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： 摘要背景：吸入性糖皮质激素（ICS）和长效β2-激动剂（LABA）的结合被治疗指南推荐用于持续性哮喘的治疗。两种这样的组合产品，沙美特罗/丙酸氟替卡松（SFC，英国Seretide GSK）和福莫特罗/布地奈德（FBC，Symbicort，阿斯利康，英国）可商购。
目的：这些研究的目的是评估和比较两种组合产品在单剂给药后直至24小时的支气管扩张持续时间。
方法：进行了两项随机，双盲，安慰剂对照，交叉研究。研究A在接受400-1200 mcg布地奈德或同等剂量的33位哮喘成人中进行。在24小时内测量一秒钟的连续呼气量（FEV1），以确定SFC（50/100 mcg）和FBC（4.5 / 160 mcg）的作用持续时间。研究B是在75名接受800-1200 mcg布地奈德或同等水平的哮喘成年人中进行的，包括4周400 mcg bd的Becotide磨合，然后用SFC 50/100 mcg bd或FBC 4.5 / 160 mcg bd进行4周治疗以交叉方式拍摄。在每4周治疗期后的第一剂和最后一剂之后，测量连续的24小时FEV1，以确定每种治疗的作用抵消。
结果：在研究A中，单次吸入SFC和FBC在16小时产生了持续的支气管扩张作用，与SFC和0.25 L（95 FBC的％CI 0.21、0.37 L），均显着高于两种治疗的安慰剂（-0.05 L； p <0.001）。在研究B中，从剂量后2-24小时开始，FEV1的下降斜率对于SFC为-16.0 ml / hr，对于FBC为-14.2 ml / hr。在24小时内，加权平均AUC为0.21 Lxmin和0.22 Lxmin，对于SFC，从剂量前FEV1到12小时的平均变化分别为0.21 Lx和FBC 0.20 L
结论：SFC和FBC均产生相似的持续支气管扩张药作用，给药后延长至12小时以上，并且在24 h时明显可测量。

BACKGROUND & AIMS: :Go/Gi coupled G-protein receptor mediated transactivation is critical in the activation of receptor tyrosine kinases (RTK). Here we show that mu opioid receptor (MOR) transactivates Flk1 and platelet-derived growth factor-beta (PDGF-beta) receptors and its agonist morphine stimulates pro-angiogenic and survival-promoting signaling in mouse retinal endothelial cells (mREC). Morphine stimulates mREC proliferation in a dose dependent fashion and promotes survival to the same extent as vascular endothelial growth factor164 (VEGF164). Morphine stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt phosphorylation in a time dependent manner like VEGF in mREC. Moreover, analogous to VEGF, morphine stimulates oncogenic signal transducer and activator of transcription 3 (STAT3) signaling. Morphine as well as VEGF-induced phospho-STAT3 and phospho-Flk1 immunoprecipitated with MOR-associated proteins. In addition morphine also stimulated MOR associated PDGF-beta receptor phosphorylation. Consistent with the relationship between VEGF and MOR we found that VEGF upregulates MOR protein and RNA expression in mREC. These data suggest that MOR associates and transactivates RTKs for Flk1 and PDGF-beta, which may have a compounding effect on angiogenic signaling in endothelium. Therefore, G-Protein coupled receptors including MOR provide novel targets to develop anti-angiogenic agents.

背景与目标： ：Go / Gi偶联的G蛋白受体介导的反式激活在受体酪氨酸激酶（RTK）的激活中至关重要。在这里，我们显示mu阿片类受体（MOR）激活Flk1和血小板衍生的生长因子-β（PDGF-β）受体，其激动剂吗啡刺激小鼠视网膜内皮细胞（mREC）促血管生成和促进生存的信号传导。吗啡以剂量依赖性方式刺激mREC增殖，并以与血管内皮生长因子164（VEGF164）相同的程度促进存活。吗啡像mREC中的VEGF一样，以时间依赖性方式刺激促分裂原活化的蛋白激酶/细胞外信号调节激酶（MAPK / ERK）和Akt磷酸化。此外，类似于VEGF，吗啡刺激致癌信号转导子和转录激活子3（STAT3）信号转导。吗啡以及VEGF诱导的磷酸化STAT3和磷酸化Flk1被MOR相关蛋白免疫沉淀。此外，吗啡还刺激了MOR相关的PDGF-β受体的磷酸化。与VEGF和MOR之间的关系一致，我们发现VEGF上调mREC中的MOR蛋白和RNA表达。这些数据表明，MOR与Flk1和PDGF-beta的RTK缔合并反激活，这可能对内皮中的血管生成信号具有复合作用。因此，包括MOR在内的G蛋白偶联受体为开发抗血管生成剂提供了新的靶标。

BACKGROUND & AIMS: :Cyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

背景与目标： ：循环性和先天性嗜中性白血球减少症是由人类嗜中性粒细胞弹性蛋白酶（HNE）基因（ELA2）突变引起的，导致免疫缺陷，其特征是血液中嗜中性粒细胞水平降低或振荡。 HNE突变可能导致酶活性下降，因此导致免疫系统功能受损。为了了解该疾病的结构基础，我们采用了生物信息学的方法来分析序列和结构水平上所有已知的HNE错义突变。我们的结果表明，这32种不同的突变对HNE的结构和功能具有多种影响，影响结构异常和聚集趋势，保持接触的稳定性以及静电性质。大部分突变位于保守氨基酸上，这通常是决定蛋白质结构和功能所必需的。大多数引起疾病的HNE错义突变会导致主要的结构变化和蛋白质稳定性的损失。一些突变也影响功能残基，导致催化活性降低或配体结合改变。我们的分析揭示了HNE中所有已知的错义突变的推定作用，因此可以阐明周期性和先天性中性粒细胞减少的结构基础。我们已经采用并分析了一组约30种不同的方法来预测氨基酸取代的影响。我们通过分析这些方法在分析众多基因，蛋白质和疾病中的适用性来提供结果和经验，以揭示蛋白质结构与功能的关系以及疾病的基因型与表型的相关性。

BACKGROUND & AIMS: :Different attempts were made to identify the variables that may be involved in the clinical course of cerebrovascular ischemia. In the case of stroke with mild severity (SMS), the clinical significance of neuroendocrine changes as well as of post-stroke depression (PSD) remains unknown. We therefore evaluated the presence of neuroendocrine changes in the acute and post-acute phase of SMS, and their potential role during convalescence. Serum cortisol, T4, T3, FT4, FT3, TSH and PRL levels were measured in 17 euthyroid patients with stroke on admission (day 1), following morning (day 2), 7 days and 3 months later. TSH and PRL secretion after TRH test were measured. Stroke severity on admission was determined by Scandinavian Stroke Scale (SSS). Montgomery-Asberg Depression Rating Scale (Madrs) was used for assessment of post-stroke depression. On admission, TSH and T3, were within normal limits and were greater compared to values on day 2. Lower basal TSH and decreased TSH response to TRH on day 2, were associated with stroke of greater severity. Delta-PRL after TRH on day 2 was higher in patients who develop PSD. Changes in serum thyroid hormones in SMS, reflects those of non-thyroidal illness. A mild stimulation of hypothalamic-pituitary-adrenal axis was detected. We provide evidence that PRL response to TRH, in the acute phase of stroke may be used as an index for early detection of PSD.

背景与目标： ：进行了不同的尝试来确定可能与脑血管缺血的临床过程有关的变量。对于轻度中风（SMS）的中风，神经内分泌变化以及中风后抑郁症（PSD）的临床意义仍然未知。因此，我们评估了SMS急性期和急性期后神经内分泌变化的存在及其在恢复期的潜在作用。在入院时（第1天），早晨（第2天），第7天和3个月后的17例中风的甲状腺功能正常的甲状腺疾病患者中测量了血清皮质醇，T4，T3，FT4，FT3，TSH和PRL的水平。测量TRH试验后的TSH和PRL分泌。入院时卒中严重程度由斯堪的纳维亚卒中量表（SSS）确定。使用蒙哥马利-阿斯伯格抑郁量表（Madrs）评估中风后抑郁。入院时，TSH和T3在正常范围之内，并且比第2天的值高。在第2天，较低的基础TSH和对TRH的TSH反应降低与严重程度更高的卒中相关。发生PSD的患者在TRH后第2天的Delta-PRL较高。 SMS中血清甲状腺激素的变化反映了非甲状腺疾病的变化。下丘脑-垂体-肾上腺轴受到轻度刺激。我们提供的证据表明，在卒中的急性期PRL对TRH的反应可用作早期检测PSD的指标。

BACKGROUND & AIMS: :Over the past decade, the old idea that the bone marrow contains endothelial cell precursors has become an area of renewed interest. While some still believe that there are no endothelial precursors in the blood, even among those who do, there is no consensus as to what they are or what they do. In this review, we describe the problems in identifying endothelial cells and conclude that expression of endothelial nitric oxide synthase may be the most reliable antigenic indicator of the phenotype. The evidence for two different classes of endothelial precursors is also presented. We suggest that, though there is no single endothelial cell precursor, we may be able to use these phenotypic variations to our advantage in better understanding their biology. We also discuss how a variety of genetic, epigenetic, and methodological differences can account for the seemingly contradictory findings on the physiological relevance of bone marrow-derived precursors in normal vascular maintenance and in response to injury. Data on the impact of tumor type and location on the contribution of bone marrow-derived cells to the tumor vasculature are also presented. These data provide hope that we may ultimately be able to predict those tumors in which bone marrow-derived cells will have a significant contribution and design therapies accordingly. Finally, factors that regulate bone marrow cell recruitment to and function in the endothelium are beginning to be identified, and several of these, including stromal derived factor 1, monocyte chemoattractant factor-1, and vascular endothelial growth factor are discussed.

背景与目标： ：在过去的十年中，关于骨髓中含有内皮细胞前体的古老观念已经引起人们的广泛关注。尽管有些人仍然认为血液中没有内皮前体，即使在有血液的人中也没有，但是关于它们是什么或它们的行为尚无共识。在这篇综述中，我们描述了鉴定内皮细胞的问题，并得出结论，内皮一氧化氮合酶的表达可能是最可靠的表型抗原指示剂。还提供了两种不同类别的内皮前体的证据。我们建议，尽管没有单个内皮细胞前体，但我们也许能够利用这些表型变异来更好地了解它们的生物学特性。我们还将讨论各种遗传，表观遗传学和方法学上的差异如何解释在正常血管维持和对损伤的反应中，骨髓来源的前体的生理相关性看似矛盾的发现。还提供了有关肿瘤类型和位置对骨髓衍生细胞对肿瘤脉管系统的影响的数据。这些数据提供了希望，使我们最终能够预测那些骨髓来源的细胞将发挥重要作用的肿瘤，并据此设计治疗方法。最后，已开始确定调节骨髓细胞向内皮募集并在内皮中起作用的因子，并讨论了其中的几种，包括基质衍生因子1，单核细胞趋化因子-1和血管内皮生长因子。

BACKGROUND & AIMS: OBJECTIVE:To compare prostate carcinoma, with and with no lymph node metastasis, to benign prostatic hyperplasia (BPH) tissue for lymphatic vessel density (LVD) and the expression of the lymph-endothelial specific growth factor, vascular endothelial growth factor C (VEGF-C), to determine their role in lymphogenic metastasis. PATIENTS, MATERIALS AND METHODS:Lymphatic vessels were stained using lymphatic vessel endothelial hyaluronan receptor 1 and assessed in standard areas. The expression of VEGF-C was assessed by the number of positive epithelial cells. The data were compared with the clinical staging. RESULTS:The lowest LVD was found in tumorous areas as opposed to periphery and nontumorous tissue (P = 0.007; P < 0.001). The highest LVD was in BPH tissue (P < 0.001). There was no correlation with clinical staging. There was more VEGF-C staining in pN1 than in pN0 and in BPH specimens (P = 0.002). CONCLUSION:LVD is not a prognostic variable for the process of lymphogenic metastasis in prostate cancer. VEGF-C is up-regulated in prostate cancer and its correlation with lymph node status suggests a role for the development of lymph node metastasis, e.g. via an increased permeability of lymphatic vessels.

背景与目标： 目的：比较有无淋巴结转移的前列腺癌与良性前列腺增生（BPH）组织的淋巴管密度（LVD）以及淋巴内皮特异性生长因子，血管内皮生长因子C（VEGF- C），确定其在淋巴转移中的作用。
患者，材料和方法：使用淋巴管内皮透明质酸受体1对淋巴管进行染色，并在标准区域进行评估。通过阳性上皮细胞的数量评估VEGF-C的表达。将数据与临床分期进行比较。
结果：与周围和非肿瘤组织相比，在肿瘤区域发现的LVD最低（P = 0.007； P <0.001）。 LVD最高的是BPH组织（P <0.001）。与临床分期无关。 pN1和BPH标本中的VEGF-C染色要多于pN0和PPH（P = 0.002）。
结论：LVD不是前列腺癌淋巴转移的预后变量。 VEGF-C在前列腺癌中被上调，并且其与淋巴结状态的相关性暗示了淋巴结转移的发展，例如肝癌的发生。通过增加淋巴管的通透性

BACKGROUND & AIMS: :Polo-like kinases (PLKs) are marked by C-terminal polo box modules with critical protein interaction and subcellular targeting roles. Slevin et al. in this issue of Structure reveal the architecture of a hidden set of polo boxes from the divergent PLK4, a critical player in centrosome duplication, shedding new light on the evolution of PLKs and their functionally related kinase ZYG-1.

背景与目标： ：Polo样激酶（PLKs）的C末端polo盒模块具有关键的蛋白质相互作用和亚细胞靶向作用。 Slevin等在本期《结构》中，我们揭示了来自不同PLK4的一组隐藏的马球盒的结构，PLK4是质体复制的关键角色，为PLK及其功能相关激酶ZYG-1的进化提供了新的思路。

BACKGROUND & AIMS: :We reviewed six cases of primary sarcomas requiring scapulectomy within the past 13 years in the Surgery Branch of the National Cancer Institute, Bethesda, Md. Five of these patients returned for evaluation of disease status, evaluation of functional defects as determined by muscle group testing, and assessment of daily living skills and limitations. We demonstrated excellent shoulder function with partial scapulectomy and significant impairment with the additional loss of the glenoid fossa. In addition, we developed a thorough method of postoperative evaluation. Involvement of rehabilitation therapists before and after operatively is integral to this process in preparation for surgery and subsequent treatment.

背景与目标： ：我们在美国马里兰州贝塞斯达的国家癌症研究所外科分院回顾了过去13年中需要进行肩ectomy骨切除术的6例原发性肉瘤。其中5例患者返回进行了疾病状态评估，通过肌肉群测试确定了功能缺陷，并评估日常生活技能和局限性。我们证实了部分肩cap骨切除术具有出色的肩部功能，并且由于关节盂窝的丢失而导致了明显的损伤。此外，我们开发了一种彻底的术后评估方法。手术前后，康复治疗师的参与是此过程不可或缺的准备手术和后续治疗的过程。

BACKGROUND & AIMS: :Musical training has emerged as a useful framework for the investigation of training-related plasticity in the human brain. Learning to play an instrument is a highly complex task that involves the interaction of several modalities and higher-order cognitive functions and that results in behavioral, structural, and functional changes on time scales ranging from days to years. While early work focused on comparison of musical experts and novices, more recently an increasing number of controlled training studies provide clear experimental evidence for training effects. Here, we review research investigating brain plasticity induced by musical training, highlight common patterns and possible underlying mechanisms of such plasticity, and integrate these studies with findings and models for mechanisms of plasticity in other domains.

背景与目标： ：音乐训练已成为研究人脑与训练有关的可塑性的有用框架。学习演奏乐器是一项高度复杂的任务，涉及多种模式和高阶认知功能的相互作用，并导致行为，结构和功能发生变化，时间范围从数天到数年不等。早期的工作着重于音乐专家和新手之间的比较，而最近，越来越多的受控训练研究为训练效果提供了明确的实验证据。在这里，我们回顾了研究由音乐训练引起的大脑可塑性的研究，突出了这种可塑性的常见模式和可能的潜在机制，并将这些研究与其他领域的可塑性机制的发现和模型相结合。

BACKGROUND & AIMS: :Flavohemoglobins (FHbs) are members of the globin superfamily, widely distributed among prokaryotes and eukaryotes that have been shown to carry out nitric oxide dioxygenase (NOD) activity. In prokaryotes, such as Escherichia coli, NOD activity is a defence mechanism against the NO release by the macrophages of the hosts' immune system during infection. Because of that, FHbs have been studied thoroughly and several drugs have been developed in an effort to fight infectious processes. Nevertheless, the protein's structural determinants involved in the NOD activity are still poorly understood. In this context, the aim of the present work is to unravel the molecular basis of FHbs structural dynamics-to-function relationship using state of the art computer simulation tools. In an effort to fulfill this goal, we studied three key processes that determine NOD activity, namely i) ligand migration into the active site ii) stabilization of the coordinated oxygen and iii) intra-protein electron transfer (ET). Our results allowed us to determine key factors related to all three processes like the presence of a long hydrophobic tunnel for ligand migration, the presence of a water mediated hydrogen bond to stabilize the coordinated oxygen and therefore achieve a high affinity, and the best possible ET paths between the FAD and the heme, where water molecules play an important role. Taken together the presented results close an important gap in our understanding of the wide and diverse globin structural-functional relationships.

背景与目标： 黄素血球蛋白（FHbs）是球蛋白超家族的成员，广泛分布于原核生物和真核生物之间，已被证明具有一氧化氮双加氧酶（NOD）活性。在诸如大肠杆菌的原核生物中，NOD活性是抵抗宿主免疫系统巨噬细胞在感染过程中释放NO的防御机制。因此，已经对FHb进行了深入研究，并开发了几种药物来对抗感染过程。然而，仍不清楚对涉及NOD活性的蛋白质的结构决定因素。在这种情况下，本工作的目的是使用最先进的计算机模拟工具来揭示FHbs结构动力学与功能关系的分子基础。为了实现这一目标，我们研究了确定NOD活性的三个关键过程，即i）配体迁移到活性位点ii）配位氧的稳定化和iii）蛋白质内电子转移（ET）。我们的结果使我们能够确定与所有三个过程相关的关键因素，例如存在长的疏水性配体迁移隧道，存在水介导的氢键以稳定配位的氧并因此实现高亲和力以及最佳的ET FAD和血红素之间的通道，其中水分子起着重要作用。综上所述，所提出的结果弥合了我们对广泛而多样的球蛋白结构-功能关系的理解中的一个重要空白。

BACKGROUND & AIMS: BACKGROUND:Choline is essential for fetal brain development, and it is not known whether a typical American diet contains enough choline to ensure optimal brain development. OBJECTIVE:The study was undertaken to determine whether supplementing pregnant women with phosphatidylcholine (the main dietary source of choline) improves the cognitive abilities of their offspring. DESIGN:In a double-blind, randomized controlled trial, 140 pregnant women were randomly assigned to receive supplemental phosphatidylcholine (750 mg) or a placebo (corn oil) from 18 wk gestation through 90 d postpartum. Their infants (n = 99) were tested for short-term visuospatial memory, long-term episodic memory, language development, and global development at 10 and 12 mo of age. RESULTS:The women studied ate diets that delivered ∼360 mg choline/d in foods (∼80% of the recommended intake for pregnant women, 65% of the recommended intake for lactating women). The phosphatidylcholine supplements were well tolerated. Groups did not differ significantly in global development, language development, short-term visuospatial memory, or long-term episodic memory. CONCLUSIONS:Phosphatidylcholine supplementation of pregnant women eating diets containing moderate amounts of choline did not enhance their infants' brain function. It is possible that a longer follow-up period would reveal late-emerging effects. Moreover, future studies should determine whether supplementing mothers eating diets much lower in choline content, such as those consumed in several low-income countries, would enhance infant brain development.

背景与目标： 背景：胆碱对胎儿的大脑发育至关重要，目前尚不清楚典型的美国饮食中是否含有足够的胆碱以确保最佳的大脑发育。
目的：本研究旨在确定孕妇补充磷脂酰胆碱（胆碱的主要饮食来源）是否能改善其后代的认知能力。
设计：在一项双盲，随机对照试验中，从怀孕18周到产后90天，随机分配了140名孕妇接受补充磷脂酰胆碱（750毫克）或安慰剂（玉米油）。他们的婴儿（n = 99）在10和12个月大时接受了短期视觉空间记忆，长期情境记忆，语言发展和整体发展的测试。
结果：这些妇女所研究的饮食中食物中的胆碱/日摄入量约为360毫克/天（孕妇的推荐摄入量约为80％，哺乳期妇女的推荐摄入量约为65％）。磷脂酰胆碱补充剂的耐受性良好。在全球发展，语言发展，短期视觉空间记忆或长期情境记忆方面，各组没有显着差异。
结论：孕妇食用含适量胆碱饮食的磷脂酰胆碱不能增强婴儿的脑功能。较长的随访期可能会显示出较晚出现的影响。此外，未来的研究应确定补充食用胆碱含量低得多的饮食的母亲（如在几个低收入国家食用的饮食）是否会增强婴儿的大脑发育。

BACKGROUND & AIMS: :Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes.

背景与目标： ：生精是一个动态过程，受生殖细胞和支持细胞之间的粘附相互作用调节。生殖细胞表达连接黏附分子-C（JAM-C，由Jam3编码），其位于细菌/ Sertoli细胞接触处。 JAM-C与生殖细胞极性和顶体形成有关。使用蛋白质组学方法，我们证明了JAM-C与发育中的生殖细胞中55 kDa的高尔基体重组堆积蛋白（GRASP55，由Gorasp2编码）相互作用。 Gorasp2-/-小鼠的产生和研究表明，基因敲除小鼠患有精子发生缺陷。在Gorasp2-/-小鼠中，精子中顶体的形成和JAM-C的极化定位发生了改变。另外，在Gorasp2-/-小鼠中，精子细胞的高尔基体形态受到干扰。与JAM-C或JAM-B配合的GRASP55的晶体结构表明，GRASP55通过PDZ介导的与JAMs的相互作用而相互作用，并导致GRASP55的构象变化。一种计算机上药效团方法鉴定出一种名为Graspin的化合物，该化合物可抑制PDZ介导的GRASP55与JAM的相互作用。用Graspin处理小鼠会阻碍JAM-C在精子细胞中的极化定位，诱导精子的过早释放，并影响减数分裂精细胞的高尔基形态。

BACKGROUND & AIMS: :The objective of the study was to evaluate the association between peripheral venous disease (PVD) and arterial endothelial dysfunction (ED). Arterial and venous diseases have been always considered as two completely different entities, but the recent discovery of a relationship between arterial and venous thrombosis have challenged this assumption. ED, considered to be an early process in the pathophysiology of atherosclerotic disease, could represent a common pathogenetic background. We studied 39 healthy volunteers (median age: 34 years; men: 25.6%). PVD was diagnosed using ultrasound examination, arterial ED using flow-mediated dilation (FMD) and FMD normalized for the peak shear rate (nFMD). Compared with controls, participants with PVD had a lower FMD (15.2 versus 23.4%, P < 0.001) and nFMD (12.7 × 10(-3) versus 19 × 10(-3)/second, P < 0.001). People with the most clinically evident disease had the worst endothelial function. In conclusion, our findings, if confirmed in larger population, might corroborate the idea that venous and arterial disease could have common causes.

背景与目标： ：该研究的目的是评估周围静脉疾病（PVD）与动脉内皮功能障碍（ED）之间的关联。动脉和静脉疾病一直被认为是两个完全不同的实体，但是最近发现动脉和静脉血栓形成之间的关系挑战了这一假设。 ED被认为是动脉粥样硬化疾病病理生理的早期过程，可能代表了常见的致病背景。我们研究了39名健康志愿者（中位年龄：34岁；男性：25.6％）。使用超声检查诊断PVD，使用流介导的扩张（FMD）诊断动脉ED，并针对峰剪切速率（nFMD）归一化FMD。与对照组相比，PVD参与者的FMD较低（15.2比23.4％，P <0.001）和nFMD（12.7×10（-3）/ 19×10（-3）/秒，P <0.001）。临床上最明显的疾病的人的内皮功能最差。总之，我们的发现，如果在更大的人群中得到证实，可能证实静脉和动脉疾病可能是常见原因的观点。

BACKGROUND & AIMS: PURPOSE:The issue of unidentified volume expansion is well recognized as a cause for resistance to antihypertensive therapy. The aim of study is to identify contribution of negative fluid balance to hypertension control and impact on endothelial and cardiac functions among primary hypertensive patients who do not have kidney failure. MATERIALS AND METHODS:This is a prospective interventional study with one-year follow-up. Preceded by volume status measurements were performed by a body composition monitor (BCM), the patients were put on ambulatory blood pressure monitoring for 24 hours. Then, echocardiographic assessments and flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) measurements were completed. Patients in one of the two groups were kept negative hydrated during trial with diuretic treatment. RESULTS:At the end of one-year follow-up, patients in negative hydrated group were found to have significantly lower CIMT, left ventricle mass index, left ventricular end-diastolic diameter, mean systolic and diastolic BP, non-dipper patient ratio, and higher FMD. In negatively hydrated group, target organ damage significantly reduced during trial. CONCLUSIONS:The significance of negative hydration status with respect to blood pressure control, endothelial and cardiac functions within primary hypertensive patients who do not suffer from kidney failure has been demonstrated.

背景与目标： 目的：不明原因的体积膨胀问题已被公认为是抗高血压治疗耐药的原因。研究的目的是在没有肾衰竭的原发性高血压患者中确定负流体平衡对高血压控制的贡献以及对内皮和心脏功能的影响。
材料与方法：这是一项为期一年的随访的前瞻性干预研究。在通过身体成分监测仪（BCM）进行体积状态测量之前，将患者进行动态血压监测24小时。然后，完成了超声心动图评估以及血流介导的扩张（FMD）和颈动脉内膜中层厚度（CIMT）的测量。两组中的一组患者在利尿剂治疗试验期间保持负水分状态。
结果：在一年的随访结束时，负水合组患者的CIMT，左心室质量指数，左心室舒张末期直径，平均收缩压和舒张压，非北斗七星患者比率显着降低，和更高的FMD。在负水合组中，试验期间靶器官损伤显着减少。
结论：在没有肾脏衰竭的原发性高血压患者中，负水合状态对血压控制，内皮和心脏功能的重要性已得到证实。

BACKGROUND & AIMS: :T cell regulation of the generation of thyroglobulin plaque-forming cells (Tg PFC) and protein A plaque-forming cells (Prot A PFC) was investigated using lymphocytes from patients with autoimmune thyroid disease. T and B cell mixed cultures (T-B MC) were carried out without mitogenic or antigenic stimulation to identify physiological T cell effects in the system. Tg PFC were found in 8 (44%) of 18 patients who had high titers of thyroglobulin antibody in their sera. Tg-specific and nonspecific immunoregulation by T cells from patients and normal subjects was studied using B cells from these eight patients in the T-B MC system. Remarkably lower values of Tg PFC induction compared to Prot A PFC induction were found after T cell addition. Normal T cells inhibited Tg PFC induction, but patient T cells did not, while the same extent of helper effects were found on Prot A PFC induction by the addition of patient and normal T cells. Irradiation (1500 rads) of T cells from patients and normal subjects significantly enhanced both TgPFC and Prot A PFC induction. Thus, Tg-specific suppressor T cells are present in all normal subjects as part of the radiosensitive suppressor T cell subset. The increase in Tg-PFC caused by irradiation-induced inhibition of Tg-specific suppressor T cell function was significantly greater in normal subjects than in patients. Histamine type 2 receptor-bearing T cells inhibited Prot A PFC induction, but not Tg PFC induction, in the autologous T-B MC system. No Tg PFC were induced from normal B cells in any combination with untreated T cells, irradiated T cells, or histamine type 2 receptor-negative T cells from patients or normal subjects. These data indicate that in vitro Tg-specific T cell regulation can be studied in the T-B MC system by using B cells from patients with autoimmune thyroid disease with high Tg antibody titers in their sera. Tg-specific suppressor T cells appear to be present in all individuals and to be involved in the regulation of Tg antibody production. The lower activity of Tg-specific suppressor T cells in patients compared to that in normal subjects may be related to Tg antibody production in vivo. This abnormality, however, is heterogeneous and is not a complete but, rather, is a relative defect of Tg-specific suppressor T cells.

背景与目标： ：使用自身免疫性甲状腺疾病患者的淋巴细胞研究了甲状腺球蛋白斑块形成细胞（Tg PFC）和蛋白A斑块形成细胞（Prot A PFC）生成的T细胞调节。在无有丝分裂或抗原刺激的情况下进行T细胞和B细胞混合培养（T-B MC），以鉴定系统中的生理性T细胞效应。在血清中滴度高的甲状腺球蛋白抗体的18例患者中，有8例（44％）发现了Tg PFC。使用来自这八名患者的B细胞在T-B MC系统中研究了来自患者和正常受试者的T细胞的Tg特异性和非特异性免疫调节。在添加T细胞后，发现Tg PFC诱导的值比Prot A PFC诱导的低得多。正常T细胞抑制Tg PFC诱导，但对患者T细胞没有抑制作用，而通过添加患者和正常T细胞对Prot A PFC诱导发现了相同程度的辅助作用。患者和正常受试者的T细胞辐射（1500 rads）显着增强了TgPFC和Prot A PFC的诱导作用。因此，Tg特异性抑制T细胞作为放射抑制性T细胞亚群的一部分存在于所有正常受试者中。由辐射诱导的Tg特异性抑制T细胞功能的抑制引起的Tg-PFC的增加在正常受试者中比在患者中显着更大。在自体T-B MC系统中，带有组胺2型受体的T细胞抑制Prot A PFC诱导，但不抑制Tg PFC诱导。正常B细胞​​与未经治疗的T细胞，经辐照的T细胞或来自患者或正常受试者的组胺2型受体阴性T细胞的任何组合均未诱导Tg PFC。这些数据表明，可以通过使用来自自身免疫性甲状腺疾病患者血清中Tg抗体滴度高的患者的B细胞，在T-B MC系统中研究体外Tg特异性T细胞调节。 Tg特异性抑制性T细胞似乎存在于所有个体中，并参与Tg抗体产生的调节。与正常受试者相比，患者中Tg特异性抑制性T细胞的活性较低可能与体内Tg抗体的产生有关。然而，这种异常是异质的，不是完全的，而是Tg特异性抑制性T细胞的相对缺陷。