本中的VEGF-C染色要多于pN0和PPH(P = 0.002)。
    结论:LVD不是前列腺癌淋巴转移的预后变量。 VEGF-C在前列腺癌中被上调,并且其与淋巴结状态的相关性暗示了淋巴结转移的发展,例如肝癌的发生。通过增加淋巴管的通透性
  • 【p21活化激酶1的耗竭会上调APC∆14 /小鼠的免疫系统,并抑制肠道肿瘤的发生。】 复制标题 收藏 收藏
    DOI:10.1186/s12885-017-3432-0 复制DOI
    作者列表:Huynh N,Wang K,Yim M,Dumesny CJ,Sandrin MS,Baldwin GS,Nikfarjam M,He H
    BACKGROUND & AIMS: BACKGROUND:P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC∆14/+ mice. METHODS:The PAK1 KO APC∆14/+ mice were generated by cross-breeding of PAK1 KO mice with APC∆14/+ mice. Splenic lymphocytes were analysed by flow cytometry, and immunohistochemical staining. The numbers of intestinal tumours were counted. Blood cells were also counted. RESULTS:Compared to APC+/+ mice, the numbers of both T- and B- lymphocytes were reduced in the spleen of APC∆14/+ mice. Depletion of PAK1 in APC∆14/+ mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC∆14/+ mice with PF-3758309, a PAK inhibitor reduced the numbers of intestinal tumours and increased the numbers of blood lymphocytes. CONCLUSION:Depletion of active PAK1 up-regulates the immune system of APC∆14/+ mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.
    背景与目标: 背景:P21激活的激酶1(PAK1)通过多种信号通路的激活刺激结直肠癌(CRC)的生长和转移。 PAK1对CRC干细胞标志物的上调也有助于CRC对5-氟尿嘧啶的抗性。这项研究的目的是研究PAK1的消耗和抑制对APC∆14 /小鼠免疫系统和肠道肿瘤形成的影响。
    方法:PAK1 KO APC∆14 /小鼠是通过将PAK1 KO小鼠与APC∆14 /小鼠杂交而产生的。通过流式细胞术和免疫组织化学染色分析脾淋巴细胞。计算肠道肿瘤的数量。还对血细胞计数。
    结果:与APC /小鼠相比,APC∆14 /小鼠脾脏中T淋巴细胞和B淋巴细胞的数量均减少。 APC∆14 /小鼠中PAK1的消耗增加了脾脏T-和B-淋巴细胞的数量,并减少了肠肿瘤的数量。用PAK抑制剂PF-3758309治疗APC∆14 /小鼠,可减少肠肿瘤的数量并增加血淋巴细胞的数量。
    结论:活性PAK1的耗尽可上调APC∆14 /小鼠的免疫系统,并抑制肠道肿瘤的发展。这些观察结果表明PAK1在对肿瘤的免疫应答中起重要作用。
  • 【突破到另一面:蛋白质通过细菌Sec系统输出。】 复制标题 收藏 收藏
    DOI:10.1042/BJ20121227 复制DOI
    作者列表:Chatzi KE,Sardis MF,Karamanou S,Economou A
    BACKGROUND & AIMS: :More than one-third of cellular proteomes traffic into and across membranes. Bacteria have invented several sophisticated secretion systems that guide various proteins to extracytoplasmic locations and in some cases inject them directly into hosts. Of these, the Sec system is ubiquitous, essential and by far the best understood. Secretory polypeptides are sorted from cytoplasmic ones initially due to characteristic signal peptides. Then they are targeted to the plasma membrane by chaperones/pilots. The translocase, a dynamic nanomachine, lies at the centre of this process and acts as a protein-conducting channel with a unique property; allowing both forward transfer of secretory proteins but also lateral release into the lipid bilayer with high fidelity and efficiency. This process, tightly orchestrated at the expense of energy, ensures fundamental cell processes such as membrane biogenesis, cell division, motility, nutrient uptake and environmental sensing. In the present review, we examine this fascinating process, summarizing current knowledge on the structure, function and mechanics of the Sec pathway.
    背景与目标: :三分之一以上的细胞蛋白质组进入和穿过膜。细菌已经发明了几种复杂的分泌系统,可以将各种蛋白质引导到胞外位置,在某些情况下可以将它们直接注射到宿主中。在这些系统中,Sec系统无处不在,必不可少,是迄今为止最广为人知的系统。最初,由于特征性信号肽,分泌多肽从细胞质中分离出来。然后它们被伴侣/飞行员靶向质膜。转运酶,一个动态的纳米机器,位于这一过程的中心,并作为具有独特性质的蛋白质传导通道。既可以使分泌蛋白向前转移,又可以高保真度和效率横向释放到脂质双层中。以能量为代价精心安排的这一过程可确保基本的细胞过程,例如膜生物发生,细胞分裂,运动,养分吸收和环境感知。在当前的审查中,我们检查了这个迷人的过程,总结了有关Sec途径的结构,功能和力学的当前知识。
  • 【胰腺内分泌肿瘤中新型治疗策略的分子标记。】 复制标题 收藏 收藏
    DOI:10.1097/MPA.0b013e31826cb243 复制DOI
    作者列表:Gilbert JA,Adhikari LJ,Lloyd RV,Halfdanarson TR,Muders MH,Ames MM
    BACKGROUND & AIMS: OBJECTIVES:Pancreatic endocrine tumors (PETs) share numerous features with gastrointestinal neuroendocrine (carcinoid) tumors. Targets of novel therapeutic strategies previously assessed in carcinoid tumors were analyzed in PETs (44 cases). METHODS:Activating mutations in EGFR, KIT, and PDGFRA and nonresponse mutations in KRAS were evaluated. Copy number of EGFR and HER-2/neu was quantified by fluorescence in situ hybridization. Expression of EGFR, PDGFRA, VEGFR1, TGFBR1, Hsp90, SSTR2A, SSTR5, IGF1R, mTOR, and MGMT was measured immunohistochemically. RESULTS:Elevated EGFR copy number was found in 38% of cases but no KRAS nonresponse mutations. VEGFR1, TGFBR1, PDGFRA, SSTR5, SSTR2A, and IGF1R exhibited the highest levels of expression in the largest percentages of PETs.Anticancer drugs BMS-754807 (selective for IGF1R/IR), 17-(allylamino)-17-demethoxygeldanamycin (17-AAG, targeting Hsp90), and axitinib (directed toward VEGFR1-3/PDGFRA-B/KIT) induced growth inhibition of human QGP-1 PET cells with IC50 values (nM) of 273, 723, and 743, respectively. At growth-inhibiting concentrations, BMS-754807 inhibited IGF1R phosphorylation; 17-AAG induced loss of EGFR, IGF1R, and VEGFR2; and axitinib increased p21(CDKN1A) expression without inhibiting VEGFR2 phosphorylation. CONCLUSIONS:Results encourage further research into multidrug strategies incorporating inhibitors targeting IGF1R or Hsp90 and into studies of axitinib combined with conventional chemotherapeutics toxic to tumor cells in persistent growth arrest.
    背景与目标: 目的:胰腺内分泌肿瘤(PET)与胃肠道神经内分泌(类癌)肿瘤具有许多特征。以前在类癌肿瘤中评估过的新型治疗策略的目标已在PET中进行了分析(44例)。
    方法:评估EGFR,KIT和PDGFRA的激活突变以及KRAS的无应答突变。通过荧光原位杂交定量EGFR和HER-2 / neu的拷贝数。免疫组织化学法检测EGFR,PDGFRA,VEGFR1,TGFBR1,Hsp90,SSTR2A,SSTR5,IGF1R,mTOR和MGMT的表达。
    结果:38%的病例发现EGFR拷贝数升高,但没有KRAS无反应突变。 VEGFR1,TGFBR1,PDGFRA,SSTR5,SSTR2A和IGF1R在最大百分比的PET中表现出最高水平的表达。抗癌药BMS-754807(对IGF1R / IR选择性),17-(烯丙胺基)-17-去甲氧基格尔德霉素(17-靶向Hsp90的AAG和阿昔替尼(针对VEGFR1-3 / PDGFRA-B / KIT)诱导人QGP-1 PET细胞的生长抑制,IC50值(nM)分别为273、723和743。在抑制生长的浓度下,BMS-754807抑制了IGF1R磷酸化。 17-AAG诱导的EGFR,IGF1R和VEGFR2丢失;阿昔替尼在不抑制VEGFR2磷酸化的情况下增加p21(CDKN1A)的表达。
    结论:结果鼓励对结合靶向IGF1R或Hsp90的抑制剂的多药策略和阿昔替尼与常规化学治疗药物联合治疗对持续生长停滞有毒的肿瘤细胞进行进一步研究。

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