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输送到内耳内淋巴中，内淋巴是一种富含钾的液体，其稳态对于听力和平衡至关重要。我们已经建立了跨这些上皮细胞的离子转运的综合数学模型，该模型结合了位于组成细胞的顶膜和基底外侧膜中的主要离子转运蛋白和通道的生物物理特性。该模型是针对开路和短路情况构建的，以测试上皮功能能力的极限，并预测稳态电压，离子浓度和跨上皮电流与各种转运蛋白和通道密度的关系。我们通过建立细胞能够与几种实验测量一致的矢量离子传输来验证模型。该模型表明，耳蜗边缘细胞对耳蜗内电位没有明显的直接贡献，并说明了特定转运蛋白活性的变化如何导致边缘细胞层和暗细胞层的K () 通量减少。特别是，我们研究了环利尿剂耳毒性的机制以及K () 和Cl(-) 转运受损的听力损失疾病，例如Jervell和Lange-Nielsen综合征以及IV型Bartter综合征。此类模拟证明了隔室建模在研究离子稳态在内耳生理和病理学中的作用方面的实用性。

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： : 使用跨时间的人群水平数据研究了抗菌药物消耗与肺炎链球菌青霉素耐药性之间的时间关系的性质。IMS Health Global Services提供了来自法国，西班牙，意大利，德国，英国和美国的1996-2003年全国门诊抗生素处方数据。监视数据由从2003年1996年相同地理区域的监视数据库中获得的肺炎链球菌分离株组成。使用用于重复测量的线性混合模型来分析耐药性与几种抗菌剂之间的关系。在任何国家，青霉素耐药性随时间的变化都可以通过滞后2年的加权累积抗菌药物消耗量来更好地解释。窄谱青霉素与较低的耐药率相关。为了影响抵抗力，需要大量减少人口消费。青霉素耐药性的峰值水平与累积暴露于抗生素类别的组合有关，这在每个国家都是独一无二的。

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：

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： : 这项研究通过使用缺乏谷氨酸-半胱氨酸连接酶修饰亚基 (Gclm) 的小鼠的小脑颗粒神经元 (CGNs)，研究了细胞抗氧化防御机制在调节软骨藻酸 (DomA) 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) 生物合成中的第一个和限速步骤。来自Gclm (-/-) 小鼠的CGNs的GSH水平非常低，并且对DomA诱导的毒性的敏感性比来自Gclm (/) 小鼠的CGNs高10倍。GSH乙酯降低，而Gcl抑制剂丁硫氨酸亚砜肟增加了DomA毒性。alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic/海藻酸盐受体和N-甲基-D-天冬氨酸 (NMDA) 受体的拮抗剂阻断了DomA毒性，并且NMDA受体被DomA诱导的l-谷氨酸释放激活。CGNs对DomA毒性的敏感性差异不是由于离子型谷氨酸受体的表达差异所致，这在两种基因型中钙反应和L-谷氨酸释放相似。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，这先于毒性，并且下降主要是由于DomA诱导的GSH外排。DomA还引起了氧化应激的增加，如活性氧种类和脂质过氧化的增加所表明的，这是在GSH外排之后。两种基因型的星形胶质细胞均对DomA毒性具有抗性，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，因此此类个体以及具有导致GSH缺乏的遗传条件或环境暴露的其他个体可能更容易受到DomA诱导的神经毒性的影响。

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： : 协调了欧洲主要研究小组在热因素领域的工作，以显着改善作为国际标准发布的所需汗率模型。进行了许多重大修改，特别是在强迫对流，身体运动和运动的影响以及皮肤温度随直肠温度的变化以及在辐射，湿度和衣服的严酷条件下的预测方面。更新了在高温环境中可接受的工作持续时间的标准，涉及岩心温度的最大升高和可接受的水损失。修订后的模型称为预测热应变模型，已通过一系列实验室和现场实验进行了验证，这些实验涉及高辐射和低辐射，湿度和空气速度的稳定和波动条件。同时被采用为ISO和CEN标准。此外，还制定了一项战略，以评估任何工作情况下的热病风险。它基于SOBANE策略的三个最高阶段: 一种 “观察” 方法，用于简单地改善工作的热条件; 一种 “分析” 方法，用于评估问题的严重性并优化解决方案的选择，以及一种 “专家” 方法，用于在需要时深入分析工作情况。

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：

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退行性疾病，是由雄激素受体 (Ar) 基因中的CAG/谷氨酰胺道扩增引起的。我们开发了肯尼迪病的小鼠模型，使用基因靶向将小鼠雄激素受体 (AR) 转化为人类序列，同时引入113谷氨酸。AR113Q小鼠出现激素和谷氨酰胺长度依赖性神经肌肉无力，其特征是肌病和神经源性骨骼肌病理的早期发生以及脊髓神经元核内包涵体的晚期发展。AR113Q男性在2-4个月时意外死亡。我们显示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 亚基的表达降低，导致下尿路骨骼肌中的肌强肌放电。AR113Q肢体肌肉显示出相似的肌病特征，并表达编码neurotrophin-4和神经胶质细胞系衍生的神经营养因子的mrna水平降低。这些数据定义了对肯尼迪病表型的重要肌病贡献，并暗示了肌肉在较低运动神经元的非细胞自主毒性中的作用。

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： : 重大损伤后的免疫损害被认为是败血症的诱发因素。与假单胞菌相比，接受亚致死性盲肠结扎和穿刺 (CLP) 并在5天后用铜绿假单胞菌攻击的小鼠肺组织中细菌生长更多，血清干扰素 γ (IFN-γ) 和白介素 (IL) 12降低，血清IL-10更高。为了测试这些细胞因子产生变化在对细菌的免疫反应中的功能意义，我们在假单胞菌攻击之前对CLP后小鼠施用IFN-γ 和anti-IL-10。施用IFN-γ 和anti-IL-10不会改善CLP后小鼠的细菌清除率或死亡率。在进一步的研究中，我们在用铜绿假单胞菌攻击之前对IL-10基因敲除小鼠施用IFN-γ。我们的结果表明，与野生型对照相比，有或没有IFN-γ 处理的IL-10基因敲除小鼠的细菌清除率或死亡率没有显着差异。最后，由于大多数死亡率发生在上述研究中假单胞菌攻击的2至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anti-IL-10对C3H/HeJ小鼠中假单胞菌清除的影响，它们不会对内毒素或革兰氏阴性细菌产生夸张的促炎反应。在接受anti-IL-10和IFN-γ 的C3H/HeJ小鼠中，假单胞菌的清除率和死亡率均未改善。这些结果表明，受抑制的IFN-γ 和IL-12反应，再加上损伤后对铜绿假单胞菌攻击的过度IL-10反应，与细菌清除或存活无关。

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： : 农业作物的许多经济上重要的特征被衡量为序数性状。序数性状的遗传基础的统计分析似乎与常规数量性状有很大不同。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中开发的广泛理论。相反，我们开发了用于顺序特征分析的多变量模型，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。进行计算机仿真以验证EM算法。分析了实际数据集以证明该方法的应用。讨论了EM算法相对于其他方法的优势。使用模拟的baclcross (BC) 种群证明了该方法在顺序性状的QTL映射中的应用。

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。

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 (红色激活的通道视紫红质) 的光遗传学刺激检查了果蝇癫痫模型中的癫痫发作敏感性。在许多方面，对癫痫敏感的突变体parabss1的光刺激会导致行为麻痹，类似于机械刺激引起的麻痹。电生理学表明，光刺激会在parabss1中引起异常的癫痫样神经元放电，随后是类似于突触衰竭的静止期，显然是造成瘫痪的原因。神经元活动的模式在恢复之前以癫痫样活动结束。我们初步确定蘑菇体是光遗传发作开始的一个明显基因座。Α/β 裂片可能是引起蘑菇体癫痫发作的主要原因。

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13头猪的40分钟冠状动脉球囊充气产生的心肌梗死实验模型中，评估了急性心肌缺血期间对应于心室去极化和复极化的几种心电图 (ECG) 衍生指标。从冠状动脉闭塞开始后的第4分钟开始迅速观察到显着变化，分别在去极化11至22分钟和复极化指数9至12分钟之间达到最大值。随后，在闭塞的后期，这些最大变化开始减少。与QRS复合物的后半部分相关的去极化变化与闪烁显像估计的危险心肌 (MaR) 呈显着但呈负相关。在闭塞期间观察到的两个更相关的峰处评估的MaR与QRS复合体向下斜率的变化之间的相关性为r = -0.75，p <0.01和r = -0.79，对于在 [公式: 参见文本] 中观察到的正偏转和负偏转，分别为p <0.01。通过评估主要观察到的正峰处的ST段抬高来分析复极化变化，也显示出负的，但与MaR无关: r = -0.34，p = 0.28。我们的结果表明，在去极化的后半部分评估的变化，例如 [公式: 参见文本] 所描述的变化，同时受到R波振幅，QRS宽度和ST电平变化的影响，与在去极化早期或ST段期间评估的其他指标相比，与缺血量的相关性更好。

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：

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：

BACKGROUND & AIMS: :Purpose. To evaluate whether 3T clinical MRI with a small-animal coil and gradient-echo (GE) sequence could be used to characterize long-term left ventricular remodelling (LVR) following nonreperfused myocardial infarction (MI) using semi-automatic segmentation software (SASS) in a rat model. Materials and Methods. 5 healthy rats were used to validate left ventricular mass (LVM) measured by MRI with postmortem values. 5 sham and 7 infarcted rats were scanned at 2 and 4 weeks after surgery to allow for functional and structural analysis of the heart. Measurements included ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), and LVM. Changes in different regions of the heart were quantified using wall thickness analyses. Results. LVM validation in healthy rats demonstrated high correlation between MR and postmortem values. Functional assessment at 4 weeks after MI revealed considerable reduction in EF, increases in ESV, EDV, and LVM, and contractile dysfunction in infarcted and noninfarcted regions. Conclusion. Clinical 3T MRI with a small animal coil and GE sequence generated images in a rat heart with adequate signal-to-noise ratio (SNR) for successful semiautomatic segmentation to accurately and rapidly evaluate long-term LVR after MI.

背景与目标： : 目的。评估是否可以使用半自动分割软件 (SASS) 在大鼠模型中使用带有小动物线圈和梯度回波 (GE) 序列的3t临床MRI来表征非再灌注心肌梗死 (MI) 后的长期左心室重塑 (LVR)。材料和方法。5只健康大鼠用于验证MRI测量的左心室质量 (LVM) 和死后值。在手术后2周和4周对5只假手术大鼠和7只梗死大鼠进行扫描，以进行心脏的功能和结构分析。测量包括射血分数 (EF)，舒张末期容积 (EDV)，收缩末期容积 (ESV) 和LVM。使用壁厚分析来量化心脏不同区域的变化。结果。健康大鼠的LVM验证表明MR与死后值之间存在高度相关性。MI后4周的功能评估显示EF显着降低，ESV，EDV和LVM增加以及梗塞和非梗塞区域的收缩功能障碍。结论。具有小动物线圈和GE序列的临床3T MRI在大鼠心脏中生成的图像具有足够的信噪比 (SNR)，可成功进行半自动分割，以准确，快速地评估MI后的长期LVR。