• 【耳蜗边缘细胞和前庭暗细胞进行矢量钾转运的计算模型。】 复制标题 收藏 收藏
    DOI:10.1152/ajpcell.00560.2005 复制DOI
    作者列表:Quraishi IH,Raphael RM
    BACKGROUND & AIMS: :Cochlear marginal cells and vestibular dark cells transport potassium into the inner ear endolymph, a potassium-rich fluid, the homeostasis of which is essential for hearing and balance. We have formulated an integrated mathematical model of ion transport across these epithelia that incorporates the biophysical properties of the major ion transporters and channels located in the apical and basolateral membranes of the constituent cells. The model is constructed for both open- and short-circuit situations to test the extremes of functional capacity of the epithelium and predicts the steady-state voltages, ion concentrations, and transepithelial currents as a function of various transporter and channel densities. We validate the model by establishing that the cells are capable of vectorial ion transport consistent with several experimental measurements. The model indicates that cochlear marginal cells do not make a significant direct contribution to the endocochlear potential and illustrates how changes to the activity of specific transport proteins lead to reduced K(+) flux across the marginal and dark cell layers. In particular, we investigate the mechanisms of loop diuretic ototoxicity and diseases with hearing loss in which K(+) and Cl(-) transport are compromised, such as Jervell and Lange-Nielsen syndrome and Bartter syndrome, type IV, respectively. Such simulations demonstrate the utility of compartmental modeling in investigating the role of ion homeostasis in inner ear physiology and pathology.
    背景与目标: :耳蜗边缘细胞和前庭暗细胞将钾转运到内耳内淋巴,这是一种富含钾的液体,其稳态对听力和平衡至关重要。我们已经制定了一个跨这些上皮细胞的离子迁移的综合数学模型,该模型整合了主要离子转运蛋白和位于组成细胞顶膜和基底外侧膜中的通道的生物物理特性。该模型适用于开路和短路情况,以测试上皮的功能极限,并预测稳态电压,离子浓度和跨上皮电流随各种转运蛋白和通道密度的变化。我们通过建立细胞能够进行矢量离子运输与几个实验测量结果一致的方法来验证模型。该模型表明,耳蜗边缘细胞对内耳蜗电位没有显着直接贡献,并说明了特定转运蛋白活性的变化如何导致跨边缘和黑暗细胞层的K()通量降低。特别是,我们研究了of利尿剂的耳毒性和机制,其中K()和Cl(-)的运输受到损害的听力损失的疾病,例如分别为IV型Jervell和Lange-Nielsen综合征和Bartter综合征。这样的模拟证明了隔室模型在研究离子稳态在内耳生理和病理中的作用方面的实用性。
  • 【抗菌药物的使用和肺炎链球菌青霉素耐药性:时间关系模型。】 复制标题 收藏 收藏
    DOI:10.1089/mdr.2006.12.158 复制DOI
    作者列表:Mera RM,Miller LA,White A
    BACKGROUND & AIMS: :The nature of the temporal relationship between antibacterial consumption and Streptococcus pneumoniae penicillin resistance is investigated using population level data across time. IMS Health Global Services provided national outpatient antibiotic prescription data for the years 1996-2003 from France, Spain, Italy, Germany, the United Kingdom, and the United States. Surveillance data consist of S. pneumoniae isolates obtained from a surveillance database in the same geographic regions from 1996 to 2003. A linear mixed model for repeated measures was used to analyze the association between resistance and several antibacterial classes through time. Changes in penicillin resistance through time in any country are better explained by the weighted cumulative antibacterial consumption with a 2-year lag. Narrow-spectrum penicillins are associated with lower resistance rates. Large reductions in consumption at the population level are needed to affect resistance. There is a peak level of penicillin resistance associated with cumulative exposure to a combination of antibiotic classes that is unique for every country.
    背景与目标: :使用跨时间的人口水平数据调查了抗菌药物消费与肺炎链球菌青霉素耐药性之间时间关系的性质。 IMS Health Global Services提供了1996-2003年法国,西班牙,意大利,德国,英国和美国的国家门诊抗生素处方数据。监测数据由1996年至2003年从同一地理区域的监测数据库中获得的肺炎链球菌分离株组成。采用线性混合模型进行重复测量,以分析耐药性与一段时间内几种抗菌剂类别之间的关联。在任何国家,青霉素耐药性随时间的变化都可以通过加权累积抗菌药消费量(滞后2年)来更好地说明。窄谱青霉素与较低的耐药率有关。需要在人口一级大幅度减少消费量以影响抵抗力。青霉素耐药性的峰值与每个国家所独有的抗生素类药物的累积接触有关。
  • 【医学生的临床推理能力与基础科学成就和临床能力测度的关系:结构方程模型。】 复制标题 收藏 收藏
    DOI:10.1097/01.ACM.0000236543.88782.b6 复制DOI
    作者列表:Donnon T,Violato C
    BACKGROUND & AIMS: BACKGROUND:The purpose of this study was to investigate the fit of a hypothesized model of medical students' diagnostic or clinical reasoning skills based on their aptitude for medical school, basic science achievement, and clinical competency measures. METHOD:A total of 589 medical students who received their MD from 1994 to 2002 participated in this study. Confirmatory factor analysis was used to evaluate the fit of theoretical models of clinical reasoning using measures of basic science and clinical knowledge. RESULTS:The results provided support for a three-factor model of medical student performance (Bentler's Comparative Fit Index = .905, standardized root mean squared residual = .054, root mean squared error of approximation = .105). The clinical reasoning skills of medical students were influenced by an independent relationship between latent variables of basic science achievement and clinical competency. CONCLUSION:The findings support a theoretical model of diagnostic or clinical reasoning that treats the basic science and clinical knowledge of medical students as distinct domains.
    背景与目标: 背景:本研究的目的是根据医学生对医学学校的才能,基础科学成就和临床能力测评的假设,研究假设模型对医学生诊断或临床推理能力的适合性。
    方法:1994年至2002年,共有589名医学博士获得了医学博士学位。验证性因素分析用于使用基础科学和临床知识的方法来评估临床推理理论模型的拟合度。
    结果:该结果为医学学生表现的三因素模型提供了支持(Bentler比较拟合指数= .905,标准化均方根残差= .054,均方根近似误差= .105)。基础医学成就的潜在变量与临床能力之间的独立关系影响着医学生的临床推理能力。
    结论:这些发现支持诊断或临床推理的理论模型,该模型将医学生的基础科学和临床知识视为不同的领域。
  • 【谷胱甘肽缺乏症遗传模型中小脑颗粒神经元中多摩酸的神经毒性。】 复制标题 收藏 收藏
    DOI:10.1124/mol.106.027748 复制DOI
    作者列表:Giordano G,White CC,McConnachie LA,Fernandez C,Kavanagh TJ,Costa LG
    BACKGROUND & AIMS: :This study investigated the role of cellular antioxidant defense mechanisms in modulating the neurotoxicity of domoic acid (DomA), by using cerebellar granule neurons (CGNs) from mice lacking the modifier subunit of glutamate-cysteine ligase (Gclm). Glutamate-cysteine ligase (Glc) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis. CGNs from Gclm (-/-) mice have very low levels of GSH and are 10-fold more sensitive to DomA-induced toxicity than CGNs from Gclm (+/+) mice. GSH ethyl ester decreased, whereas the Gcl inhibitor buthionine sulfoximine increased DomA toxicity. Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors and of N-methyl-D-aspartate (NMDA) receptors blocked DomA toxicity, and NMDA receptors were activated by DomA-induced l-glutamate release. The differential susceptibility of CGNs to DomA toxicity was not due to a differential expression of ionotropic glutamate receptors, as evidenced by similar calcium responses and L-glutamate release in the two genotypes. A calcium chelator and several antioxidants antagonized DomA-induced toxicity. DomA caused a rapid decrease in cellular GSH, which preceded toxicity, and the decrease was primarily due to DomA-induced GSH efflux. DomA also caused an increase in oxidative stress as indicated by increases in reactive oxygen species and lipid peroxidation, which was subsequent to GSH efflux. Astrocytes from both genotypes were resistant to DomA toxicity and presented a diminished calcium response to DomA and a lack of DomA-induced L-glutamate release. Because polymorphisms in the GCLM gene in humans are associated with low GSH levels, such individuals, as well as others with genetic conditions or environmental exposures that lead to GSH deficiency, may be more susceptible to DomA-induced neurotoxicity.
    背景与目标: :这项研究利用缺乏谷氨酸-半胱氨酸连接酶(Gclm)修饰子亚基的小鼠的小脑颗粒神经元(CGNs),研究了细胞抗氧化剂防御机制在调节多摩酸(DomA)的神经毒性中的作用。谷氨酸-半胱氨酸连接酶(Glc)催化谷胱甘肽(GSH)生物合成中的第一步和限速步骤。来自Gclm(/)小鼠的CGNs的GSH水平非常低,对DomA诱导的毒性的敏感性比来自Gclm(/)小鼠的CGNs高10倍。 GSH乙酯减少,而Gcl抑制剂丁硫氨酸亚砜亚胺增加DomA毒性。 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/海藻酸酯受体和N-甲基-D-天冬氨酸(NMDA)受体的拮抗剂可阻断DomA毒性,并且NMDA受体被DomA诱导的L-谷氨酸激活。释放。 CGN对DomA毒性的敏感性差异不归因于离子型谷氨酸受体的差异表达,这由两种基因型的相似钙反应和L-谷氨酸释放所证明。钙螯合剂和几种抗氧化剂拮抗DomA诱导的毒性。 DomA导致细胞GSH迅速下降,而毒性先于毒性下降,而下降主要归因于DomA诱导的GSH外排。 DomA还引起氧化应激的增加,如活性氧和脂质过氧化作用的增加所表明的,这是GSH流出后的结果。两种基因型的星形胶质细胞都对DomA毒性有抵抗力,并且对DomA的钙反应减弱,并且缺乏DomA诱导的L-谷氨酸释放。由于人类GCLM基因的多态性与低GSH水平相关,因此此类个体以及遗传条件或环境暴露导致GSH缺乏的其他个体可能更容易受到DomA诱导的神经毒性。
  • 【通过预测的热应变模型评估职业热应力。】 复制标题 收藏 收藏
    DOI:10.2486/indhealth.44.380 复制DOI
    作者列表:Malchaire JB
    BACKGROUND & AIMS: :The work of the main European research teams in the field of thermal factors was coordinated in order to improve significantly the Required Sweat Rate model published as an international standard. Many significant modifications were brought, in particular concerning the effects of forced convection, body movements and exercise and the prediction of the skin temperature as a function of the rectal temperature and in case of severe conditions of radiation, humidity and clothing. The criteria for acceptable work durations in hot environments were updated concerning the maximum increase in core temperature and the acceptable water loss. The revised model, called Predicted Heat Strain model, was validated through a set of lab and field experiments involving stable and fluctuating conditions with high and low radiation, humidity and air velocity. It is meanwhile adopted as an ISO and CEN standard. In addition, a strategy was developed to assess the risks of heat disorders in any working situation. It is based on the three highest stages of the SOBANE strategy: an "Observation" method for improving simply the thermal conditions of work; an "Analysis" method to evaluate the magnitude of the problem and optimise the choice of solutions and an "Expert" method for in depth analysis of the working situation when needed.
    背景与目标: :协调了主要的欧洲研究团队在热因素领域的工作,以便显着改善作为国际标准发布的“要求的出汗率”模型。带来了许多重要的改进,特别是关于强制对流,身体运动和运动的影响以及根据直肠温度以及在严重的辐射,湿度和衣服条件下根据皮肤温度预测皮肤温度的方面。更新了高温环境下可接受的工作时间标准,有关核心温度的最大升高和可接受的水分流失。经过修订的模型称为预测的热应变模型,已通过一组实验室和现场实验进行了验证,这些实验涉及稳定和波动的条件,以及高低辐射,湿度和空气速度。同时,它被用作ISO和CEN标准。此外,还制定了一项策略来评估在任何工作情况下发生热病的风险。它基于SOBANE策略的三个最高阶段:“观察”方法,用于简单地改善工作的热工条件;一种“分析”方法,用于评估问题的严重程度并优化解决方案的选择;另一种“专家”方法,用于在需要时对工作状况进行深入分析。
  • 【JTE-607是一种多种细胞因子产生抑制剂,可改善SCID小鼠异种移植急性髓细胞白血病模型中的疾病。】 复制标题 收藏 收藏
    DOI:10.1016/j.exphem.2006.05.016 复制DOI
    作者列表:Uesato N,Fukui K,Maruhashi J,Tojo A,Tajima N
    BACKGROUND & AIMS: OBJECTIVE:Accumulating findings suggest that in acute myeloid leukemia (AML) patients, proinflammatory cytokines and growth factors play important roles in the proliferation and survival of AML cells in an autocrine and paracrine manner, leading to deterioration of AML. JTE-607 is a multiple cytokine inhibitor that potently suppresses production of proinflammatory cytokines. In the present study, we investigated the potency of JTE-607 as an antileukemic agent by exploiting a SCID mouse acute leukemia model. METHODS:SCID mice injected with anti-asialo-GM1 antibody were exposed to sublethal total-body irradiation at a dose of 3 Gy and then inoculated intravenously with AML cells. JTE-607 was administered using osmotic minipumps. The effects of JTE-607 on mouse survival time, human interleukin (IL)-8 levels in mouse plasma, and proportion of human CD45(+) cells in the bone marrow were studied. RESULTS:The survival time of the mice was strictly dependent on the number of U-937 cells proliferating in vivo. Administration of JTE-607 during the initial 7 days significantly prolonged survival of the mice, suggesting killing activity of JTE-607 against AML cells in vivo. Delayed administration of JTE-607 also prolonged the survival of mice bearing established leukemia with an effect comparable to the maximum tolerable dose of cytarabine. Flow cytometer analysis of bone marrow cells revealed decreased number of human CD45(+) cells. Human IL-8 level was also reduced by JTE-607. CONCLUSION:Our results indicate that JTE-607 has potential to be a new class of antileukemic drug that exerts inhibitory activities against both the proliferation and proinflammatory cytokine production of AML cells.
    背景与目标: 目的:大量研究结果表明,在急性髓细胞性白血病(AML)患者中,促炎性细胞因子和生长因子以自分泌和旁分泌方式在AML细胞的增殖和存活中起重要作用,从而导致AML恶化。 JTE-607是一种多细胞因子抑制剂,可有效抑制促炎细胞因子的产生。在本研究中,我们通过利用SCID小鼠急性白血病模型研究了JTE-607作为抗白血病药物的效力。
    方法:将注射了抗亚洲人GM1抗体的SCID小鼠暴露于3 Gy剂量的亚致死性全身照射下,然后静脉注射AML细胞。 JTE-607使用渗透微型泵进行管理。研究了JTE-607对小鼠存活时间,小鼠血浆中人白介素(IL)-8水平以及骨髓中人CD45()细胞比例的影响。
    结果:小鼠的存活时间严格取决于体内增殖的U-937细胞数量。在最初的7天中施用JTE-607可以显着延长小鼠的存活期,表明JTE-607在体内对AML细胞具有杀伤活性。 JTE-607的延迟给药也延长了已确诊白血病的小鼠的存活,其作用与阿糖胞苷的最大耐受剂量相当。骨髓细胞的流式细胞仪分析显示人类CD45()细胞数量减少。 JTE-607也降低了人IL-8水平。
    结论:我们的结果表明,JTE-607有潜力成为一类新型的抗白血病药物,对AML细胞的增殖和促炎性细胞因子产生均具有抑制作用。
  • 【雄激素依赖性病理显示在小鼠敲入模型中肌病对肯尼迪病表型的贡献。】 复制标题 收藏 收藏
    DOI:10.1172/JCI28773 复制DOI
    作者列表:Yu Z,Dadgar N,Albertelli M,Gruis K,Jordan C,Robins DM,Lieberman AP
    BACKGROUND & AIMS: :Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.
    背景与目标: :肯尼迪病是一种以雄激素依赖性神经肌肉无力为特征的变性疾病,是由雄激素受体(Ar)基因中的CAG /谷氨酰胺束扩张引起的。我们开发了肯尼迪病的小鼠模型,使用基因靶向技术将小鼠雄激素受体(AR)转化为人类序列,同时引入113种谷氨酰胺。 AR113Q小鼠发展出激素和谷氨酰胺长度依赖性神经肌肉无力,其特征是肌病性和神经源性骨骼肌病理的早期发生以及脊髓神经元中神经元核内包涵体的发育较晚。 AR113Q男性意外死于2-4个月。我们表明,这种雄激素依赖性死亡反映了骨骼肌氯化物通道1(CLCN1)和骨骼肌钠通道α亚基的表达下降,导致下尿路骨骼肌的肌强直放电。 AR113Q肢体肌肉表现出相似的肌病特征,并表达编码Neurotrophin-4和神经胶质细胞源性神经营养因子的mRNA水平下降。这些数据定义了对肯尼迪病表型的重要肌病性贡献,并暗示了肌肉在下运动神经元的非细胞自主毒性中的作用。
  • 【在CLP后免疫抑制的小鼠模型中,IL-10中和和IFN-γ的联合使用不能改善细菌清除率和死亡率。】 复制标题 收藏 收藏
    DOI:10.1097/01.shk.0000226343.70904.4f 复制DOI
    作者列表:Murphey ED,Sherwood ER
    BACKGROUND & AIMS: :Immunocompromise after a major injury is presumed to be a predisposing factor for sepsis. Mice subjected to sublethal cecal ligation and puncture (CLP) and challenged 5 days later with Pseudomonas aeruginosa had more bacterial growth in lung tissue, lower serum interferon gamma (IFN-gamma) and interleukin (IL) 12,and higher serum IL-10 when compared with sham CLP mice challenged with Pseudomonas. To test the functional significance of these alterations in cytokine production in the immune response to bacteria, we administered IFN-gamma and anti-IL-10 to post-CLP mice before the Pseudomonas challenge. Administration of IFN-gamma and anti-IL-10 did not improve bacterial clearance or mortality in post-CLP mice. In further studies, we administered IFN-gamma to IL-10 knockout mice before a challenge with P. aeruginosa. Our results showed no significant differences in bacterial clearance or mortality in IL-10 knockout mice with or without IFN-gamma treatment compared with wild-type controls. Finally, because most mortality occurred within 2 to 3 days of the Pseudomonas challenge in the aforementioned studies and was likely associated with a marked proinflammatory response, we investigated the effect of IFN-gamma and anti-IL-10 on clearance of Pseudomonas in C3H/HeJ mice, which do not mount an exaggerated proinflammatory response to endotoxin or Gram-negative bacteria. Neither clearance of the Pseudomonas bacteria nor mortality was improved in C3H/HeJ mice receiving anti-IL-10 and IFN-gamma. These results suggest that the suppressed IFN-gamma and IL-12 responses, in combination with an exaggerated IL-10 response to P. aeruginosa challenge after injury, do not correlate with bacterial clearance or survival.
    背景与目标: :大伤后的免疫功能低下被认为是败血症的诱因。进行半致死盲肠结扎和穿刺(CLP)并在5天后用铜绿假单胞菌攻击的小鼠的肺组织中细菌生长更多,血清干扰素-γ(IFN-γ)和白介素(IL)12更低,而血清IL-10更高。与假单胞菌攻击的假CLP小鼠相比。为了测试这些变化对细菌免疫反应中细胞因子产生的功能意义,我们在假单胞菌攻击之前向CLP后小鼠施用了IFN-γ和抗IL-10。在CLP后小鼠中,IFN-γ和抗IL-10的使用不能改善细菌清除率或死亡率。在进一步的研究中,我们在铜绿假单胞菌攻击之前向IL-10敲除小鼠施用了IFN-γ。我们的结果表明,与野生型对照相比,接受或未接受IFN-γ治疗的IL-10基因敲除小鼠的细菌清除率或死亡率无显着差异。最后,由于在上述研究中大多数死亡发生在假单胞菌攻击后的2到3天内,并且可能与明显的促炎反应有关,因此我们研究了IFN-γ和抗IL-10对C3H / 3中假单胞菌清除的影响HeJ小鼠,对内毒素或革兰氏阴性细菌没有过度的促炎反应。接受抗IL-10和IFN-γ的C3H / HeJ小鼠的假单胞菌细菌清除率和死亡率均未提高。这些结果表明,损伤后抑制的IFN-γ和IL-12反应,加上对损伤后铜绿假单胞菌攻击的过度IL-10反应,与细菌清除率或存活率无关。
  • 【序数特征分析的多元模型。】 复制标题 收藏 收藏
    DOI:10.1038/sj.hdy.6800885 复制DOI
    作者列表:Xu S,Xu C
    BACKGROUND & AIMS: :Many economically important characteristics of agricultural crops are measured as ordinal traits. Statistical analysis of the genetic basis of ordinal traits appears to be quite different from regular quantitative traits. The generalized linear model methodology implemented via the Newton-Raphson algorithm offers improved efficiency in the analysis of such data, but does not take full advantage of the extensive theory developed in the linear model arena. Instead, we develop a multivariate model for ordinal trait analysis and implement an EM algorithm for parameter estimation. We also propose a method for calculating the variance-covariance matrix of the estimated parameters. The EM equations turn out to be extremely similar to formulae seen in standard linear model analysis. Computer simulations are performed to validate the EM algorithm. A real data set is analyzed to demonstrate the application of the method. The advantages of the EM algorithm over other methods are addressed. Application of the method to QTL mapping for ordinal traits is demonstrated using a simulated baclcross (BC) population.
    背景与目标: :许多农作物的重要经济特征都是按序性状衡量的。对序性状遗传基础的统计分析似乎与常规的定量性状完全不同。通过Newton-Raphson算法实现的广义线性模型方法在分析此类数据时提供了更高的效率,但并未充分利用线性模型领域开发的广泛理论。相反,我们开发了用于序性状分析的多元模型,并实现了用于参数估计的EM算法。我们还提出了一种计算估计参数的方差-协方差矩阵的方法。事实证明,EM方程与标准线性模型分析中的公式极为相似。执行计算机仿真以验证EM算法。分析实际数据集以演示该方法的应用。解决了EM算法相对于其他方法的优点。使用模拟的baclcross(BC)群体证明了该方法在序性状QTL定位中的应用。
  • 【体内VEGF亚型与VEGFR-1,VEGFR-2和神经纤毛蛋白的相互作用:人骨骼肌的计算模型。】 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)家族与现有成人血管的维护以及血管生成,新血管的萌发有关。为了研究骨骼肌中VEGF家族成员对VEGF受体(VEGFRs)的促血管生成激活作用,我们建立了VEGF同种型(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。我们建立了我们的体外VEGF同工型和受体酪氨酸激酶(VEGFR-1和VEGFR-2)和无信号Neuropilin-1共受体之间的生化相互作用的验证模型。该模型是通用模型,可以应用于任何组织。在这里,我们应用该模型来模拟VEGF同工型在人股外侧肌中的运输,这在生理实验中已得到广泛研究。模拟预测了静息(非运动)肌肉中VEGF亚型的分布和VEGFR信号的激活。肌肉中很少有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。但是,间质隔离VEGF(165)不会影响稳态受体结合。在没有神经纤毛蛋白的情况下,VEGF(121)和VEGF(165)的行为相似,但是神经纤毛蛋白会增强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,它为设计和评估治疗方法提供了平台。
  • 【用光遗传学刺激在人类癫痫的果蝇黑腹果蝇模型中癫痫易感性的研究。】 复制标题 收藏 收藏
    DOI:10.1534/genetics.116.194779 复制DOI
    作者列表:Saras A,Wu VV,Brawer HJ,Tanouye MA
    BACKGROUND & AIMS: :We examined seizure-susceptibility in a Drosophila model of human epilepsy using optogenetic stimulation of ReaChR (red-activatable channelrhodopsin). Photostimulation of the seizure-sensitive mutant parabss1 causes behavioral paralysis that resembles paralysis caused by mechanical stimulation, in many aspects. Electrophysiology shows that photostimulation evokes abnormal seizure-like neuronal firing in parabss1 followed by a quiescent period resembling synaptic failure and apparently responsible for paralysis. The pattern of neuronal activity concludes with seizure-like activity just prior to recovery. We tentatively identify the mushroom body as one apparent locus of optogenetic seizure initiation. The α/β lobes may be primarily responsible for mushroom body seizure induction.
    背景与目标: :我们使用ReaChR(红色激活的视紫红质)的光遗传学刺激,在人癫痫的果蝇模型中检查了癫痫发作的易感性。癫痫发作敏感突变体parabss1的光刺激会在许多方面引起类似于机械刺激引起的瘫痪的行为麻痹。电生理学表明,光刺激会引起parabss1异常的癫痫样神经元放电,然后是类似于突触衰竭的静止期,显然是造成瘫痪的原因。神经元活动的模式以恢复前的癫痫样活动结束。我们初步确定蘑菇体是光遗传性癫痫发作的一个明显部位。 α/β瓣可能是引起蘑菇体癫痫发作的主要原因。
  • 【猪心肌梗死模型中心室去极化和复极化变化的特征。】 复制标题 收藏 收藏
    DOI:10.1088/0967-3334/33/12/1975 复制DOI
    作者列表:Romero D,Ringborn M,Demidova M,Koul S,Laguna P,Platonov PG,Pueyo E
    BACKGROUND & AIMS: :In this study, several electrocardiogram (ECG)-derived indices corresponding to both ventricular depolarization and repolarization were evaluated during acute myocardial ischemia in an experimental model of myocardial infarction produced by 40 min coronary balloon inflation in 13 pigs. Significant changes were rapidly observed from minute 4 after the start of coronary occlusion, achieving their maximum values between 11 and 22 min for depolarization and between 9 and 12 min for repolarization indices, respectively. Subsequently, these maximum changes started to decrease during the latter part of the occlusion. Depolarization changes associated with the second half of the QRS complex showed a significant but inverse correlation with the myocardium at risk (MaR) estimated by scintigraphic images. The correlation between MaR and changes of the downward slope of the QRS complex, [Formula: see text], evaluated at the two more relevant peaks observed during the occlusion, was r = -0.75, p < 0.01 and r = -0.79, p < 0.01 for the positive and negative deflections observed in [Formula: see text], temporal evolution, respectively. Repolarization changes, analyzed by evaluation of ST segment elevation at the main observed positive peak, also showed negative, however non-significant correlation with MaR: r = -0.34, p = 0.28. Our results suggest that changes evaluated in the latter part of the depolarization, such as those described by [Formula: see text], which are influenced by R-wave amplitude, QRS width and ST level variations simultaneously, correlate better with the amount of ischemia than other indices evaluated in the earlier part of depolarization or during the ST segment.
    背景与目标: :在这项研究中,在急性心肌缺血期间,在13只猪的40分钟冠状动脉球囊扩张产生的心肌梗塞实验模型中,评估了与心室去极化和复极化同时对应的几个心电图(ECG)衍生指标。从开始进行冠状动脉闭塞后的第4分钟开始迅速观察到显着变化,分别在去极化的11至22分钟和重新极化的9至12分钟之间达到最大值。随后,在咬合的后期,这些最大变化开始减少。与QRS波复杂度的后半部分相关的去极化变化显示与闪烁显像图像估计的危险心肌(MaR)有显着但相反的相关性。在咬合期间观察到的两个相关峰上,MaR与QRS络合物的向下斜率变化之间的相关性为[r = -0.75,p <0.01和r = -0.79,p分别在[公式:参见文本],时间演变中观察到的正挠度和负挠度<0.01。通过评估在主要观察到的正峰处的ST段抬高来分析的复极化变化也显示为负,但与MaR的相关性不显着:r = -0.34,p = 0.28。我们的结果表明,在去极化后期评估的变化(如[公式:请参见文本]所述)受R波幅度,QRS宽度和ST水平变化的同时影响,与缺血量的相关性更好。比在去极化早期或ST段评估的其他指数要高。
  • 【基因治疗可减少色素失禁模型中的癫痫发作。】 复制标题 收藏 收藏
    DOI:10.1002/ana.24981 复制DOI
    作者列表:Dogbevia GK,Töllner K,Körbelin J,Bröer S,Ridder DA,Grasshoff H,Brandt C,Wenzel J,Straub BK,Trepel M,Löscher W,Schwaninger M
    BACKGROUND & AIMS: OBJECTIVE:Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. METHODS:In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood-brain barrier (BBB) were monitored. RESULTS:The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. INTERPRETATION:The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104.
    背景与目标: 目的:色素失禁(IP)是一种遗传性疾病,可导致严重的神经系统症状,例如癫痫发作,但尚无特效治疗方法。 IP是由使Nemo基因失活的致病变体引起的。通过基因疗法替代Nemo可能会提供治疗益处。
    方法:在IP小鼠模型中,我们施用了单次静脉内剂量的腺相关病毒(AAV)载体AAV-BR1-CAG-NEMO,将Nemo基因传递至脑内皮。监测自发性癫痫发作和血脑屏障(BBB)的完整性。
    结果:内皮靶向基因治疗改善了血脑屏障的完整性。同时,它减少了癫痫发作的发生并延迟了发作的发生。静脉内注射AAV-BR1-CAG-NEMO载体的新生小鼠在载体注射后11个月未出现肝细胞癌或其他重大不良反应,表明该载体具有良好的安全性。
    解释:数据表明,血脑屏障是抗癫痫治疗的目标,更具体地说,它为脑内皮靶向基因疗法在IP中的治疗益处提供了证据。 Ann Neurol 2017; 82:93-104。
  • 【结肠镜检查结果阴性的人的重新筛查:来自微观模拟模型的结果。】 复制标题 收藏 收藏
    DOI:10.7326/0003-4819-157-9-201211060-00005 复制DOI
    作者列表:Knudsen AB,Hur C,Gazelle GS,Schrag D,McFarland EG,Kuntz KM
    BACKGROUND & AIMS: BACKGROUND:Persons with a negative result on screening colonoscopy are recommended to repeat the procedure in 10 years. OBJECTIVE:To assess the effectiveness and costs of colonoscopy versus other rescreening strategies after an initial negative colonoscopy result. DESIGN:Microsimulation model. DATA SOURCES:Literature and data from the Surveillance, Epidemiology, and End Results program. TARGET POPULATION:Persons aged 50 years who had no adenomas or cancer detected on screening colonoscopy. TIME HORIZON:Lifetime. PERSPECTIVE:Societal. INTERVENTION:No further screening or rescreening starting at age 60 years with colonoscopy every 10 years, annual highly sensitive guaiac fecal occult blood testing (HSFOBT), annual fecal immunochemical testing (FIT), or computed tomographic colonography (CTC) every 5 years. OUTCOME MEASURES:Lifetime cases of colorectal cancer, life expectancy, and lifetime costs per 1000 persons, assuming either perfect or imperfect adherence. RESULTS OF BASE-CASE ANALYSIS:Rescreening with any method substantially reduced the risk for colorectal cancer compared with no further screening (range, 7.7 to 12.6 lifetime cases per 1000 persons [perfect adherence] and 17.7 to 20.9 lifetime cases per 1000 persons [imperfect adherence] vs. 31.3 lifetime cases per 1000 persons with no further screening). In both adherence scenarios, the differences in life-years across rescreening strategies were small (range, 30 893 to 30 902 life-years per 1000 persons [perfect adherence] vs. 30 865 to 30 869 life-years per 1000 persons [imperfect adherence]). Rescreening with HSFOBT, FIT, or CTC had fewer complications and was less costly than continuing colonoscopy. RESULTS OF SENSITIVITY ANALYSIS:Results were sensitive to test-specific adherence rates. LIMITATION:Data on adherence to rescreening were limited. CONCLUSION:Compared with the currently recommended strategy of continuing colonoscopy every 10 years after an initial negative examination, rescreening at age 60 years with annual HSFOBT, annual FIT, or CTC every 5 years provides approximately the same benefit in life-years with fewer complications at a lower cost. Therefore, it is reasonable to use other methods to rescreen persons with negative colonoscopy results. PRIMARY FUNDING SOURCE:National Cancer Institute.
    背景与目标: 背景:建议对结肠镜检查结果阴性的人在10年内重复进行此程序。
    目的:评估结肠镜检查结果阴性后结肠镜检查与其他重新筛查策略相比的有效性和成本。
    设计:微仿真模型。
    数据来源:来自监视,流行病学和最终结果程序的文献和数据。
    目标人群:50岁以上未通过结肠镜检查发现腺瘤或癌症的人。
    时间地平线:终生。
    观点:社会。
    干预措施:从60岁开始,每10年进行一次结肠镜检查,从60岁开始不再进行进一步的筛查或重新筛查,每年每5年进行一次高灵敏度的愈创木脂粪潜血试验(HSFOBT),年度粪便免疫化学试验(FIT)或计算机断层摄影结肠成像(CTC)。
    观察指标:假设完全或不完全依从性,大肠癌的终生病例,预期寿命和每千人的终生成本。
    基础病例分析结果:与不进行进一步筛查相比,采用任何方法进行的重新筛查均大大降低了结直肠癌的风险(范围:每千人7.7至12.6例终生病例[完美依从性],每千人[17.7至20.9例终生病例[不完全依从性] ]与每1000人中31.3例终生病例的比较(无进一步筛查)。在这两种依从性方案中,重新筛查策略的生命年差异很小(范围为每千人30 893至30 902个生命年[完美依从],而每千人30 865至30 869个生命年[不完美依从] ])。与连续结肠镜检查相比,用HSFOBT,FIT或CTC进行重新筛查的并发症更少,成本也更低。
    敏感性分析结果:结果对特定于测试的依从率敏感。
    局限性:关于重新筛查的数据有限。
    结论:与目前推荐的初始阴性检查后每10年继续进行结肠镜检查的策略相比,在60岁时每年进行HSFOBT,每年FIT或CTC的每5年进行一次重新筛查,可在生命年中获得大致相同的收益,并发症发生率更低较低的成本。因此,使用其他方法对结肠镜检查结果阴性的人进行重新筛查是合理的。
    主要资金来源:美国国家癌症研究所。
  • 【小儿心脏手术后局部静脉血氧饱和度与混合静脉血饱和度的关系。】 复制标题 收藏 收藏
    DOI:10.1111/aas.12016 复制DOI
    作者列表:Moreno GE,Pilán ML,Manara C,Magliola R,Vassallo JC,Balestrini M,Lenz AM,Krynski M,Althabe M,Landry L
    BACKGROUND & AIMS: BACKGROUND:Central venous oxygen saturation (ScvO2) remains the gold standard surrogate for tissue oxygen extraction in paediatric cardiac surgery. Near-infrared spectroscopy (NIRS) has been developed as a non-invasive diagnostic tool for regional oxygen saturation. The aim was to compare regional oxygen saturation measured by NIRS with ScvO2 in postoperative paediatric cardiac patients. METHODS:In this prospective study, we included newborns and infants younger than 45 days undergoing heart surgery. We recorded continuous ScvO2 and NIRS regional saturation placed on the forehead (B) and right flank (S) for 48 h postoperatively. A Bland-Altman's analysis was used to assess the agreement between these measurements. RESULTS:A total of 23 patients were included with a median age of 12 days (2-46) and median weight of 3.1 kg (2.3-4.47). The mean difference (MD) ScvO2- B NIRS was 10.45% with limits of agreement (LOA) -17.23 to 38.13% and ScvO2- S NIRS MD 7.16% with LOA: -25.51 to 39.84%. The single ventricle ScvO2- S NIRS subgroup had MD within ± 5%; however, wide LOA was observed. The remaining subgroups showed MD nearly above ± 5%, with wide LOA. CONCLUSIONS:The regional oxygen saturation of brain and kidney did not match ScvO2 as estimation of global tissue perfusion. Nevertheless, NIRS may still provide information regarding regional circulation that may help in the management of neonatal cardiac surgery patients.
    背景与目标: 背景:中央静脉血氧饱和度(ScvO2)仍然是小儿心脏外科手术中组织氧提取的金标准。近红外光谱法(NIRS)已被开发为一种用于区域血氧饱和度的非侵入性诊断工具。目的是比较由NIRS和ScvO2测得的小儿心脏术后患者的局部血氧饱和度。
    方法:在这项前瞻性研究中,我们纳入了进行心脏手术的45岁以下的新生儿和婴儿。我们记录了连续的ScvO2和NIRS区域饱和度放置在术后48 h的前额(B)和右胁(S)上。用布兰德-奥特曼(Bland-Altman)分析来评估这些测量之间的一致性。
    结果:总共纳入23名患者,中位年龄为12天(2-46),中位体重为3.1 kg(2.3-4.47)。 ScvO2-B NIRS的平均差异(MD)为10.45%,协议限制(LOA)为-17.23至38.13%,Slovo2- S NIRS MD的7.16%LOA为-25.51至39.84%。单心室ScvO2-S NIRS亚组的MD≤±5%。但是,观察到广泛的LOA。其余亚组的MD值接近±5%,LOA较宽。
    结论:脑和肾脏的局部血氧饱和度与ScvO2不符,无法估计整体组织灌注。尽管如此,NIRS仍可能提供有关区域循环的信息,这可能有助于新生儿心脏外科手术患者的管理。

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