BACKGROUND & AIMS: :The aim of this study was to assess the clinical value of serum oestradiol concentration 8 days after embryo transfer (D8E2) and beta-human chorionic gonadotrophin (HCG-beta) concentration 12 days after embryo transfer (D12HCG-beta) in the prediction of pregnancy and the outcome of pregnancy following assisted reproduction, taking into account the day of transfer, which was either day 3 (D3) or day 5 (D5). The objective was to improve patient counselling by giving quantitative and reliable predictive information instead of non-specific uncertainties. A total of 2035 embryo transfer cycles performed between January 2003 and June 2005 were analysed retrospectively. Biochemical pregnancy, ectopic pregnancy and first-trimester abortions were classified as non-viable pregnancies; pregnancies beyond 12 weeks gestation were classified as ongoing pregnancies (OP). Significantly higher D8E2 and D12HCG-beta were obtained in D5 transfers compared with D3 transfers with regard to pregnancy and OP (P

BACKGROUND & AIMS: PURPOSE:Peptide growth factors are known accelerators of corneal wound healing, probably mediated through increased proliferation of the cells; however, information about their effect on keratocyte motility is lacking. The influence of peptide growth factors on keratocyte migratory activity was investigated, using the following growth factors: platelet derived growth factor (PDGF-BB), epidermal growth factor (EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I) and transforming growth factor-beta-1 (TGF-beta 1).

METHODS:Keratocytes were seeded on gels of type 1 collagen, growth factor added, and the cells left to migrate for 72 hours. Subsequently, the number of keratocytes at the different levels in the collagen gel was evaluated by optically sectioning the gel at 20 microns, intervals, with an inverted phase contrast microscope.

RESULTS:PDGF, EGF and bFGF at 10 ng/ml, all increased the number of keratocytes at the different levels of the gel as compared to a non-stimulated control (p < 0.05 or p < 0.01, students t-test). TGF-beta proved to be a strong inhibitor of keratocyte migration, decreasing the number of keratocytes observed at every level in the gel (p < 0.05 and p < 0.01, students t-test), whereas no effect of IGF-I and aFGF was found. During the 72 hours of migration, no contraction of the collagen gels was observed. Autoradiography of histological sections of the gels showed that during the 72-hour period only TGF-beta and 10% fetal bovine serum induced an increase in keratocyte proliferation.

CONCLUSION:PDGF, EGF and bFGF increase keratocyte migration, independent of proliferation in a collagen gel invasion assay and might promote corneal wound healing, not only by increasing cell proliferation, but also through increased motility.

背景与目标： 目的 : 肽生长因子是已知的角膜伤口愈合的促进剂，可能是通过细胞增殖增加介导的; 但是，缺乏有关它们对角质细胞运动的影响的信息。用以下生长因子: 血小板衍生生长因子 (pdgf-bb)，表皮生长因子 (EGF)，酸性成纤维细胞生长因子 (aFGF)，碱性成纤维细胞生长因子 (bFGF)，胰岛素样生长因子-I (igf-i) 和转化生长因子-β1 (tgf-β1)。
方法 : 将角质细胞接种在1型胶原蛋白的凝胶上，添加生长因子，细胞迁移72小时。随后，通过用倒置相差显微镜以20微米的间隔光学切片来评估胶原蛋白凝胶中不同水平的角质形成细胞的数量。
结果 :PDGF，EGF和bFGF为10 ng/ml，与未刺激的对照相比，在凝胶的不同水平下，所有这些都增加了角质细胞的数量 (p <0.05或p <0.01，学生t检验)。TGF-β 被证明是角质细胞迁移的强抑制剂，减少了在凝胶中每个水平观察到的角质细胞的数量 (p <0.05和p <0.01，学生t检验)，而没有发现igf-i和aFGF的作用。在迁移的72小时内，未观察到胶原蛋白凝胶的收缩。凝胶组织学切片的放射自显影显示，在72小时内，只有TGF-β 和10% 胎牛血清诱导角质细胞增殖增加。
结论 :PDGF，EGF和bFGF增加角质细胞迁移，在胶原蛋白凝胶侵袭试验中独立于增殖，并且可能不仅通过增加细胞增殖，而且通过增加运动性来促进角膜伤口愈合。

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: 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：

BACKGROUND & AIMS: Genetic studies have recently revealed a role for transforming growth factor-beta-1 (TGF-beta 1) and its receptors (TGF-beta Rs I and II as well as endoglin) in embryonic vascular assembly and in the establishment and maintenance of vessel wall integrity. The purpose of this review is threefoldfirst, to reassess previous studies on TGF-beta and endothelium in the light of these recent findings; second, to describe some of the well-established as well as controversial issues concerning TGF-beta and its regulatory role in angiogenesis; and third, to explore the notion of "context' with respect to TGF-beta and endothelial cell function. Although the focus of this review will be on the endothelium, other vascular wall cells are also likely to be important in the pathogenesis of the vascular lesions revealed by genetic studies.

背景与目标： 遗传研究最近揭示了转化生长因子-beta-1 (TGF-beta 1) 及其受体 (TGF-beta Rs I和II以及endoglin) 在胚胎血管组装以及血管壁完整性的建立和维持中的作用。这篇综述的目的是三重首先，根据这些最新发现重新评估先前关于TGF-β 和内皮的研究; 第二，描述一些关于TGF-β 及其在血管生成中的调节作用的公认的和有争议的问题; 第三，探讨TGF-β 和内皮细胞功能的 “背景” 概念。尽管本综述的重点将放在内皮上，但其他血管壁细胞也可能在遗传学研究揭示的血管病变的发病机理中很重要。

BACKGROUND & AIMS: The expression and localization of hepatocyte growth factor/scatter factor (HGF/SF) were examined immunohistochemically in 59 human coronary artery lesions retrieved by directional coronary atherectomy and compared with the localization of transforming growth factor beta isoforms (TGF-beta 1, -beta 2, and -beta 3). In 21 of the 59 specimens (35.6%) HGF-like immunoreactivity (HGF-IR) was revealed. The HGF immunopositivity rate of 45% (14/31) in thrombotic tissue was significantly (P < 0.05) higher than the rates of 7.3% (4/55), 7.1% (3/42), and 0% (0/14) in fibrous tissue, neointimal hyperplasia and atheromatous gruel, respectively. Immunoreactivity for HGF was much weaker than that for TGF-beta isoforms in these components except in thrombotic tissue. These cells exhibiting strong HGF-IR were inflammatory cells such as monocytes/macrophages in thrombotic tissue, in tissue lesions adjacent to a thrombus, and outside the capillary walls in a portion of the neovascularized lesions. Smooth muscle cells (SMCs) hardly demonstrated HGF-IR. In contrast, in control coronary arteries obtained at autopsy, the HGF-IR was strongly expressed in SMCs. These findings suggest that HGF produced by macrophages play a part in the process of coronary plaque formation attributable to thrombus in man.

背景与目标： 通过免疫组织化学检查了通过定向冠状动脉粥样斑块切除术检索的59例人冠状动脉病变中肝细胞生长因子/散射因子 (HGF/SF) 的表达和定位，并将其与转化生长因子 β 亚型 (tgf-β1，-β2和-β3) 的定位进行了比较。在59个标本中的21个 (35.6%) 中，HGF样免疫反应性 (hgf-ir) 被揭示。血栓组织中45% (14/31) 的HGF免疫阳性率显着 (P < 0.05) 高于纤维组织，新内膜增生和动脉粥样硬化稀粥中的7.3% (4/55)，7.1% (3/42) 和0% (0/14)。分别。除血栓形成组织外，这些成分中HGF的免疫反应性比TGF-β 同工型的免疫反应性弱得多。这些表现出强hgf-ir的细胞是炎性细胞，例如血栓形成组织中，与血栓相邻的组织病变以及部分新生血管病变的毛细血管壁外部的单核细胞/巨噬细胞。平滑肌细胞 (smc) 几乎不显示HGF-IR。相反，在尸检获得的对照冠状动脉中，hgf-ir在smc中强烈表达。这些发现表明，巨噬细胞产生的HGF在人类血栓形成引起的冠状动脉斑块形成过程中发挥了作用。

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: 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。

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。