BACKGROUND & AIMS: Thrombin activation requires assembly of a prothrombinase complex of activated coagulation factors on an anionic phospholipid surface, classically provided by activated platelets. We have previously shown that anionic phosphatidylserine is exposed by rat vascular smooth muscle cells (VSMCs) undergoing apoptosis after serum withdrawal. In this study, using a chromogenic assay, we have shown thrombin generation by apoptotic VSMCs expressing c-myc (VSMC-myc) with an area under the thrombin-generation curve (AUC) of 305 +/- 17 nmol x min/L and a peak thrombin (PT) of 154 +/- 9 nmol/L. The thrombin-generating potential of the apoptotic VSMC-myc cells was greater than that of unactivated platelets (P = .003 for AUC; P = .0002 for PT) and similar to calcium-ionophore activated platelets (AUC of 332 +/- 15 nmol x min/L, P = .3; PT of 172 +/- 8 nmol/L, P = .2). Thrombin activation was also seen with apoptotic human VSMCs (AUC of 211 +/- 8 nmol x min/L; PT of 103 +/- 4 nmol/L) and was inhibited by annexin V (P < .0001 for AUC and PT). VSMC-myc cells maintained in serum generated less thrombin than after serum withdrawal (P = .0002 for AUC and PT). VSMCs derived from human coronary atherosclerotic plaques that apoptose even in serum also generated thrombin (AUC of 260 +/- 2 nmol x min/L; PT of 128 +/- 4 nmol/L). We conclude that apoptotic VSMCs possess a significant thrombin-generating capacity secondary to phosphatidylserine exposure. Apoptotic cells within atherosclerotic plaques may allow local thrombin activation, thereby contributing to disease progression.

背景与目标： 凝血酶的活化需要活化的凝血因子的凝血酶原酶复合物在阴离子磷脂表面上的组装，这通常是由活化的血小板提供的。先前我们已经表明，在撤离血清后，发生凋亡的大鼠血管平滑肌细胞（VSMC）会暴露出阴离子磷脂酰丝氨酸。在这项研究中，我们使用发色试验显示了表达c-myc（VSMC-myc）的凋亡VSMC的凝血酶生成，其凝血酶生成曲线（AUC）下方的面积为305 /-17 nmol x min / L，凝血酶峰值（PT）为154 9 nmol / L。凋亡的VSMC-myc细胞的凝血酶生成潜能大于未激活的血小板（对于AUC，P = .003；对于PT，P = .0002），类似于钙离子载体激活的血小板（AUC为332 /-15 nmol） xmin / L，P ＝ 0.3； PT为172 / 8-nmol / L，P ＝ 0.2）。在凋亡的人VSMC中也观察到凝血酶活化（AUC为211 /-8 nmol x min / L； PT为103 /-4 nmol / L），并被膜联蛋白V抑制（对于AUC和PT，P <.0001）。血清中维持的VSMC-myc细胞产生的凝血酶少于血清中止后产生的凝血酶（对于AUC和PT，P = .0002）。源自甚至在血清中也会凋亡的人冠状动脉粥样硬化斑块的VSMC也会产生凝血酶（AUC为260 /-2 nmol x min / L； PT为128 /-4 nmol / L）。我们得出结论，凋亡性VSMC具有继磷脂酰丝氨酸暴露后的显着凝血酶生成能力。动脉粥样硬化斑块中的凋亡细胞可能允许局部凝血酶活化，从而促进疾病进展。

BACKGROUND & AIMS: Cardiac troponin T (cTnT) and troponin I (cTnI) have been suggested as new, more specific markers of myocardial cellular damage. The objective of this study was to examine how the distributions of cTnI and cTnT were affected in postinfarction left ventricular remodeled (LVR) myocardium. At 2 months postinfarct in a porcine heart failure model, both Western blot and biochemical assay analyses were performed on left ventricular myocardium remote from the infarct zone in ligation animals (n = 8). Results were compared with data from the left ventricular myocardium from similar sized healthy (control) pigs (n = 7). Autoradiograms from Western blot analysis showed that the protein mass for cTnI and cTnT in LVR hearts decreased 80% (P < 0.001) and 40% (P < 0.02), respectively, when compared with nondiseased tissue. Similarly, the concentrations for cTnI and cTnT in LVR hearts decreased 42% (P < 0.05) and 70% (P < 0.001), respectively, compared with nondiseased normal tissue. The clinical assumption is that the appearance of cTnI and cTnT in the blood is proportional to chronic loss of cTnI and cTnT from injured myocardium associated with left ventricular remodeling.

背景与目标： 心肌肌钙蛋白T（cTnT）和肌钙蛋白I（cTnI）被认为是心肌细胞损伤的新的，更具体的标志物。这项研究的目的是检查梗死后左心室重构（LVR）心肌中cTnI和cTnT的分布如何受到影响。在猪心力衰竭模型中，梗死后2个月，在结扎动物中，对远离梗死区的左心室心肌进行了Western blot和生化分析（n = 8）。将结果与来自类似大小的健康（对照）猪（n = 7）的左心室心肌的数据进行比较。 Western blot分析的放射自显影照片显示，与未患病的组织相比，LVR心脏中cTnI和cTnT的蛋白质质量分别降低了80％（P <0.001）和40％（P <0.02）。同样，与未患病的正常组织相比，LVR心脏中cTnI和cTnT的浓度分别降低了42％（P <0.05）和70％（P <0.001）。临床假设是血液中cTnI和cTnT的出现与左心室重构相关的心肌损伤导致cTnI和cTnT的慢性丧失成比例。

BACKGROUND & AIMS: These experiments were designed to determine whether glycogenolysis was influenced by the glycogen concentration of vascular smooth muscle. Segments of hog carotid artery smooth muscle were allowed to synthesize variable amounts of 1-[13C]glucosyl units of glycogen. Artery segments were then isometrically contracted in the presence of 2-[13C]glucose. Prior to and after isometric contraction, measurements were made of tissue glycogen content and superfusate glucose and lactate concentrations. 2-[13C]Lactate and 3-[13C]lactate peak intensities in the superfusate were measured using 13C-NMR spectroscopy. The tissue glycogen content decreased exponentially during the 4.5 h of isometric contraction (R2 = 0.990), despite more than a 3-fold range of glycogen concentration prior to contraction. The extent of glycogen utilization during a 3 h isometric contraction varied linearly with the precontraction glycogen concentration (R2 = 0.727). Lactate production specifically from glycogen breakdown increased with an increase in precontraction glycogen concentration (R2 = 0.620). During a 3 h isometric contraction neither the glucose utilization (R2 = 0.007) nor lactate production specifically produced from glucose (R2 = 0.00002) varied with the precontraction glycogen concentration. It is concluded that the rate of glycogenolysis is determined by the content of glycogen during prolonged contractions. In addition, precontraction glycogen levels influence the pathway for glycogen utilization but not the pathway for glucose utilization. Therefore, glycolysis and glycogenolysis behave independently in vascular smooth muscle.

背景与目标： 设计这些实验以确定糖原分解是否受血管平滑肌糖原浓度的影响。允许猪颈动脉平滑肌节段合成糖原的1- [13C]葡糖基单元。然后在2- [13C]葡萄糖存在下，等距收缩动脉段。在等距收缩之前和之后，对组织糖原含量以及超融合葡萄糖和乳酸浓度进行了测量。使用13C-NMR光谱法测量超熔液中的2- [13C]乳酸盐和3- [13C]乳酸盐峰强度。尽管在收缩前糖原浓度的3倍范围内，组织糖原含量在等长收缩的4.5小时内呈指数下降（R2 = 0.990）。在3小时的等距收缩过程中，糖原利用的程度随收缩前糖原浓度的变化而线性变化（R2 = 0.727）。糖原分解产生的乳酸的产量随收缩前糖原浓度的增加而增加（R2 = 0.620）。在3小时的等距收缩过程中，葡萄糖利用量（R2 = 0.007）或由葡萄糖专门产生的乳酸产量（R2 = 0.00002）都不会随收缩前糖原浓度的变化而变化。结论是糖原分解的速率取决于长时间收缩过程中糖原的含量。另外，收缩前糖原水平影响糖原利用的途径，但不影响葡萄糖利用的途径。因此，糖酵解和糖原分解作用在血管平滑肌中独立发生。

BACKGROUND & AIMS: The Dlx homeobox gene family is expressed in a complex pattern within the embryonic craniofacial ectoderm and ectomesenchyme. A previous study established that Dlx-2 is essential for development of proximal regions of the murine first and second branchial arches. Here we describe the craniofacial phenotype of mice with mutations in Dlx-1 and Dlx-1 and -2. The skeletal and soft tissue analyses of mice with Dlx-1 and Dlx-1 and -2 mutations provide additional evidence that the Dlx genes regulate proximodistal patterning of the branchial arches. This analysis also elucidates distinct and overlapping roles for Dlx-1 and Dlx-2 in craniofacial development. Furthermore, mice lacking both Dlx-1 and -2 have unique abnormalities, including the absence of maxillary molars. Dlx-1 and -2 are expressed in the proximal and distal first and second arches, yet only the proximal regions are abnormal. The nested expression patterns of Dlx-1, -2, -3, -5, and -6 provide evidence for a model that predicts the region-specific requirements for each gene. Finally, the Dlx-2 and Dlx-1 and -2 mutants have ectopic skull components that resemble bones and cartilages found in phylogenetically more primitive vertebrates.

背景与目标： Dlx同源盒基因家族以复杂的模式在胚胎颅面外胚层和外间质内表达。先前的研究表明，Dlx-2对于鼠的第一和第二分支弓近端区域的发育至关重要。在这里，我们描述了具有Dlx-1和Dlx-1和-2突变的小鼠的颅面表型。具有Dlx-1和Dlx-1和-2突变的小鼠的骨骼和软组织分析提供了其他证据，证明Dlx基因调节branch弓的近现代模式。该分析还阐明了Dlx-1和Dlx-2在颅面发育中的独特作用和重叠作用。此外，缺乏Dlx-1和-2的小鼠具有独特的异常，包括不存在上颌磨牙。 Dlx-1和-2在近端和远端第一和第二弓形中表达，但仅近端区域异常。 Dlx-1，-2，-3，-5和-6的嵌套表达模式为预测每个基因的区域特定要求的模型提供了证据。最后，Dlx-2，Dlx-1和-2突变体具有异位的头骨成分，类似于在系统发育上较原始的脊椎动物中发现的骨骼和软骨。

BACKGROUND & AIMS: :Continuous changes in the length of smooth muscles require a highly organized sarcolemmal structure. Yet, smooth muscle cells also adapt rapidly to altered environmental cues. Their sarcolemmal plasticity must lead to profound changes which affect transmembrane signal transduction as well as contractility. We have established porcine vascular and human visceral smooth muscle cultures of epithelioid and spindle-shaped morphology and determined their plasma membrane properties. Epithelioid cells from both sources contain a higher ratio of cholesterol to glycerophospholipids, and express a less diverse range of lipid-associated annexins. These findings point to a reduction in efficiency of membrane segregation in epithelioid cells. Moreover, compared to spindle-shaped cells, cholesterol is more readily extracted from epithelioid cells with methyl-beta-cyclodextrin and its synthesis is more susceptible to inhibition with lovastatin. The inability of epithelioid cells to process vasoactive metabolites, such as angiotensin or nucleotides further indicates that contractile properties are impaired. Phenotypic plasticity extends beyond the loss of smooth muscle cell marker genes. The plasma membrane has undergone profound functional changes which are incompatible with cyclic foreshortening, but might be important in the development of vascular disease.

背景与目标： ：平滑肌长度的连续变化需要高度组织化的肌膜结构。然而，平滑肌细胞也能迅速适应变化的环境提示。它们的肌膜可塑性必须导致深刻的变化，从而影响跨膜信号转导和收缩。我们已经建立了上皮样和纺锤形形态的猪血管和人内脏平滑肌培养物，并确定了它们的质膜特性。来自两种来源的上皮样细胞都含有较高的胆固醇与甘油磷脂比例，并且表达的脂质相关膜联蛋白的变化范围较小。这些发现表明上皮样细胞中膜分离的效率降低。而且，与纺锤形细胞相比，用甲基-β-环糊精更容易从上皮样细胞中提取胆固醇，并且其合成更容易受到洛伐他汀的抑制。上皮样细胞不能处理血管活性代谢产物，例如血管紧张素或核苷酸，这进一步表明收缩特性受到损害。表型可塑性超出了平滑肌细胞标记基因丧失的范围。质膜已经发生了深刻的功能变化，这与循环缩短不相容，但是在血管疾病的发展中可能很重要。

BACKGROUND & AIMS: :It is well-recognised that steady-state isometric muscle force is decreased following active shortening (force depression, FD) and increased following active stretch (force enhancement, FE). It has also been demonstrated that passive muscle force is increased following active stretch (passive FE). Several studies have reported that FD increases with shortening amplitude and that FE and passive FE increase with stretch amplitude. Here, we investigate whether these trends continue with further increases in shortening or stretch amplitude. Experiments were performed using in situ cat soleus muscles (n=8 for FD; n=7 for FE and passive FE). FD, FE and passive FE were measured after shortening or stretch contractions that covered as wide a range of amplitudes as practically possible without damaging the muscles. FD increased approximately linearly with shortening amplitude, over the full range of amplitudes investigated. This is consistent with the hypothesis that FD arises from a stress-induced inhibition of crossbridges. FE increased with stretch amplitude only up to a point, and then levelled off. Passive FE, and the transient increase in force at the end of stretch, showed relationships to stretch amplitude that were qualitatively very similar to the relationship for FE, increasing only until the same critical stretch amplitude had been reached. We conclude that FE and passive FE do not increase with stretch amplitude under all circumstances. This finding has important consequences for determining the mechanisms underlying FE and passive FE because any mechanism that is proposed to explain them must be able to predict it.

背景与目标： ：众所周知，稳态等距肌肉力量在主动缩短（力量压迫，FD）后降低，而在主动伸展（力量增强，FE）后增加。还已经证明，主动拉伸（被动FE）后，被动肌肉的力量会增加。几项研究报告说，FD随着幅度的减小而增加，而FE和被动FE随拉伸幅度而增加。在这里，我们调查这些趋势是否继续缩短或拉伸幅度的进一步增加。使用原位猫的比目鱼肌进行实验（FD为n = 8； FE和被动FE为n = 7）。 FD，FE和被动FE是在收缩或拉伸收缩后测量的，收缩或拉伸收缩实际上覆盖了尽可能宽的幅度范围，而不会损坏肌肉。在所研究的整个振幅范围内，FD随振幅的减小而近似线性地增加。这与FD由应力诱导的跨桥抑制作用引起的假设相一致。 FE随拉伸幅度仅增加到一个点，然后趋于平稳。被动有限元，以及拉伸结束时力的瞬时增加，表明与拉伸幅度的关系在质量上与有限元的关系非常相似，仅在达到相同的临界拉伸幅度之前才增加。我们得出结论，在所有情况下，有限元和无源有限元都不会随拉伸幅度的增加而增加。这一发现对确定有限元和被动有限元的机制具有重要意义，因为提议用来解释它们的任何机制都必须能够对其进行预测。

BACKGROUND & AIMS: :Angiostensin II (Ang II) regulates the migration and proliferation of vascular smooth muscle cells. Recent studies indicate that intermediate-conductance Ca2+ -activated K+ (IKca) channels have an important role in cell migration and proliferation. It is not known, however, whether the action of Ang II is linked to IKca channel regulation. Here, we investigated the modulation of IKca channels by Ang II in artery smooth muscle cells. Functional IKca channel expression in cultured embryonic rat aorta smooth muscle (A10) cells was studied using the patch-clamp technique. These cells predominantly express IKca channels. In contrast, large-conductance Ca2+ -activated K+ (BKca) currents were rarely observed in excised patches. Ang II increased the IKca current in a contration-dependent manner. Losartan (1.0 microM), an AT1 selective antagonist, abolished the activation of IKca channels by Ang II. Pretreatment with 100 microM myristoylated protein kinase C inhibitor peptide 20-28 or 10 microM GF109203X completely abolished the AngII-induced activation of IKca currents, whereas the action of Ang II was not prevented in the presence of 100 microM Rp-cyclic 3', 5'-hydrogen phosphotiate adenosine triethylammonium, a protein kinase A inhibitor, or 1.0 microM KT-5823, a protein kinase G inhibitor. A membrane permeant analogue of diacylglycerol 1, 2-dioctanoyl-sn-glycerol (10 microM) induced the activation of IKca currents. These data suggest that Ang II activates IKca channels through the activation of protein kinase C, and the AT1 receptor is involved in the regulation of these channels.

背景与目标： ：血管紧张素II（Ang II）调节血管平滑肌细胞的迁移和增殖。最近的研究表明，中导Ca2激活的K（IKca）通道在细胞迁移和增殖中具有重要作用。但是，尚不清楚Ang II的作用是否与IKca通道调节有关。在这里，我们研究了血管平滑肌细胞中Ang II对IKca通道的调节作用。使用膜片钳技术研究了在培养的大鼠大鼠主动脉平滑肌（A10）细胞中功能性IKca通道的表达。这些细胞主要表达IKca通道。相反，在切除的斑块中很少观察到大电导的Ca2激活的K（BKca）电流。 Ang II以依赖冲突的方式增加了IKca电流。 Losartan（1.0 microM），一种AT1选择性拮抗剂，取消了Ang II对IKca通道的激活。用100 microM肉豆蔻酰化的蛋白激酶C抑制剂肽20-28或10 microM GF109203X进行的预处理完全消除了AngII诱导的IKca电流激活，而在存在100 microM Rp-环3'，5的情况下并未阻止Ang II的作用。 -磷酸磷酸氢腺苷三乙铵，一种蛋白激酶A抑制剂，或1.0 microM KT-5823，一种蛋白激酶G抑制剂。二酰基甘油1、2-二辛酰基-sn-甘油（10 microM）的膜渗透类似物诱导了IKca电流的激活。这些数据表明，Ang II通过蛋白激酶C的激活来激活IKca通道，而AT1受体参与了这些通道的调节。

BACKGROUND & AIMS: :Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.

背景与目标： ：胶质瘤是高度致死性的肿瘤，目前尚无法治愈。替莫唑胺是最近引入的烷基化剂，已在治疗高级神经胶质瘤中产生了显着的益处。然而，从头或获得性化学抗性经常发生，并且归因于O6-甲基鸟嘌呤-DNA甲基转移酶水平的增加或失配修复能力的丧失。但是，极少的神经胶质瘤过表达O6-甲基鸟嘌呤-DNA甲基转移酶或错配修复缺陷，提示其他机制可能与对替莫唑胺的抗性有关。本研究的目的是从人类神经胶质瘤细胞系（SNB-19）产生抗替莫唑胺的变体，并使用大规模的基因组和转录分析来研究获得的替莫唑胺抗性的分子基础。两个独立获得的替莫唑胺抗性变体对其他烷基化剂[1,3-双（2-氯乙基）-1-亚硝基脲和卡铂]无交叉抗性，并且共有遗传变异，例如2p区域丢失和扩增丢失染色体4和16q区域。核型改变与亲本SNB-19细胞系中先前存在的抗性细胞的克隆选择相容。基因芯片分析显示，在17,000个基因中，有78个在亲代细胞和两种替莫唑胺耐药变体之间差异表达。没有人参与已知的抗性机制，例如DNA修复，而有趣的是，参与分化的几个基因被下调。数据表明，在该模型中获得对替莫唑胺的抗药性是由于在亲本肿瘤中选择了分化程度较低的抗药性细胞而引起的。

BACKGROUND & AIMS: :The purpose of this study was to test the hypothesis that runners having different running economies show differences in the mechanical and morphological properties of their muscle-tendon units (MTU) in the lower extremities. Twenty eight long-distance runners (body mass: 76.8+/-6.7 kg, height: 182+/-6 cm, age: 28.1+/-4.5 years) participated in the study. The subjects ran on a treadmill at three velocities (3.0, 3.5 and 4.0 m s(-1)) for 15 min each. The V(O(2)) consumption was measured by spirometry. At all three examined velocities the kinematics of the left leg were captured whilst running on the treadmill using a high-speed digital video camera operating at 250 Hz. Furthermore the runners performed isometric maximal voluntary plantarflexion and knee extension contractions at eleven different MTU lengths with their left leg on a dynamometer. The distal aponeuroses of the gastrocnemius medialis (GM) and vastus lateralis (VL) were visualised by ultrasound during plantarflexion and knee extension, respectively. The morphological properties of the GM and VL (fascicle length, angle of pennation, and thickness) were determined at three different lengths for each MTU. A cluster analysis was used to classify the subjects into three groups according to their V(O(2)) consumption at all three velocities (high running economy, N=10; moderate running economy, N=12; low running economy, N=6). Neither the kinematic parameters nor the morphological properties of the GM and VL showed significant differences between groups. The most economical runners showed a higher contractile strength and a higher normalised tendon stiffness (relationship between tendon force and tendon strain) in the triceps surae MTU and a higher compliance of the quadriceps tendon and aponeurosis at low level tendon forces. It is suggested that at low level forces the more compliant quadriceps tendon and aponeurosis will increase the force potential of the muscle while running and therefore the volume of active muscle at a given force generation will decrease.

背景与目标： ：这项研究的目的是检验以下假设：具有不同运行经济状况的跑步者在下肢的肌腱单位（MTU）的机械和形态特性上存在差异。参加研究的有28名长跑运动员（体重：76.8 /-6.7公斤，身高：182 / -6厘米，年龄：28.1 /-4.5岁）。受试者分别以三种速度（3.0、3.5和4.0 m s（-1））在跑步机上跑步15分钟。 V（O（2））消耗量通过肺活量测定法进行测量。在所有三个检查的速度下，使用在250 Hz下运行的高速数码摄像机在跑步机上跑步时，捕获左腿的运动学信息。此外，跑步者在其左腿放在测力计上以11种不同的MTU长度进行等距最大自愿足底屈曲和膝盖伸展收缩。分别在足底屈曲和膝关节屈伸期间通过超声观察腓肠肌的远端腱膜（GM）和股外侧肌（VL）。对于每个MTU，在三种不同的长度下确定了GM和VL的形态学特性（纤维束长度，垂垂角度和厚度）。根据所有三个速度（高运行经济性，N = 10；中等运行经济性，N = 12；低运行经济性，N = 6）。 GM和VL的运动学参数和形态学特性均未显示组之间的显着差异。最经济的跑步者在肱三头肌MTU中表现出更高的收缩强度和更高的标准化肌腱刚度（肌腱力与肌腱应变之间的关系），在低水平的肌腱力下，股四头肌和腱膜的顺应性更高。建议在低水平的力量下，股四头肌和腱膜的顺应性会增加跑步时肌肉的力量，因此在给定的力量产生下，活跃肌肉的体积会减少。

BACKGROUND & AIMS: OBJECTIVE:The aim of the present investigation was to characterize the effects of supraphysiological doses of the anabolic androgenic steroid nandrolone decanoate (ND) on the fertility of female rats, as well as on the morphology of their uterus. STUDY DESIGN:Female Wistar rats (n=15) received a subcutaneous injection of ND (15 mg/kg) once daily during a 2-week period, while the control animals (n=10) were administered vehicle alone (arachidis oleum) in the same manner. Estrus behavior was evaluated 4 weeks after termination of this treatment and in cases where signs of receptivity were present, the female rat was given the opportunity to copulate with a male. After breeding, the female animals were sacrificed and their uteri examined histomorphologically. RESULTS:All ND-treated animals exhibited abnormal vaginal smears, whereas all of the control smears were normal. Most (73%) of the treated females demonstrated normal estrus behavior (i.e., willingness) on the day of mating, but none got pregnant; whereas all of the control rats became pregnant. The female rats receiving the ND showed an enhanced rate of weight gain and the myometrium thickness of their uteri was significantly increased, while the endometrium was significantly thinner. Furthermore, ND caused a significant proportion of the treated animals to display tortuous and irregularly branching endometrial glands, as well as a lack of the physiologically normal infiltration of eosinophilic leukocytes into the endometrium (endometrial eosinophilic homing), a finding that has not been reported previously. CONCLUSION:The present findings indicate that high doses of ND cause morphological and physiological alterations in the uterus of female rats that are associated with a suppression of their reproductive capacity.

背景与目标： 目的：本研究的目的是表征同化雄性类固醇癸酸nandrolone癸酸酯的超生理剂量对雌性大鼠生育能力以及子宫形态的影响。
研究设计：Wistar雌性大鼠（n = 15）在2周内每天一次皮下注射ND（15 mg / kg），而对照组（n = 10）单独给予媒介物（花生油）。同样的方式。终止该治疗4周后评估发情行为，并且在出现接受迹象的情况下，给予雌性大鼠与雄性交配的机会。繁殖后，将雌性动物处死并对其子宫进行组织形态学检查。
结果：所有接受ND治疗的动物均表现出异常的阴道涂片，而所有对照涂片均正常。接受治疗的大多数女性（73％）在交配当天表现出正常的发情行为（即意愿），但没有人怀孕；而所有对照大鼠都怀孕了。接受ND的雌性大鼠体重增加率增加，子宫肌层厚度明显增加，而子宫内膜明显变薄。此外，ND导致相当一部分被治疗的动物表现出曲折和不规则分支的子宫内膜腺体，并且缺乏正常的嗜酸性白细胞进入子宫内膜的生理正常浸润（子宫内膜嗜酸性归巢），这一发现以前未见报道。 。
结论：本研究结果表明，高剂量的ND可导致雌性大鼠子宫形态和生理改变，从而抑制其生殖能力。

BACKGROUND & AIMS: Epoxyeicosatrienoic acids (EETs) are endothelium-derived arachidonic acid metabolites of cytochrome P450. They dilate coronary arteries, open K+ channels, and hyperpolarize vascular smooth muscles. However, the mechanisms of these smooth muscle actions remain unknown. This study examined the effects of EETs on the large-conductance Ca(2+)-activated K+ channel (KCa) in smooth muscle cells of small bovine coronary arteries. In cell-attached patch-clamp experiments, 11,12-EET produced a 0.5- to 10-fold increase in the activity of the KCa channels when added in concentrations of 1, 10, and 100 nmol/L. In the inside-out excised membrane patch mode, 11,12-EET was without effect on the activity of the KCa channel unless GTP (0.5 mmol/L) or GTP and ATP (1 mmol/L) were added to the bath solution. In the presence of GTP and ATP, the increase in the KCa channel activity with 11,12-EET in inside-out patches was comparable to that in cell-attached patches. This effect of 11,12-EET in inside-out patches was blocked by the addition of GDP-beta-S (100 mumol/L). In outside-out patches, 11,12-EET also increased the KCa channel activity when GTP and ATP were added to the pipette solution. The addition of a specific anti-Gs alpha antibody (100 nmol/L) in the pipette solution completely blocked the activation of the KCa channels induced by 11,12-EET. An anti-G beta gamma or anti-Gi alpha antibody was without effect. We conclude that 11,12-EET activates the KCa channels by a Gs alpha-mediated mechanism. This mechanism contributes to the effects of EETs as endothelium-derived hyperpolarizing factors to hyperpolarize and relax arterial smooth muscle.

背景与目标： 环氧二十碳三烯酸（EET）是内皮细胞色素P450的花生四烯酸代谢产物。它们扩张冠状动脉，打开K通道，并使血管平滑肌超极化。但是，这些平滑肌动作的机制仍然未知。这项研究检查了EETs对小牛冠状动脉平滑肌细胞中大电导Ca（2）激活的K通道（KCa）的影响。在贴有细胞的膜片钳实验中，当以1、10和100 nmol / L的浓度添加时，11,12-EET使KCa通道的活性增加0.5至10倍。在由内而外的切膜模式下，除非将GTP（0.5 mmol / L）或GTP和ATP（1 mmol / L）添加到浴液中，否则11,12-EET对KCa通道的活性没有影响。在存在GTP和ATP的情况下，由内而外的贴片中11,12-EET的KCa通道活性的增加与细胞附着的贴片中的KCa通道活性的增加相当。通过添加GDP-β-S（100 mumol / L），阻止了由内而外的11,12-EET的这种作用。在外向斑块中，将GTP和ATP添加到移液器中时，11,12-EET也增加了KCa通道活性。在移液器中添加特异性抗Gsα抗体（100 nmol / L）完全阻断了11,12-EET诱导的KCa通道的激活。抗Gβγ或抗Giα抗体无效。我们得出的结论是11,12-EET通过Gs alpha介导的机制激活了KCa通道。这种机制有助于将EETs作为内皮源的超极化因子来使动脉平滑肌超极化和松弛。

BACKGROUND & AIMS: :The distinction between ectopic hamartomatous thymoma and sarcoma is difficult, and preoperative biopsy and intraoperative histopathological examination fail to give a definitive diagnosis. It is important to recognise ectopic hamartomatous thymoma as one of the differential diagnoses of a cervical tumour.

背景与目标： ：异位错构瘤性胸腺瘤和肉瘤之间的区别很困难，术前活检和术中组织病理学检查不能做出明确的诊断。重要的是要认识到异位错构瘤性胸腺瘤是宫颈肿瘤的鉴别诊断之一。

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。我们建立在我们的体外VEGF同工型和受体酪氨酸激酶（VEGFR-1和VEGFR-2）和非信号神经pilin-1共受体之间的生化相互作用的验证模型的基础上。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。

BACKGROUND & AIMS: :Insulin resistance affecting skeletal muscle metabolism is present in the prehypertensive state. The aim of our study was to test the hypothesis that blood pressure value is related to skeletal muscle composition, measured by (31)P magnetic resonance (MR) spectroscopy, and to insulin sensitivity in the offspring of hypertensive parents (OH) and healthy controls. Study groups consisted of 10 healthy young lean OH with normal glucose tolerance, confirmed with oral glucose tolerance test, and 13 controls matched for age, sex, and body mass index. Insulin action was estimated as glucose disposal (M), glucose metabolic clearance rate (MCR), and insulin sensitivity index (M/I) during a 10-hour hyperinsulinemic euglycemic clamp. The sum of immunoreactive insulin values from the oral glucose tolerance test was calculated. (31)P MR spectroscopy was performed on a whole-body MR scanner (Siemens Vision, Erlangen, Germany) operating at 1.5 T and equipped with actively shielded gradient coils. There were no differences in common metabolic and anthropometric parameters between OH and controls except for the blood pressure, which was in the range of normal to high-normal level in OH. Mean blood pressure was significantly higher in OH (95.73 +/- 4.39 vs 83.76 +/- 3.95 mm Hg; P < .001). Trend toward insulin resistance was registered in OH with significantly lower M/I (0.74 +/- 0.47 vs 1.42 +/- 0.65 mg x kg(-1) x min(-1) x mIU(-1) x L(-1); P < .05). There were no significant differences in total serum magnesium (sMg) levels between OH and controls, although a positive correlation exists between sMg and insulin sensitivity expressed as M (r = 0.63, P < .01), MCR (r = 0.54, P < .01), and M/I (r = 0.51, P < .05). No differences in signal intensities of phosphocreatine (PCr), phosphomonoesters, phosphodiesters, inorganic phosphates (Pi), adenosine triphosphates (Patp and betaATP), and calculated concentrations of intracellular ionized magnesium (Mgi) and H(+) ions between the groups were detected. Systolic blood pressure correlates positively with PCr/Patp (r = 0.43, P < .05), Pi/Patp (r = 0.413, P < .05), and Pi/betaATP (r = 0.48, P < .05). Diastolic blood pressure correlates positively only with the ratio Pi/betaATP (r = 0.42, P < .05). The sum of immunoreactive insulin values correlates with PCr/betaATP (r = 0.53, P < .01) and with Pi/betaATP (r = 0.6, P < .01). In conclusion, increase in blood pressure and insulin resistance were confirmed in offspring of OH. Insulin sensitivity is related to sMg and the elevation of blood pressure is associated with the activation of energy metabolism in skeletal muscle. The relationship between muscle energetic characteristics and markers of insulin resistance suggests that the alteration of energy metabolism may be present in early stages of metabolic syndrome.

背景与目标： ：在高血压前状态下，会影响骨骼肌新陈代谢的胰岛素抵抗。我们研究的目的是检验以下假设：血压值与通过（31）P磁共振（MR）光谱法测量的骨骼肌成分以及高血压父母（OH）和健康对照的后代的胰岛素敏感性有关。研究组包括10名健康正常的年轻瘦肉OH，其葡萄糖耐量正常，经口服葡萄糖耐量试验确认，另有13个对照的年龄，性别和体重指数匹配。在10小时高胰岛素正常血糖钳制期间，胰岛素作用估计为葡萄糖处置（M），葡萄糖代谢清除率（MCR）和胰岛素敏感性指数（M / I）。计算来自口服葡萄糖耐量试验的免疫反应性胰岛素值的总和。 （31）P MR光谱是在全身MR扫描仪（Siemens Vision，Erlangen，德国）上以1.5 T操作并配备有源屏蔽梯度线圈进行的。 OH和对照组之间的共同代谢和人体测量学参数没有差异，除了血压处于OH正常水平到高正常水平的范围之内。 OH中的平均血压显着升高（95.73 /-4.39与83.76 /-3.95 mm Hg； P <.001）。在OH中出现胰岛素抵抗的趋势，M / I显着降低（0.74 /-0.47对1.42 /-0.65 mg x kg（-1）x min（-1）x mIU（-1）x L（-1）; P <.05）。尽管sMg与胰岛素敏感性之间呈正相关，以M（r = 0.63，P <.01），MCR（r = 0.54，P < .01）和M / I（r = 0.51，P <.05）。两组之间没有发现磷酸肌酸（PCr），磷酸单酯，磷酸二酯，无机磷酸盐（Pi），三磷酸腺苷（Patp和betaATP）的信号强度差异以及计算出的细胞内离子化镁（Mgi）和H（）离子浓度。收缩压与PCr / Patp（r = 0.43，P <.05），Pi / Patp（r = 0.413，P <.05）和Pi / betaATP（r = 0.48，P <.05）正相关。舒张压仅与Pi / betaATP比率呈正相关（r = 0.42，P <.05）。免疫反应性胰岛素值的总和与PCr / betaATP（r = 0.53，P <.01）和Pi / betaATP（r = 0.6，P <.01）相关。总之，在OH的后代中证实了血压升高和胰岛素抵抗。胰岛素敏感性与sMg有关，而血压升高与骨骼肌能量代谢的激活有关。肌肉能量特性与胰岛素抵抗标志物之间的关系表明，能量代谢的改变可能在代谢综合征的早期出现。

BACKGROUND & AIMS: :Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development and metabolism of nearly all vertebrate tissues. In skeletal muscle, TH plays a critical role in regulating the function of satellite cells, the bona fide skeletal muscle stem cells. Deiodinases (D2 and D3) have been found to modulate the expression of various TH target genes in satellite cells. Regulation of the expression and activity of the deiodinases constitutes a cell-autonomous, pre-receptor mechanism that controls crucial steps during the various phases of myogenesis. Here, we review the roles of deiodinases in skeletal muscle stem cells, particularly in muscle homeostasis and upon regeneration. We focus on the role of T3 in stem cell functions and in commitment towards lineage progression. We also discuss how deiodinases might be therapeutically exploited to improve satellite-cell-mediated muscle repair in skeletal muscle disorders or injury.

背景与目标： 甲状腺激素（TH）调节至关重要的生物学功能，例如几乎所有脊椎动物组织的正常生长，发育和代谢。在骨骼肌中，TH在调节卫星细胞（真正的骨骼肌干细胞）的功能中起着至关重要的作用。已发现脱碘酶（D2和D3）可调节卫星细胞中各种TH靶基因的表达。脱碘酶的表达和活性的调节构成了细胞自主的前受体机制，该机制在肌生成的各个阶段中控制关键步骤。在这里，我们回顾了脱碘酶在骨骼肌干细胞中的作用，特别是在肌肉稳态和再生中。我们专注于T3在干细胞功能中的作用以及对谱系进展的承诺。我们还将讨论如何在骨骼肌疾病或损伤中治疗性利用脱碘酶来改善卫星细胞介导的肌肉修复。