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In vivo short-term expression of a hypertrophic cardiomyopathy mutation in adult rabbit myocardium: myofibrillar incorporation without early disarray. 成年兔心肌肥厚性心肌病突变的体内短期表达:无早期紊乱的肌纤维掺入。
Pub Date : 1999-01-01 DOI: 10.1046/j.1525-1381.1999.09416.x
Q Yu, G Zhao, A J Marian

Cardiac myocyte disarray is the pathological hallmark of hypertrophic cardiomyopathy (HCM), a disease of sarcomeric proteins. Mutations in the cardiac troponin T (cTnT), a major gene responsible for HCM, are associated with severe myocyte disarray. To study the pathogenesis of cardiac myocyte disarray, we expressed normal and mutant cTnT proteins in the myocardium of adult rabbits via direct intramyocardial injection of recombinant adenoviruses. Aliquots of 1010 plaque-forming units of normal (Ad/CMV/cTnT-Arg92) and mutant (Ad/CMV/cTnT-Gln92) recombinant viruses or a control vector (Ad/DeltaE) virus were mixed with equal aliquots of a reporter virus (Ad/CMV/Lac-Z) and co-injected into the myocardium of adult rabbits (n = 12). One week following gene transfer, thin myocardial sections were obtained and analyzed for beta-galactosidase, messenger RNA (mRNA) and protein expression, hematoxylin and eosin, Masson's trichrome, immunofluorescence staining, and electron microscopy. The efficiency of gene transfer varied from 2% to 60% of the cells in an area approximately 2.5 mm in length. Northern blotting confirmed expression of the transgenes into mRNA. Immunoblotting of the myofibrillar protein extracts and indirect immunofluorescence staining confirmed expression and incorporation of the transgene proteins into myofibrils. Expression of the mutant cTnT was up to 18% of the endogenous. Light and electron microscopic studies showed normal cardiac myocyte and sarcomere structures. Thus, despite incorporation of the mutant cTnT-Gln92, stable myofibrillar formation and sarcomere assembly proceeded in vivo. The absence of myocyte and sarcomere disarray may reflect the duration, or the level of expression, or the extent of myofibrillar incorporation of the mutant cTnT-Gln92, as well as the site and timing of expression of the transgenes, and interspecies variation in the pathogenesis of HCM.

心肌细胞紊乱是肥厚性心肌病(HCM)的病理标志,肥厚性心肌病是一种肉瘤蛋白疾病。心肌肌钙蛋白T (cTnT)是导致HCM的主要基因,其突变与严重的心肌细胞紊乱有关。为了研究心肌细胞紊乱的发病机制,我们通过在成年兔心肌内直接注射重组腺病毒来表达正常和突变的cTnT蛋白。将等量的1010个斑块形成单位的正常(Ad/CMV/cTnT-Arg92)和突变(Ad/CMV/cTnT-Gln92)重组病毒或对照载体(Ad/DeltaE)病毒与等量的报告病毒(Ad/CMV/Lac-Z)混合,共同注射到成年兔的心肌中(n = 12)。基因转移一周后,取心肌薄片,分析β -半乳糖苷酶、信使RNA (mRNA)和蛋白表达、苏木精和伊红、马松三色、免疫荧光染色和电镜。在长度约为2.5 mm的区域内,基因转移的效率从2%到60%不等。Northern blotting证实转基因表达为mRNA。肌原纤维蛋白提取物的免疫印迹和间接免疫荧光染色证实了转基因蛋白在肌原纤维中的表达和掺入。突变体cTnT的表达量高达内源性的18%。光镜和电镜检查显示心肌细胞和肌节结构正常。因此,尽管加入了突变体cTnT-Gln92,体内仍能进行稳定的肌原纤维形成和肌节组装。肌细胞和肌瘤紊乱的缺失可能反映了突变体cTnT-Gln92的持续时间、表达水平或肌纤维结合的程度,以及转基因表达的位置和时间,以及HCM发病机制中的种间变异。
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引用次数: 7
Using genetically engineered mice to understand apolipoprotein-B deficiency syndromes in humans. 利用基因工程小鼠了解人类载脂蛋白b缺乏综合征。
M Raabe, E Kim, M Véniant, L B Nielsen, S G Young

Several human diseases are characterized by defects in the synthesis and secretion of the apolipoprotein (apo) B-containing lipoproteins. Familial hypobetalipoproteinemia is caused by mutations in the apo-B gene and is characterized by abnormally low plasma concentrations of apo-B and low-density lipoprotein (LDL) cholesterol. Another apo-B deficiency syndrome, abetalipoproteinemia, is caused by mutations in the gene for microsomal triglyceride transfer protein (MTP). MTP is a microsomal protein that is thought to transfer lipids to the apo-B protein as it is translated, allowing it to attain the proper conformation for lipoprotein assembly. A third apo-B deficiency syndrome, Anderson's disease (or chylomicron retention disease), is characterized by the inability to secrete apo-B-containing chylomicrons from the intestine but an apparently normal capacity to secrete lipoproteins from the liver. To more fully understand these human apo-B deficiency syndromes, our laboratory has generated and characterized gene-targeted mouse models. This review summarizes what has been learned from these animal models.

几种人类疾病的特点是载脂蛋白(apo) b -含脂蛋白的合成和分泌缺陷。家族性低脂蛋白血症是由载脂蛋白b基因突变引起的,其特征是血浆载脂蛋白b和低密度脂蛋白(LDL)胆固醇浓度异常低。另一种载脂蛋白b缺乏综合征,即脂蛋白血症,是由微粒体甘油三酯转移蛋白(MTP)基因突变引起的。MTP是一种微粒体蛋白,被认为在其翻译时将脂质转移到载脂蛋白b蛋白,使其获得适当的脂蛋白组装构象。第三种载脂蛋白b缺乏综合征,安德森病(或乳糜微粒滞留病),其特征是不能从肠道分泌含载脂蛋白b的乳糜微粒,但从肝脏分泌脂蛋白的能力明显正常。为了更充分地了解这些人类载脂蛋白b缺乏综合征,我们的实验室已经建立并表征了基因靶向小鼠模型。这篇综述总结了从这些动物模型中学到的东西。
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引用次数: 0
Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. 白细胞介素-6型细胞因子刺激间充质祖细胞向成骨细胞谱系分化。
Y Taguchi, M Yamamoto, T Yamate, S C Lin, H Mocharla, P DeTogni, N Nakayama, B F Boyce, E Abe, S C Manolagas

Cytokines that transduce their signals either through glycoprotein 130 (gp130) homodimers or gp 130/leukemia inhibitory factor (LIF) receptor beta heterodimers are potent inducers of osteoclast development in vitro as well as in vivo; and interleukin (IL)-6 has been recognized as an important pathogenic factor in diseases characterized by increased bone remodeling, such as the osteoporosis of sex steroid deficiency. Based on evidence that the same cytokines can also promote committed osteoblast differentiation and stimulate bone formation in vitro and in vivo and that mesenchymal cell differentiation toward the osteoblast lineage may be a prerequisite for osteoclastogenesis, we have investigated whether gp130 activation can affect the differentiation of uncommitted mesenchymal progenitors. Using as our model murine embryonic fibroblasts (EF), we found that IL-6 or IL-11 in combination with their soluble receptors (sIL-6R or sIL-11R) increased dose-dependently the number of alkaline phosphatase (AP)-positive cells in 3-6-day-long cultures. Moreover, EF cells maintained with IL-6/sIL-6R in the presence of ascorbic acid and beta-glycerophosphate expressed osteocalcin messenger RNA (mRNA) by 2 weeks and formed a matrix containing mineralized collagen fibers by 3 weeks. This prodifferentiation effect was specific for the osteoblastic lineage, as we found no evidence for increased differentiation of chondrocytes, adipocytes, or muscle cells. Unlike IL-6/sIL-6R, LIF, oncostatin M (OSM), and ciliary neurotrophic factor (CNTF) did not promote osteoblastic differentiation of EF cells. This pattern of specificity was accounted for by the finding that EF cells express gp130, but not the ligand-binding subunit of the IL-6 receptor (gp80) nor the LIF receptor beta. These observations add credence to the contention that increased production of gp130-utilizing cytokines and their receptors in pathological conditions like sex steroid deficiency is indeed responsible for not only the increased osteoclastogenesis, but also the increased osteoblastogenesis, and thereby for the increased rate of bone remodeling.

通过糖蛋白130 (gp130)同二聚体或gp130 /白血病抑制因子(LIF)受体β异二聚体转导信号的细胞因子是体外和体内破骨细胞发育的有效诱导剂;白细胞介素(IL)-6已被认为是以骨重塑增加为特征的疾病的重要致病因素,如性类固醇缺乏症引起的骨质疏松症。有证据表明,同样的细胞因子也可以促进成骨细胞的分化,并在体外和体内刺激骨形成,而间充质细胞向成骨细胞谱系的分化可能是破骨细胞发生的先决条件,我们研究了gp130的激活是否会影响未分化的间充质祖细胞的分化。使用我们的模型小鼠胚胎成纤维细胞(EF),我们发现IL-6或IL-11联合它们的可溶性受体(sIL-6R或sIL-11R)在3-6天的培养中剂量依赖性地增加了碱性磷酸酶(AP)阳性细胞的数量。此外,在抗坏血酸和β -甘油磷酸存在下,用IL-6/sIL-6R维持的EF细胞在2周时表达骨钙素信使RNA (mRNA),在3周时形成含有矿化胶原纤维的基质。这种预分化效应是成骨细胞谱系特有的,因为我们没有发现软骨细胞、脂肪细胞或肌肉细胞分化增加的证据。与IL-6/sIL-6R不同,LIF、抑制素M (OSM)和睫状神经营养因子(CNTF)不能促进EF细胞成骨分化。发现EF细胞表达gp130,但不表达IL-6受体的配体结合亚基(gp80)和LIF受体β,从而解释了这种特异性模式。这些观察结果为以下论点提供了证据:在性类固醇缺乏等病理条件下,利用gp130的细胞因子及其受体的产生增加,确实不仅导致破骨细胞生成增加,而且导致成骨细胞生成增加,从而导致骨重塑率增加。
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引用次数: 0
Introduction. 介绍。
J B West
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引用次数: 0
Stress-induced injury of pulmonary capillaries. 应激性肺毛细血管损伤。
J B West, O Mathieu-Costello

The lung is particularly vulnerable to injury because the blood-gas barrier is so extremely thin. Furthermore, the mechanical stresses in the barrier become very high when capillary pressure is raised, or when the lung is inflated to a high volume. The strength of the blood-gas barrier on the thin side can be attributed to the type IV collagen in the basement membranes. Abnormally high stresses in the walls of the pulmonary capillaries result in ultrastructural changes including disruptions of both the alveolar epithelial and capillary endothelial layers. All Thoroughbred racehorses break their pulmonary capillaries when they gallop. Also, elite human athletes develop changes in the permeability of the blood-gas barrier at high levels of exercise. Pathological conditions resulting in stress failure include: 1) high-altitude pulmonary edema; 2) neurogenic pulmonary edema; 3) severe left ventricular failure; 4) mitral stenosis; and 5) overinflation of the lung. There is a spectrum of low permeability to high permeability edema as the capillary pressure is raised. Remodeling of pulmonary capillaries apparently occurs at high capillary pressures. It is likely that the extracellular matrix of the capillaries is continuously regulated in response to capillary wall stress.

肺特别容易受伤,因为血气屏障非常薄。此外,当毛细血管压力升高或肺膨胀到很大体积时,屏障中的机械应力变得非常高。薄侧血气屏障的强度可归因于基底膜中的IV型胶原蛋白。肺毛细血管壁的异常高应力导致超微结构改变,包括肺泡上皮和毛细血管内皮层的破坏。所有的纯种马在奔跑时都会折断肺毛细血管。此外,优秀的人类运动员在高水平的运动中会发生血气屏障渗透性的变化。导致应激衰竭的病理情况包括:1)高原肺水肿;2)神经源性肺水肿;3)严重的左心室衰竭;4)二尖瓣狭窄;5)肺部过度膨胀。随着毛细血管压力的升高,出现从低渗透性到高渗透性水肿的频谱。肺动脉毛细血管重构明显发生在高毛细血管压力下。很可能毛细血管的细胞外基质在响应毛细血管壁应力时受到持续调节。
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引用次数: 0
Clinical research in medical schools: seizing the opportunity. 医学院临床研究:抓住机遇。
R E Meyer, P F Griner, J Weissman

Academic medical centers (AMCs) face challenges to the achievement of their potential in clinical research. These challenges include reduced support of research from clinical revenue, cultural impediments to clinical research within the traditional value system of research-intensive AMCs, and potential problems of patient access to clinical research in intensive managed care environments. This article considers options to strengthen clinical research that have been developed at some medical centers. While much attention is being directed to the expansion of clinical trials in many AMCs, this effort needs to be linked to a cohesive strategy for clinical research being conducted in an academic environment. The article also addresses the subject of training and career development. It concludes with the opinion that the "crisis" in clinical research in academic medical centers provides the opportunity to define, more explicitly, the nature and scope of the investment in clinical research, and to define strategies that will bring added value to knowledge generated from basic research and to the teaching and patient care missions of these centers.

学术医学中心(amc)面临着在临床研究中发挥潜力的挑战。这些挑战包括临床收入对研究的支持减少,研究密集型amc传统价值体系中对临床研究的文化障碍,以及患者在重症管理护理环境中获得临床研究的潜在问题。本文考虑了一些医疗中心已经开发的加强临床研究的方案。虽然很多注意力都集中在许多国家的临床试验的扩大上,但这一努力需要与在学术环境中进行的临床研究的一个有凝聚力的战略联系起来。这篇文章还讨论了培训和职业发展的问题。报告的结论认为,学术医疗中心临床研究的"危机"提供了机会,可以更明确地确定临床研究投资的性质和范围,并确定将为基础研究产生的知识以及这些中心的教学和病人护理任务带来附加价值的战略。
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引用次数: 0
Ventilator-induced injury: from barotrauma to biotrauma. 呼吸机所致损伤:从气压创伤到生物创伤。
L N Tremblay, A S Slutsky

Mechanical ventilation is an indispensable tool in the management of respiratory and ventilatory failure. However, ventilation per se may also initiate or exacerbate lung injury, contributing to patient morbidity and mortality. In this review, we examine the current mechanisms of ventilator-induced injury including those that primarily involve physical disruption of the lung, as well as those more recently described that involve cell- and inflammatory-mediator-induced injury. The latter have received attention of late because of the possible systemic sequelae such as multiple system organ failure, the primary cause of death of patients with acute respiratory distress syndrome. Although much remains to be elucidated about the mechanisms of ventilator-induced injury, it is hoped that novel approaches addressing both the physiologic as well as molecular effects of ventilation will lead to innovative therapeutic approaches that improve patient outcome.

机械通气是治疗呼吸和通气衰竭不可缺少的工具。然而,通气本身也可能引发或加重肺损伤,导致患者发病率和死亡率。在这篇综述中,我们研究了目前呼吸机诱导损伤的机制,包括那些主要涉及肺的物理破坏,以及那些最近被描述的涉及细胞和炎症介质诱导的损伤。后者由于可能出现多系统器官衰竭等全身性后遗症,是急性呼吸窘迫综合征患者死亡的主要原因,近来受到重视。尽管关于呼吸机诱导损伤的机制仍有许多有待阐明,但希望解决通气的生理和分子效应的新方法将导致创新的治疗方法,从而改善患者的预后。
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引用次数: 0
Identification of quantitative trait loci for non-insulin-dependent diabetes mellitus that interact with body weight in the Otsuka Long-Evans Tokushima Fatty rat. 大冢Long-Evans德岛肥胖大鼠非胰岛素依赖型糖尿病与体重相互作用的数量性状位点鉴定
D H Moralejo, S Wei, K Wei, S Weksler-Zangen, G Koike, H J Jacob, T Hirashima, K Kawano, K Sugiura, Y Sasaki, T Ogino, T Yamada, K Matsumoto

Non-insulin-dependent diabetes mellitus (NIDDM) is a prototypical multifactorial disease. Genetic predisposition and obesity are major risk factors for NIDDM development and the interactions between these factors are likely to be important in the etiology of this disease. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is one of the best animal models of NIDDM, since the OLETF rat develops NIDDM with mild obesity that is very similar to human NIDDM. Therefore, the OLETF rat is a powerful model for investigating the interaction between genetic susceptibility to NIDDM and obesity. In this study, our goal was to clarify the relationship between an individual NIDDM susceptibility locus and obesity in the OLETF using a molecular genetics approach. We identified four novel quantitative trait loci (QTLs) that contribute to the susceptibility to NIDDM, none of which shows significant linkage with body weight. However, Nidd1/of on chromosome 7 and Nidd2/of on chromosome 14 have an interaction with body weight. In contrast, one locus was mapped to chromosome 10 for body weight, but not to fasting or postprandial glucose levels. These data illustrate that NIDDM and body weight are under separate genetic control in the OLETF yet interact to yield the final disease phenotype in the two Nidd/of loci. In addition, body weight could be used in place of body mass index as an indicator of obesity in our experimental system of genetic study. This study will facilitate the understanding of the complex interaction between genetic susceptibility to NIDDM and obesity.

非胰岛素依赖性糖尿病(NIDDM)是一种典型的多因素疾病。遗传易感性和肥胖是NIDDM发展的主要危险因素,这些因素之间的相互作用可能在该病的病因学中很重要。大冢Long-Evans Tokushima Fatty (OLETF)大鼠是NIDDM的最佳动物模型之一,因为OLETF大鼠发展为NIDDM并伴有轻度肥胖,与人类NIDDM非常相似。因此,OLETF大鼠是研究NIDDM遗传易感性与肥胖之间相互作用的有力模型。在这项研究中,我们的目标是利用分子遗传学方法阐明OLETF中个体NIDDM易感性位点与肥胖之间的关系。我们发现了4个新的与NIDDM易感性相关的数量性状位点(qtl),其中没有一个与体重有显著联系。然而,第7染色体上的Nidd1/of和第14染色体上的Nidd2/of与体重有相互作用。相比之下,一个基因座被定位到10号染色体上,与体重有关,但与禁食或餐后血糖水平无关。这些数据表明,在OLETF中,NIDDM和体重受单独的遗传控制,但在两个Nidd/of位点中相互作用产生最终的疾病表型。此外,在我们的基因研究实验系统中,体重可以代替体重指数作为肥胖的指标。这项研究将有助于理解NIDDM遗传易感性与肥胖之间复杂的相互作用。
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引用次数: 0
Alveolar epithelial fluid transport: basic mechanisms and clinical relevance. 肺泡上皮液体运输:基本机制和临床相关性。
M A Matthay, H R Flori, E R Conner, L B Ware

New evidence indicates that alveolar fluid clearance is driven by active sodium transport across the alveolar epithelium. Several in vivo as well as some in vitro studies indicate that vectorial sodium transport drives fluid clearance across the alveolar epithelium. This transport process can be upregulated by both catecholamine-dependent and catecholamine-independent mechanisms. Water transport appears to move across the alveolar epithelium primarily via transcellular water channels, recently termed aquaporins. Under some conditions, net alveolar fluid clearance continues even in the presence of acute lung injury. It is now possible to study the rate and mechanisms of alveolar fluid clearance in patients with either hydrostatic or increased permeability pulmonary edema. In addition, it may be possible to increase the rate of alveolar fluid clearance and hence the resolution of pulmonary edema in some patients, using aerosolized beta-adrenergic agonist therapy.

新的证据表明,肺泡液清除是由活跃的钠转运通过肺泡上皮驱动的。一些体内和一些体外研究表明,钠载体运输驱动肺泡上皮的液体清除。这种转运过程可以通过儿茶酚胺依赖性和儿茶酚胺非依赖性机制上调。水运输似乎主要通过跨细胞水通道在肺泡上皮中移动,最近被称为水通道蛋白。在某些情况下,即使存在急性肺损伤,净肺泡液清除仍在继续。现在有可能研究流体静力性或渗透性增加肺水肿患者肺泡液清除的速率和机制。此外,使用雾化的-肾上腺素能激动剂治疗可能会增加肺泡液清除率,从而缓解某些患者的肺水肿。
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引用次数: 0
Surfactant and acute lung injury. 表面活性剂与急性肺损伤。
A H Jobe, M Ikegami

This brief review will emphasize four interconnected pathways that can lead to functional abnormalities of surfactant that contribute to lung mechanics and gas exchange abnormalities in acute lung injury. Type II cells, the cells that make and secrete all of the lipids and proteins in surfactant, can be injured, resulting in disruption of metabolic pathways. The normal alveolar conversion of surfactant from active to inactive forms can accelerate with lung injury to deplete the active alveolar pool of surfactant. Alveolar-capillary damage from mechanical ventilation or cytokines will result in interstitial and alveolar edema, and alveolar edema can inhibit surfactant function by a variety of mechanisms. The host defense systems in the lung include macrophages and surfactant protein-A (SP-A). Injury can result in SP-A depletion, macrophage activation, and migration of activated granulocytes into the lungs with release of inflammatory cytokines, oxidants, and proteases that can interfere with surfactant function.

本文将着重介绍急性肺损伤中导致表面活性剂功能异常的四种相互关联的途径,这些途径可导致肺力学和气体交换异常。II型细胞,制造和分泌表面活性剂中的所有脂质和蛋白质的细胞,可能会受到伤害,导致代谢途径中断。正常肺泡表面活性剂从活性到非活性的转化可随着肺损伤而加速,使活性肺泡表面活性剂池耗竭。机械通气或细胞因子对肺泡毛细血管的损伤会导致间质和肺泡水肿,肺泡水肿可通过多种机制抑制表面活性剂的功能。肺中的宿主防御系统包括巨噬细胞和表面活性剂蛋白a (SP-A)。损伤可导致SP-A耗竭、巨噬细胞活化和活化的粒细胞迁移到肺部,并释放炎症细胞因子、氧化剂和蛋白酶,干扰表面活性剂的功能。
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引用次数: 0
期刊
Proceedings of the Association of American Physicians
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