• 【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,并表达编码神经营养蛋白4和神经胶质细胞源性神经营养因子的mRNA降低水平。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的联合使用不会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。通过牛顿-拉夫森算法实现的广义线性模型方法论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发展的广泛理论。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)种群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(红色激活性视紫红质)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异常的癫痫发作样神经元放电,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波复合体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)呈显着但呈负相关。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ST段抬高而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缓了发作的发生。静脉内注射AAV-BR1-CAG-NEMO载体的新生小鼠在载体注射后11个月未发生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: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,任何方法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(无进一步筛查)相比。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1000人30 893至30 902生命年[完美依从]与每1000人30 865至30 869年生命[不完全依从] ])。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。
  • 【非再灌注心肌梗死大鼠模型中的长期左心室重构:使用3T临床扫描仪进行的连续MR成像。】 复制标题 收藏 收藏
    DOI:10.1155/2012/504037 复制DOI
    作者列表:Saleh MG,Sharp SK,Alhamud A,Spottiswoode BS,van der Kouwe AJ,Davies NH,Franz T,Meintjes EM
    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。使用半自动分割软件(SASS)评估具有小动物线圈和梯度回波(GE)序列的3T临床MRI是否可用于表征非再灌注心肌梗死(MI)后的长期左心室重构(LVR)在大鼠模型中。材料和方法。使用5只健康大鼠通过验尸值验证通过MRI测量的左心室质量(LVM)。在手术后第2和第4周对5只假大鼠和7只梗塞的大鼠进行了扫描,以便对心脏进行功能和结构分析。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。使用壁厚分析对心脏不同区域的变化进行定量。结果。在健康大鼠中的LVM验证表明MR和验尸值之间存在高度相关性。 MI后4周的功能评估显示,梗塞区和非梗塞区的EF明显降低,ESV,EDV和LVM升高,以及收缩功能障碍。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,从而准确快速地评估MI后的长期LVR。
  • 【慢性肺泡II型肺泡上皮细胞长期暴露于烟草特异性致癌物NNK会导致恶性转化:一种新的体外肺致癌模型。】 复制标题 收藏 收藏
    DOI:10.1002/mc.21987 复制DOI
    作者列表:Mennecier G,Torres LN,Cogliati B,Sanches DS,Mori CM,Latorre AO,Chaible LM,Mackowiak II,Nagamine MK,Da Silva TC,Fukumasu H,Dagli ML
    BACKGROUND & AIMS: :Lung cancer is the leading cause of cancer-related mortality in both men and women throughout the world. This disease is strongly associated with tobacco smoking. The aim of this manuscript was to establish an in vitro model that mimics the chronic exposures of alveolar epithelial type II cells to the tobacco-specific nitrosamine carcinogen, NNK. Immortalized non-neoplastic alveolar epithelial cells type II, (E10 cells), from BALB/c mice were exposed to low concentration of NNK (100 pM) during 5, 10, 15, and 20 cycles of 48 h. NNK-transformed cells showed an increase of proliferation rate and motility. Moreover, these cells underwent epithelial-to-mesenchymal transition (EMT). Increased migratory capacity and EMT were correlated to the time of exposure to NNK. NNK-transformed cells were tested for their growth and metastatic capacity in vivo. Subcutaneous injection of cells exposed to NNK for 20 cycles (E10-NNK20 clone) into BALB/c mice led to the formation of subcutaneous tumors that arose after 40 ± 17 d in all animals, which died 95 ± 18 d after cell inoculation, with lymph nodes and lung metastasis. The morphological characteristics of tumors were compatible with metastatic undifferentiated carcinoma. Cells exposed to NNK for 5-10 cycles did not display metastatic capacity, while those exposed for 15 cycles displayed low capacity. Our results show that prolonged exposures to NNK led the cells to increasingly acquire malignant properties. The cellular model presented in this study is suitable for studying the molecular events involved in the different stages of malignant transformation.
    背景与目标: :肺癌是全世界男女癌症相关死亡率的主要原因。这种疾病与吸烟密切相关。该手稿的目的是建立一个体外模型,该模型模仿肺泡II型肺泡上皮细胞长期暴露于烟草特有的亚硝胺致癌物NNK。来自BALB / c小鼠的永生化II型非肿瘤性肺泡上皮细胞(E10细胞)在48?h的5、10、15和20个周期中暴露于低浓度的NNK(100 pM)。 NNK转化的细胞显示出增殖率和运动性的增加。而且,这些细胞经历了上皮到间充质转化(EMT)。迁徙能力和EMT的增加与接触NNK的时间有关。测试了NNK转化的细胞的体内生长和转移能力。在BALB / c小鼠中皮下注射暴露于NNK 20个周期的细胞(E10-NNK20克隆)导致皮下肿瘤的形成,所有动物在40±±17 d后出现,在接种细胞后95±±18 d死亡。淋巴结转移和肺转移。肿瘤的形态学特征与转移性未分化癌相容。暴露于NNK 5-10个周期的细胞不显示转移能力,而暴露15个周期的细胞则显示低转移能力。我们的结果表明,长时间暴露于NNK会使细胞越来越多地获得恶性特性。在这项研究中提出的细胞模型适用于研究与恶性转化的不同阶段有关的分子事件。
  • 【产后头三周的产妇心理健康:照料者支持的影响和分娩的主观经历-纵向路径模型。】 复制标题 收藏 收藏
    DOI:10.3109/0167482X.2012.730584 复制DOI
    作者列表:Gürber S,Bielinski-Blattmann D,Lemola S,Jaussi C,von Wyl A,Surbek D,Grob A,Stadlmayr W
    BACKGROUND & AIMS: OBJECTIVE:Acute stress reactions (ASR) and postpartum depressive symptoms (PDS) are frequent after childbirth. The present study addresses the change and overlap of ASR and PDS from the 1- to 3-week postpartum and examines the interplay of caregiver support and subjective birth experience with regard to the development of ASR/PDS within a longitudinal path model. METHOD:A total of 219 mothers completed questionnaires about caregiver support and subjective birth experience (Salmon's Item List) at 48-6-h postpartum. ASR and PDS were measured for 1- and 3-week postpartum. The Impact of Event Scale (IES) was used to assess ASR, and the Edinburgh Postnatal Depression Scale (EPDS) was used to assess PDS. RESULTS:ASR was frequent 1-week postpartum (44.7%) and declined till week 3 (24.8%, p <.001), while the prevalence of PDS was continuous (14.2% week 1; 12.6% week 3; p = .380). Favorable reports of caregiver support were related to better subjective childbirth experience, which was related to lower ASR and PDS (controlled for age, mode of delivery, parity, EDA and duration of childbirth). CONCLUSION:High quality of intrapartum care and positive birth experiences facilitate psychological adjustment in the first 3-week postpartum.
    背景与目标: 目的:分娩后经常出现急性应激反应(ASR)和产后抑郁症状(PDS)。本研究探讨了产后1至3周ASR和PDS的变化和重叠,并研究了纵向路径模型中ASR / PDS的发展过程中照顾者支持和主观分娩经历之间的相互作用。
    方法:共有219位母亲在产后48-6小时完成了有关照顾者支持和主观出生经历的调查表(Salmon项目列表)。在产后1周和3周测量ASR和PDS。事件影响量表(IES)用于评估ASR,爱丁堡产后抑郁量表(EPDS)用于评估PDS。
    结果:ASR在产后1周内很常见(44.7%),并下降到第3周(24.8%,p <.001),而PDS的发生率是连续的(第1周为14.2%;第3周为12.6%; p = .380) )。良好的照料者支持报告与更好的主观分娩经历有关,这与较低的ASR和PDS有关(控制了年龄,分娩方式,均等,EDA和分娩时间)。
    结论:高质量的产期护理和积极的分娩经历有助于产后前三周的心理调节。
  • 【饮食抗拒性改变患者的综合治疗训练模型】 复制标题 收藏 收藏
    DOI:10.3305/nh.2012.27.3.5690 复制DOI
    作者列表:Calvo Sagardoy R,Gallego Morales LT,García de Lorenzo y Mateos A
    BACKGROUND & AIMS: :The need to find effective treatments for patients with Anorexia or Bulimia nervosa has led to the professionals who care for them to develop new forms of treatment that take into account the variables that cause resistance to change. Patients in this study (2006-2009) have the following characteristics: 340 patients who have 7 or more years of evolution and/or have tried numerous previous treatments without having succeeded in starting and / or maintaining the desired changes, that allowed them to recover steadily. As the proposed treatment, the patient-treatment team is based on the principles of the training model. It considers the patient holistically, it informs and provides him with resources to increase its commitment to change. Teaches the patient to take care physically and mentally as a way to regain their health and leave the disorder in a stable way. Includes family members as essential support in the recovery of their closest. Therapists require extensive experience in the treatment of ED, flexibility, ability to integrate with other team members even if they use different theoretical models, skills for group sessions, ability to handle negative emotions and frustration tolerance. Finally, the model presented below has been implemented, recovered patients whose stay in the disorder exceeded 15 years of development and led to permanent occupational disability.
    背景与目标: 由于需要为患有厌食症或神经性贪食症的患者找到有效的治疗方法,因此引起了专业人士的关注,他们开发出了新的治疗形式,其中考虑到了引起抵抗力变化的因素。本研究(2006-2009年)的患者具有以下特征:340位患者经历了7年或更长时间的进化和/或尝试过多种先前的治疗而未成功开始和/或维持所需的改变,从而使他们得以康复稳步。作为建议的治疗方法,患者治疗团队基于培训模型的原则。它从整体上考虑患者,为患者提供信息并为其提供资源,以增加其对变化的承诺。教给病人身心上的照顾,以恢复健康并稳定地摆脱疾病。包括家庭成员,以帮助他们恢复最亲密的关系。治疗师需要在ED的治疗方面具有丰富的经验,灵活性,与其他团队成员融为一体的能力,即使他们使用不同的理论模型,小组会议的技能,应对负面情绪的能力和挫败感的容忍度也是如此。最终,实施了以下模型,恢复了在该疾病中停留超过15年并导致永久性职业残疾的患者。
  • 【远程缺血性调节可在外伤性脑损伤的小鼠模型中保留认知能力和运动协调性。】 复制标题 收藏 收藏
    DOI:10.1097/TA.0000000000001626 复制DOI
    作者列表:Sandweiss AJ,Azim A,Ibraheem K,Largent-Milnes TM,Rhee P,Vanderah TW,Joseph B
    BACKGROUND & AIMS: INTRODUCTION:Management of traumatic brain injury (TBI) is focused on minimizing or preventing secondary brain injury. Remote ischemic conditioning (RIC) is an established treatment modality that has been shown to improve patient outcomes in different clinical settings by influencing inflammatory insults. In a clinical trial, RIC showed amelioration of SB100 and neuron-specific enolase. The aim of our study was to further elucidate the mechanisms and outcome when applying RIC in a mouse model of traumatic brain injury. METHODS:We subjected 100 male C57BL mice to a closed-skull cortical-controlled impact injury. Two hours after the TBI, the animals were allocated to either the RIC group (n = 50) or the sham group (n = 50). By clamping the exposed femoral artery, we induced RIC by six 4-minute cycles of ischemia and reperfusion. Circulating levels of S100-B, neuron-specific enolase, and glial fibrillary acidic protein were measured at multiple time points. Animals were additionally observed daily for cognition and motor coordination via novel object recognition and rotarod. Brain sections were stained and evaluated for neuronal injury at post-TBI Day 5. RESULTS:The RIC animals had a significantly higher recognition index than did sham at 24, 48, and 72 hours after intervention. Rotarod latency was higher in the RIC animals compared to the sham animals at all-time points, and statistically significant at 120 hours after intervention. The RIC group demonstrated preserved cognitive function and motor coordination compared to the sham. On hematoxylin and eosin and immunohistochemical staining of brain sections, there was less area of neuronal degeneration and astrocytosis, respectively, in the RIC group compared to the sham group. There was no significant difference in systemic neuronal markers between the RIC and sham animals. CONCLUSION:Remote ischemic conditioning 2 hours after injury preserved cognitive functions and motor coordination in a mouse model of TBI. Remote ischemic conditioning can preserve viability of neurons and astrocytes after TBI and has potential as a clinically noninvasive and relatively easy method to improve outcome after TBI. LEVEL OF EVIDENCE:Therapeutic studies, randomized controlled trial, level I.
    背景与目标: 简介:创伤性脑损伤(TBI)的管理重点在于最大程度地减少或预防继发性脑损伤。远程缺血性调节(RIC)是一种既定的治疗方式,已显示可通过影响炎症损伤改善不同临床环境下的患者预后。在一项临床试验中,RIC显示SB100和神经元特异性烯醇化酶得到改善。我们研究的目的是进一步阐明将RIC应用于创伤性脑损伤小鼠模型的机制和结果。
    方法:我们对100只雄性C57BL小鼠进行了闭合颅骨皮质控制的撞击伤害。 TBI后两小时,将动物分为RIC组(n = 50)或假组(n = 50)。通过夹紧暴露的股动脉,我们通过六个4分钟的缺血和再灌注周期诱导RIC。在多个时间点测量了S100-B,神经元特异性烯醇化酶和神经胶质原纤维酸性蛋白的循环水平。每天还通过新颖的物体识别和旋转仪观察动物的认知和运动协调。在TBI后第5天对脑切片进行染色并评估其神经元损伤。
    结果:在干预后24、48和72小时,RIC动物的识别指数明显高于假手术。与假手术动物相比,RIC动物的Rotarod潜伏期在所有时间点都更高,并且在干预后120小时具有统计学意义。与假手术相比,RIC组显示出保留的认知功能和运动协调能力。关于苏木精和曙红以及脑切片的免疫组织化学染色,与假手术组相比,RIC组的神经元变性和星形胶质细胞减少的区域分别较少。 RIC动物和假动物之间的系统神经元标记没有显着差异。
    结论:TBI小鼠模型在损伤后2小时可进行远程缺血调节,以保持认知功能和运动协调性。远端缺血性调理可以保留TBI后神经元和星形胶质细胞的活力,并具有作为临床无创且相对容易的方法来改善TBI后预后的潜力。
    证据级别:治疗研究,随机对照试验,I级。
  • 【那瓦印度药用植物(墨西哥):作为一种消炎模型和抗菌作用,对NF-κB的抑制作用。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(96)80064-X 复制DOI
    作者列表:Bork PM,Schmitz ML,Weimann C,Kist M,Heinrich M
    BACKGROUND & AIMS: :Selected plants documented as medicinal in an ethnobotanical study with the Nahua of the Sierra de Zongolica (Veracruz, Mexico) were evaluated for anti-inflammatory and antibacterial activity. One of the potential sides of action of anti-inflammatory drugs is the transcription factor NF-κB. This factor is essential for the immune, inflammatory, and acute phase responses. We therefore tested extracts from a total of 28 plants used by the Nahua Indians for their potential effect on the activation of the transcription factor NF-κB. The leaves of Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae) was the only extract which showed inhibitory activity. Nonspecific DNA binding activities were not noticably influenced. Phytochemical studies to isolate the active principle and further biochemical studies in order to better understand the mode of action of this NF-κB inhibitor have been initiated. Five plants showed noteworthy antibacterial activity against some pathogenic (Staphylococcus aureus ATCC 25933 and Yersinia enterocolitica 03) and nonpathogenic (E. coli DSM 1077, Micrococcus luteus DSM 348) microorganism: Acacia cornigera, Cuscuta tinctoria, Ludwigia octovalvis, Lysiloma divaricata, and Tithonia diversifolia.
    背景与目标: :对与塞拉利昂德宗加利卡(Naerra of Zongolica)(墨西哥韦拉克鲁斯市)的纳瓦族人种植物学研究中证明为药用的植物进行了抗炎和抗菌活性评估。抗炎药的潜在作用之一是转录因子NF-κB。该因子对于免疫,炎症和急性期反应至关重要。因此,我们测试了纳瓦族印第安人使用的总共28种植物的提取物对转录因子NF-κB活化的潜在影响。 Tithonia diversifolia(Hemsl。)A. Gray(菊科)的叶子是唯一显示出抑制活性的提取物。非特异性DNA结合活性未受到明显影响。已经启动了植物化学研究以分离活性成分,并进行了进一步的生物化学研究以更好地了解这种NF-κB抑制剂的作用方式。五株植物对某些病原微生物(金黄色葡萄球菌ATCC 25933和小肠结肠炎耶尔森氏菌03)和非病原微生物(大肠杆菌DSM 1077,微球菌luteus DSM 348)表现出显着的抗菌活性:洋槐金合欢,弯角弯孢菌,路德维希氏八角形藻,香根草。
  • 【在沃勒氏变性的离体模型中,细胞外ATP抑制雪旺氏细胞的去分化和增殖。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbrc.2012.11.057 复制DOI
    作者列表:Shin YH,Lee SJ,Jung J
    BACKGROUND & AIMS: :After nerve injury, Schwann cells proliferate and revert to a phenotype that supports nerve regeneration. This phenotype-changing process can be viewed as Schwann cell dedifferentiation. Here, we investigated the role of extracellular ATP in Schwann cell dedifferentiation and proliferation during Wallerian degeneration. Using several markers of Schwann cell dedifferentiation and proliferation in sciatic explants, we found that extracellular ATP inhibits Schwann cell dedifferentiation and proliferation during Wallerian degeneration. Furthermore, the blockage of lysosomal exocytosis in ATP-treated sciatic explants is sufficient to induce Schwann cell dedifferentiation. Together, these findings suggest that ATP-induced lysosomal exocytosis may be involved in Schwann cell dedifferentiation.
    背景与目标: 神经损伤后,雪旺细胞增殖并恢复为支持神经再生的表型。这种改变表型的过程可以看作是雪旺氏细胞去分化。在这里,我们调查了Wallerian变性过程中胞外ATP在雪旺氏细胞去分化和增殖中的作用。使用坐骨神经外植体中雪旺氏细胞去分化和增殖的几种标记,我们发现细胞外ATP在Wallerian变性过程中抑制雪旺氏细胞去分化和增殖。此外,在ATP处理的坐骨神经外植体中溶酶体胞吐作用的阻断足以诱导雪旺细胞去分化。在一起,这些发现表明,ATP诱导的溶酶体胞吐作用可能与雪旺氏细胞去分化有关。

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