• 【[分子生物学为日常医学病毒学服务。2.在病毒学诊断中的应用]。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Wattré P
    BACKGROUND & AIMS: :Molecular biology techniques are applied for the diagnosis of meningoencephalitis due to herpesviruses, enteroviruses or polyomaviruses, for the diagnosis of human cytomegalovirus, human parvovirus B19, varicella-zoster virus and rubella virus infections occurring during pregnancy, for the diagnosis and the management of retrovirus infections (HIV and HTLV) and of hepatitis (HBV and HCV), for papillomavirus typing and to detect a link between virus and clinical manifestations (cardiomyopathy or insulinodependent diabetes with coxsackievirus B: Kaposi's sarcoma with HHV 8) or to investigate an environmental contamination with viruses. These new molecular markers which are both qualitative and quantitative represent an important advance in the field of viral diagnosis research, in the monitoring of viral load during the course of infection, in the therapy control of viral disease and in the epidemiology of virus spread. Standardization and automatization are obtained using available commercial reagents and kits.
    背景与目标: : 分子生物学技术用于诊断由疱疹病毒,肠病毒或多瘤病毒引起的脑膜脑炎,用于诊断人巨细胞病毒病毒,人细小病毒B19,水痘病毒病毒和怀孕期间发生的风疹病毒病毒,用于诊断和管理复古病毒感染 (HIV和HTLV) 和肝炎 (HBV和HCV),乳头瘤病毒分型,并检测病毒与临床表现 (心肌病或胰岛素依赖型糖尿病与柯萨奇病毒B: 卡波西氏肉瘤与HHV 8) 或调查病毒es的环境污染。这些定性和定量的新分子标记物代表了病毒诊断研究领域,感染过程中病毒载量的监测,病毒性疾病的治疗控制以及病毒传播流行病学领域的重要进展。使用可用的商业试剂和试剂盒可获得标准化和自动化。
  • 【设计为MMP-3抑制剂的2-邻苯二甲酰亚胺戊二酸类似物的硅铅系列初步研究。】 复制标题 收藏 收藏
    DOI:10.1021/ci0601362 复制DOI
    作者列表:Amin EA,Welsh WJ
    BACKGROUND & AIMS: :Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.
    背景与目标: : 基质金属蛋白酶 (MMPs) 由于其在肿瘤转移以及退行性疾病 (如骨关节炎和类风湿性关节炎) 的兴起和传播中的作用而成为深入研究的主题。初步设计了140类药物小分子基质metalloproteinase-3抑制剂,作为优化和合成的起始支架,使用一系列高度预测性的三维定量构效关系模型,包括比较分子场分析和比较分子相似性指数分析,对接和得分。沙利度胺被选为新铅系列的骨架,因为它适度抑制MMP-3,具有抗血管生成作用,并且易于进行结构修饰。根据辛醇-水分配系数ClogP估计,大多数新化合物表现出中等至高的预测生物活性和良好的生物利用度。化合物102尤其表现出对MMP-3极其有利的预测活性; 具有适度的生物利用度; 满足Lipinski的五法则; 并显示出有望进一步优化,合成和实验评估作为潜在的辅助抗癌或抗风湿治疗剂。
  • 【小鼠6号染色体上的2 mb YAC重叠群和自然杀伤基因复合物的物理图谱。】 复制标题 收藏 收藏
    DOI:10.1006/geno.1997.4721 复制DOI
    作者列表:Brown MG,Fulmek S,Matsumoto K,Cho R,Lyons PA,Levy ER,Scalzo AA,Yokoyama WM
    BACKGROUND & AIMS: :We have constructed a physical map of a > 2-Mb region on mouse chromosome 6 that contains the natural killer gene complex (NKC). The map comprises a contig of 14 overlapping yeast artificial chromosomes onto which we positioned 25 NKC markers. NKC genetically linked genes encode > 17 proteins that directly control innate NK cell-mediated tumor lysis and disease resistance. Herein we show that Nkrp1 genes are clustered in a region flanked by A2m and Cd69 genes and that most Ly49 genes are clustered in a distal region -1 Mb distant. Importantly, syntenic intervals of mouse chromosome 6 and human chromosome 12p that include the NKC are conserved. NKC species conservation suggests that the human NKC may contain orthologues for the mouse viral disease resistance genes, Cmv1 and Rmp1. The high-resolution NKC map will facilitate investigation of NKC gene regulation and identification of phenotypically defined gene products that confer NK cell defense against viral pathogens.
    背景与目标: : 我们已经在小鼠6号染色体上构建了一个> 2-Mb区域的物理图,其中包含自然杀伤基因复合物 (NKC)。该图谱包含14个重叠的酵母人工染色体的重叠群,我们在其上定位了25个NKC标记。NKC基因连接的基因编码> 17种直接控制先天NK细胞介导的肿瘤溶解和抗病的蛋白质。在本文中,我们显示Nkrp1基因聚集在A2m和Cd69基因两侧的区域中,并且大多数Ly49基因聚集在远端区域-1 Mb远处。重要的是,包含NKC的小鼠6号染色体和人类12p染色体的同义间隔是保守的。NKC物种保护表明,人类NKC可能包含小鼠病毒抗病基因Cmv1和rmp1的直系同源物。高分辨率NKC图谱将有助于NKC基因调控的研究和表型定义的基因产物的鉴定,这些基因产物赋予NK细胞针对病毒病原体的防御能力。
  • 【人类Achaete-Scute同源物2 (ASCL2,HASH2) 映射到11p15.5号染色体,接近IGF2,并在绒毛外滋养细胞中表达。】 复制标题 收藏 收藏
    DOI:10.1093/hmg/6.6.859 复制DOI
    作者列表:Alders M,Hodges M,Hadjantonakis AK,Postmus J,van Wijk I,Bliek J,de Meulemeester M,Westerveld A,Guillemot F,Oudejans C,Little P,Mannens M
    BACKGROUND & AIMS: Here we describe the cloning of the human Achaete Scute Homologue 2 (HASH2) gene, officially designated ASCL2 (Achaete Scute complex like 2), a homologue of the Drosophila Achaete and Scute genes. In mouse, this gene is imprinted and maps to chromosome 7. We mapped the human homologue close to IGF2 and H19 at 11p15.5, the human region syntenic with mouse chromosome 7, indicating that this imprinted region is highly conserved in mouse and man. HASH2 is expressed in the extravillus trophoblasts of the developing placenta only. The lack of HASH2 expression in non-malignant hydatidiform (androgenetic) moles indicates that HASH2 is also imprinted in man.

    背景与目标: 在这里,我们描述了人类Achaete Scute同源物2 (HASH2) 基因的克隆,该基因正式命名为ASCL2 (Achaete Scute complex like 2),这是果蝇Achaete和Scute基因的同源物。在小鼠中,该基因被印记并映射到7号染色体。我们在11p15.5处绘制了接近IGF2和H19的人类同源物,该人类区域与小鼠7号染色体同义,表明该印迹区域在小鼠和人类中高度保守。HASH2仅在发育中的胎盘的绒毛外滋养细胞中表达。HASH2在非恶性葡萄胎 (雄激素) 痣中缺乏表达,表明HASH2在人类中也有印记。
  • 【吸入类固醇/长效 β2激动剂组合产品可改善成人哮喘患者的24小时肺功能。】 复制标题 收藏 收藏
    DOI:10.1186/1465-9921-7-110 复制DOI
    作者列表:Lötvall J,Langley S,Woodcock A
    BACKGROUND & AIMS: BACKGROUND:The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. OBJECTIVES:The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS:Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS:In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively CONCLUSION:Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.
    背景与目标:
  • 【交联聚 (1-乙烯基-2-吡咯烷酮) 凝胶对静态细胞培养中细胞生长的影响。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Hong Y,Chirila TV,Fitton JH,Ziegelaar BW,Constable IJ
    BACKGROUND & AIMS: Poly(1-vinyl-2-pyrrolidinone) (PVP) and copolymers of 1-vinyl-2-pyrrolidinone are insoluble in water when crosslinked but they can absorb very large amounts of water to become syringe-injectable hydrogels. Such gels have been investigated recently as potential substitutes for the vitreous humour in the eye. In this study, during the cytotoxic evaluation by sulforhodamine B colorimetric assay of variously crosslinked PVP gels, it was found that many of them showed protective/growth promoting effects on 3T3 mouse fibroblasts in static cultures, a phenomenon encountered previously only with aqueous solutions of a limited number of natural or synthetic polymers. Particularly, the gels crosslinked with diethylene glycol dimethacrylate (DEGDMA) induced a significant enhancement of cell proliferation, especially in serum-free cultures. No correlation between this effect and the essential gel properties (chemical composition, viscoelasticity and equilibrium water content) could be established. The study demonstrated that crosslinked PVP hydrogels showed a serum-like growth promoting effect on an anchorage-dependent cell line, which may be due to physical protection, inability of the insoluble gels to penetrate cell membranes, and their ability to mimic the extracellular matrix.

    背景与目标: 聚 (1-乙烯基-2-吡咯烷酮) (PVP) 和1-乙烯基-2-吡咯烷酮的共聚物在交联时不溶于水,但它们可以吸收大量的水,成为可注射器注射的水凝胶。最近已经研究了这种凝胶作为眼睛玻璃体液的潜在替代品。在这项研究中,在通过sulforhodamine B比色法对各种交联的PVP凝胶进行细胞毒性评估期间,发现其中许多凝胶对静态培养中的3T3小鼠成纤维细胞表现出保护/促进生长的作用,这种现象以前仅在水溶液中遇到。有限数量的天然或合成聚合物。特别是,与二甘醇二甲基丙烯酸酯 (DEGDMA) 交联的凝胶可显着增强细胞增殖,尤其是在无血清培养物中。无法建立这种作用与基本凝胶特性 (化学成分,粘弹性和平衡水含量) 之间的相关性。研究表明,交联的PVP水凝胶对锚定依赖性细胞系表现出类似血清的生长促进作用,这可能是由于物理保护,不溶性凝胶无法穿透细胞膜以及它们模仿细胞外基质的能力。
  • 【印度链球菌JCM中含2-脱氧链霉菌的抗生素的生物合成3268: 2-脱氧-scyllo-肌糖合酶的表征。】 复制标题 收藏 收藏
    DOI:10.1038/ja.2006.51 复制DOI
    作者列表:Hirayama T,Tamegai H,Kudo F,Kojima K,Kakinuma K,Eguchi T
    BACKGROUND & AIMS: :A part of the new biosynthetic gene cluster for 2-deoxystreptamine-containing antibiotics was identified from Streptoalloteichus hindustanus. The alloH gene in the gene cluster was deduced to encode 2-deoxy-scyllo-inosose synthase and the expressed protein AlloH was confirmed to have this enzyme activity. Furthermore, biochemical properties of AlloH were studied.
    背景与目标: : 从Streptoalloteichus hindustanus中鉴定出了含2-脱氧链霉菌的抗生素的新生物合成基因簇的一部分。推导了基因簇中的alloH基因编码2-脱氧-scyllo-肌糖合酶,并确认表达的蛋白AlloH具有该酶活性。此外,还研究了AlloH的生化特性。
  • 【腺病毒药物2-氨基嘌呤可防止细胞蛋白质合成的抑制。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.87.18.7115 复制DOI
    作者列表:Huang JT,Schneider RJ
    BACKGROUND & AIMS: :Adenovirus infection results in the suppression of cellular protein synthesis, but the mechanism has not been established. In this report we demonstrate that the shut-off of cellular protein synthesis by adenovirus is prevented in cells by treatment with the drug 2-aminopurine. Treatment with 2-aminopurine is shown to prevent suppression of cellular translation without disrupting the normal viral block in the transport of cellular mRNAs from the nucleus to the cytoplasm. We show that viral suppression of cellular protein synthesis occurs concomitant with activation of the interferon-induced double-stranded RNA-activated inhibitor (DAI), a protein kinase, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha), but that prevention of host cell shut-off by 2-aminopurine occurs without a decrease in kinase activity or a dephosphorylation of eIF-2 alpha. Results are presented that indicate that activation of DAI kinase and phosphorylation of eIF-2 alpha may be required but are not sufficient to achieve inhibition of cellular protein synthesis during adenovirus infection. We suggest that other events, in particular the modification of additional initiation factors, are likely involved in viral inhibition of cellular translation.
    背景与目标: : 腺病毒感染导致细胞蛋白质合成的抑制,但机制尚未建立。在本报告中,我们证明了通过用药物2-氨基嘌呤处理可防止细胞中腺病毒对细胞蛋白质合成的切断。显示用2-氨基嘌呤处理可防止抑制细胞翻译,而不会破坏细胞mrna从细胞核到细胞质转运中的正常病毒阻滞。我们显示,细胞蛋白合成的病毒抑制与干扰素诱导的双链RNA激活抑制剂 (DAI),蛋白激酶的激活以及真核起始因子2 (eIF-2 α) 的 α 亚基的磷酸化同时发生,但是,通过2-氨基嘌呤阻止宿主细胞关闭而不会降低激酶活性或eIF-2 α 的去磷酸化。结果表明DAI激酶的活化和eIF-2 α 的磷酸化可能是必需的,但不足以在腺病毒感染期间实现细胞蛋白合成的抑制。我们建议其他事件,尤其是其他起始因子的修饰,可能与病毒对细胞翻译的抑制有关。
  • 【Β1-和 β2-肾上腺素能受体在三环抗抑郁药的抗伤害感受作用中的意义。】 复制标题 收藏 收藏
    DOI:10.1016/s0924-977x(97)00411-2 复制DOI
    作者列表:Micó JA,Gibert-Rahola J,Casas J,Rojas O,Serrano MI,Serrano JS
    BACKGROUND & AIMS: Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulusbeta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

    背景与目标: 三环抗抑郁药已被证明可用于治疗不同病因的疼痛。单胺能系统似乎与这种现象有关。在这项研究中,使用物理和化学伤害性测试在小鼠中研究了选择性 β1- (CGP 20712A) 和 β2- (ICI 118551) 肾上腺素能阻滞剂对地昔帕明和去甲替林的抗伤害感受作用的影响,该测试涉及中枢神经系统 (CNS) 中不同水平的感觉-运动整合。进行活性测试以检测 “假阳性” 或 “假阴性” 结果。获得的结果表明,CGP 20712A和ICI 118551都能够在物理测试 (热板和甩尾) 中拮抗这些抗抑郁药的抗伤害感受作用。然而,在化学测试 (乙酸和福尔马林) 中,所使用的抗抑郁药的镇痛作用仅被CGP 20712A拮抗。这些结果表明,地昔帕明和去甲替林的镇痛作用是由 β-肾上腺素受体介导的。涉及的 β-肾上腺素能受体取决于伤害性刺激的类型,当刺激是物理刺激时,β1和 β2都涉及,但当刺激是化学刺激时,只有 β1涉及。
  • 【VEGF亚型与体内VEGFR-1,VEGFR-2和神经纤毛蛋白的相互作用: 人类骨骼肌的计算模型。】 复制标题 收藏 收藏
    DOI:10.1152/ajpheart.00637.2006 复制DOI
    作者列表:Mac Gabhann F,Popel AS
    BACKGROUND & AIMS: :The vascular endothelial growth factor (VEGF) family of cytokines is involved in the maintenance of existing adult blood vessels as well as in angiogenesis, the sprouting of new vessels. To study the proangiogenic activation of VEGF receptors (VEGFRs) by VEGF family members in skeletal muscle, we develop a computational model of VEGF isoforms (VEGF(121), VEGF(165)), their cell surface receptors, and the extracellular matrix in in vivo tissue. We build upon our validated model of the biochemical interactions between VEGF isoforms and receptor tyrosine kinases (VEGFR-1 and VEGFR-2) and nonsignaling neuropilin-1 coreceptors in vitro. The model is general and could be applied to any tissue; here we apply the model to simulate the transport of VEGF isoforms in human vastus lateralis muscle, which is extensively studied in physiological experiments. The simulations predict the distribution of VEGF isoforms in resting (nonexercising) muscle and the activation of VEGFR signaling. Little of the VEGF protein in muscle is present as free, unbound extracellular cytokine; the majority is bound to the cell surface receptors or to the extracellular matrix. However, interstitial sequestration of VEGF(165) does not affect steady-state receptor binding. In the absence of neuropilin, VEGF(121) and VEGF(165) behave similarly, but neuropilin enhances the binding of VEGF(165) to VEGFR-2. This model is the first to study VEGF tissue distribution and receptor activation in human muscle, and it provides a platform for the design and evaluation of therapeutic approaches.
    背景与目标: : 细胞因子的血管内皮生长因子 (VEGF) 家族参与现有成人血管的维持以及血管生成,新血管的萌发。为了研究骨骼肌中VEGF家族成员对VEGF受体 (VEGFRs) 的促血管生成激活,我们建立了VEGF同工型 (VEGF(121),VEGF(165)),它们的细胞表面受体和细胞外基质的计算模型。体内组织。我们建立在我们验证的VEGF同工型与受体酪氨酸激酶 (VEGFR-1和VEGFR-2) 之间的生化相互作用的模型,以及体外非信号neuropilin-1共受体。该模型是通用的,可以应用于任何组织; 在这里,我们应用该模型来模拟人外侧肌中VEGF同工型的运输,这在生理实验中得到了广泛的研究。模拟预测了静息 (非运动) 肌肉中VEGF亚型的分布以及VEGFR信号传导的激活。肌肉中几乎没有VEGF蛋白以游离的,未结合的细胞外细胞因子的形式存在; 大多数与细胞表面受体或细胞外基质结合。然而,VEGF(165) 的间质隔离不影响稳态受体结合。在不存在神经菌毛蛋白的情况下,VEGF(121) 和VEGF(165) 表现相似,但是神经菌毛蛋白增强VEGF(165) 与VEGFR-2的结合。该模型是第一个研究人肌肉中VEGF组织分布和受体激活的模型,它为治疗方法的设计和评估提供了平台。
  • 【断裂修复后跟腱伸长: 2种术后方案的随机比较。】 复制标题 收藏 收藏
    DOI:10.1177/0363546506293255 复制DOI
    作者列表:Kangas J,Pajala A,Ohtonen P,Leppilahti J
    BACKGROUND & AIMS: BACKGROUND:A few prospective controlled trials comparing early functional rehabilitation after Achilles tendon repair and non-operative immobilization have been reported. HYPOTHESES:There is no difference in Achilles tendon elongation between early motion and immobilization after Achilles tendon repair. Tendon elongation does not correlate with the clinical outcome. STUDY DESIGN:Randomized clinical trial; Level of evidence, 2. METHODS:Fifty patients with acute Achilles tendon rupture were randomized postoperatively to receive either early movement of the ankle between neutral and plantar flexion in a brace for 6 weeks or immobilization in tension using a below-knee cast with the ankle in a neutral position for 6 weeks. Full weightbearing was allowed after 3 weeks in both groups. Standardized radiographs to measure previously placed radiographic markers were taken on the first day postoperatively and at 1, 3, 6, 12, 24 weeks postoperatively, with the final radiograph a mean of 60 (SD, 6.4) weeks postoperatively. The outcome was assessed at the 3-month and final checkups by the clinical scoring method described by Leppilahti et al and included subjective factors and objective factors. RESULTS:Tendon elongation occurred in both groups but was somewhat less in the early motion group (median 2 mm in the early motion group vs median 5 mm in the cast group a mean of 60 weeks postoperatively, P = .054). The elongation curves first rose and then slowly fell in both groups. The patients who had less elongation achieved a better clinical outcome (rho = -.42, P = .017). Tendon elongation did not correlate significantly with age, body mass index, or isokinetic peak torques. CONCLUSION:Achilles tendon elongation was somewhat less in the early motion group and correlated with the clinical outcome scores. We recommend early functional postoperative treatment after Achilles rupture repair.
    背景与目标:
  • 【PDT联合COX-2抑制剂萘丁美酮治疗新生血管性arpd后黄斑萎缩的进展。】 复制标题 收藏 收藏
    DOI:10.5507/bp.2012.066 复制DOI
    作者列表:Sin M,Chrapek O,Karhanova M,Pracharova Z,Langova K,Rehak J
    BACKGROUND & AIMS: AIM:To evaluate photodynamic therapy (PDT) combined with the preferential the cyclooxygenase-2 (COX-2) inhibitor, nabumetone in the treatment of the neovascular age-related macular degeneration (ARMD). METHODS:A prospective, double-blind, randomized study on 60 patients with subfoveal CNV secondary to ARMD without any previous treatment. Patients were divided into a nabumetone or placebo group. The main endpoints were the change of best-corrected visual acuity (BCVA), central macular thickness (CRT) and number of required PDT treatments. RESULTS:In the nabumetone group, 27 patients (90%) and 28 (93%) in the placebo group completed the follow-up of 12 months. In the nabumetone group, the mean CRT decreased from 332 μm (SD 68 μm) to 220 μm (SD 46 μm). In the placebo group, CRT decreased from 331 μm (SD 72 μm) to 254 μm (SD 61 μm). The mean BCVA was 0.68 log MAR (SD 0.22 log MAR) in the nabumetone group and 0.62 log MAR (SD 0.23 log MAR) in the placebo group at baseline. This stabilised in the placebo group to 0.66 log MAR (SD 0.33) but deteriorated in the nabumetone group to 0.86 log MAR (SD 0.41 log MAR). There was a significant reduction in the number of required PDTs in the nabumetone group, but significant progression of the RPE atrophy area. CONCLUSION:Combined PDT with oral intake of the COX-2 inhibitor, nabumetone reduced the number of required PDT retreatments, but worsening BCVA caused by macular atrophy progression. Therefore the combination of the PDT with the nabumetone is not recommended.
    背景与目标:
  • 【非小细胞肺癌中的自噬和Bcl-2/BNIP3死亡调节途径。】 复制标题 收藏 收藏
    DOI:10.1111/apm.12026 复制DOI
    作者列表:Karpathiou G,Sivridis E,Koukourakis M,Mikroulis D,Bouros D,Froudarakis M,Bougioukas G,Maltezos E,Giatromanolaki A
    BACKGROUND & AIMS: :We recently showed that non-small cell lung carcinomas (NSCLCs) are of dismal prognosis when encompassing accelerated autophagic activity. The regulation of this abnormally functioning degradation system and its association with hypoxia and apoptosis in lung carcinoma patients is unexplored. In this study we used 115 NSCLC tissues to examine the immunohistochemical expression of four distinct molecules - the major regulator of autophagy Beclin 1, the anti-apoptotic and anti-autophagic protein Bcl-2, the pro-apoptotic and pro-autophagic protein BNIP3, and a marker of hypoxia and glucolysis, the glucose transporter Glut 1. Most cases showed reduced reactivity for Beclin 1 (62%) and Bcl-2 (82%) proteins, almost half of our sample revealed strong BNIP3 expression (57%), whereas most of the carcinomas strongly expressed Glut 1 antigen (71%). Beclin 1 expression showed no association with survival. Bcl-2 positivity was a marker of good prognosis (p = 0.04), whereas BNIP3 (p = 0.0004) and Glut 1 (p = 0.03) expression correlated with poor outcome in Stage I disease. Autophagic status was negatively associated with Bcl-2 (p = 0.0006), but positively with Glut 1 expression (p = 0.001). In conclusion, the accelerated autophagic status in NSCLC is unrelated to Beclin 1 and BNIP3 expression, but does show significant association with Bcl-2 reactivity. Furthermore, we showed important correlations between glucolysis and autophagy, guiding new pathways in future lung carcinoma research.
    背景与目标: : 我们最近发现,当包括加速的自噬活性时,非小细胞肺癌 (nsclc) 的预后很差。尚未探索这种功能异常的降解系统的调节及其与肺癌患者缺氧和凋亡的关系。在这项研究中,我们使用了115个NSCLC组织来检查四个不同分子的免疫组织化学表达-自噬的主要调节剂Beclin 1,抗凋亡和抗自噬蛋白Bcl-2,促凋亡和自噬蛋白BNIP3,以及缺氧和葡萄糖溶解的标志物,葡萄糖转运蛋白Glut 1。大多数病例显示对Beclin 1 (62%) 和Bcl-2 (82%) 蛋白的反应性降低,几乎一半的样本显示BNIP3强表达 (57%),而大多数癌强烈表达Glut 1抗原 (71%)。Beclin 1表达与生存率无关。Bcl-2阳性是预后良好的标志 (p = 0.04),而BNIP3 (p = 0.0004) 和Glut 1 (p = 0.03) 表达与I期疾病不良预后相关。自噬状态与Bcl-2呈负相关 (p = 0.0006),但与Glut 1表达呈正相关 (p = 0.001)。总之,NSCLC的加速自噬状态与Beclin 1和BNIP3表达无关,但确实显示出与Bcl-2反应性的显着关联。此外,我们还显示了葡萄糖溶解与自噬之间的重要相关性,为未来肺癌研究提供了新的途径。
  • 【脑弥散和T(2): 持续高原缺氧期间急性高山病的MRI预测因子。】 复制标题 收藏 收藏
    DOI:10.1038/jcbfm.2012.184 复制DOI
    作者列表:Hunt JS Jr,Theilmann RJ,Smith ZM,Scadeng M,Dubowitz DJ
    BACKGROUND & AIMS: :Diffusion magnetic resonance imaging (MRI) provides a sensitive indicator of cerebral hypoxia. We investigated if apparent diffusion coefficient (ADC) and transverse relaxation (T(2)) predict symptoms of acute mountain sickness (AMS), or merely indicate the AMS phenotype irrespective of symptoms. Fourteen normal subjects were studied in two groups; unambiguous AMS and no-AMS at 3,800 m altitude (intermediate AMS scores were excluded). T(2) relaxation was estimated from a T(2) index of T(2)-weighted signal normalized by cerebrospinal fluid signal. Measurements were made in normoxia and repeated after 2 days sustained hypoxia (AMS group symptomatic and no-AMS group asymptomatic) and after 7 days hypoxia (both groups asymptomatic). Decreased ADC directly predicted AMS symptoms (P<0.05). Apparent diffusion coefficient increased in asymptomatic subjects, or as symptoms abated with acclimatization. This pattern was similar in basal ganglia, white matter, and gray matter. Corpus callosum behaved differently; restricted diffusion was absent (or rapidly reversed) in the splenium, and was sustained in the genu. In symptomatic subjects, T(2,index) decreased after 2 days hypoxia and further decreased after 7 days. In asymptomatic subjects, T(2,index) initially increased after 2 days, but decreased after 7 days. T(2,index) changes were not predictive of AMS symptoms. These findings indicate that restricted diffusion, an indicator of diminished cerebral energy status, directly predicts symptoms of AMS in humans at altitude.
    背景与目标: 扩散磁共振成像 (MRI) 提供了脑缺氧的敏感指标。我们调查了表观扩散系数 (ADC) 和横向松弛 (T(2)) 是否可以预测急性高山病 (AMS) 的症状,或者仅指示AMS表型而与症状无关。研究了两组中的14名正常受试者; 3,800  m高度的明确AMS和no-AMS (排除中间AMS得分)。T(2) 松弛是根据脑脊液信号归一化的T(2) 加权信号的T(2) 指数估算的。在常氧下进行测量,并在持续缺氧2天 (有症状的AMS组和无症状的no-AMS组) 和缺氧7天 (两组均无症状) 后重复进行。ADC降低直接预测AMS症状 (P<0.05)。在无症状的受试者中,表观扩散系数增加,或者随着症状的适应而减轻。这种模式在基底神经节,白质和灰质中相似。Call体的行为不同; 脾脏中不存在 (或迅速逆转) 受限的扩散,并在基因组中持续存在。在有症状的受试者中,缺氧2 d后T(2,指数) 降低,7 d后进一步降低。在无症状的受试者中,T(2,指数) 在2天后最初增加,但在7天后降低。T(2,指数) 变化不能预测AMS症状。这些发现表明,受限的扩散是大脑能量状态降低的指标,直接预测了人类在海拔地区的AMS症状。
  • 【来自右室流出道的良性室性早搏复合物触发了2型LQTS患者的多形性室性心动过速。】 复制标题 收藏 收藏
    DOI:10.2169/internalmedicine.51.8565 复制DOI
    作者列表:Sato A,Chinushi M,Sonoda K,Abe A,Izumi D,Furushima H
    BACKGROUND & AIMS: :A 57-year-old woman showed frequent premature ventricular complexes (PVCs) originating from the right ventricular outflow tract (RVOT), and some of the PVCs triggered polymorphic ventricular tachycardia (PVT). Structural heart diseases were ruled out by conventional cardiac examinations. Radiofrequency catheter ablation was successful in eliminating the PVCs and subsequent PVT. However, epinephrine infusion unmasked her prolonged QT interval, and a genetic analysis revealed a KCNH2 mutation (R694H) as the cause of latent type-2 long QT syndrome (LQTS). This case suggests that latent LQTS may work as an arrhythmogenic substrate of PVT triggered by a benign form of RVOT-PVCs in patients with a structurally normal heart.
    背景与目标: : 一名57岁的女性表现出频繁的源自右心室流出道 (RVOT) 的室性早搏 (pvc),其中一些pvc触发了多形性室性心动过速 (PVT)。常规心脏检查排除了结构性心脏病。射频导管消融成功消除了pvc和随后的PVT。然而,肾上腺素输注揭示了她延长的QT间期,基因分析显示KCNH2突变 (R694H) 是潜伏性2型长QT综合征 (LQTS) 的原因。这种情况表明,在结构正常的心脏患者中,潜在的LQTS可能是由良性形式的rvot-pvc触发的PVT的致心律失常底物。

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