BACKGROUND & AIMS: CONTEXT:In animal models, estrogen inhibits atherogenesis by inhibiting many of the early steps of atherosclerotic plaque formation. However, the lack of cardioprotective effect by postmenopausal hormone replacement therapy and possible increase in cardiovascular events observed during the first year after the initiation of hormone replacement therapy may suggest that once the plaque is formed, estrogen may have additional effects that may counteract its beneficial outcomes. Indeed, the effect of estrogen on plaque stability has not been identified. OBJECTIVE:We hypothesized that 17beta-estradiol (E2) may cause increased apoptosis in human coronary artery endothelial cells (HCAECs). This effect would explain an adverse effect on plaque stability in vivo. INTERVENTION(S) AND MAIN OUTCOME MEASURE(S):The effect of E2 on apoptosis, cell proliferation, and expression of proapoptotic molecules Fas and Fas ligand (FasL) in cultured HCAECs was evaluated. RESULTS:HCAECs in culture treated with E2 showed an increase in DNA strand breaks and nuclear fragmentation indicative of apoptosis. E2 treatment also induced a significant concentration-dependent increase in Fas mRNA and protein expressions in HCAECs. Moreover, the expression of FasL mRNA and secretion of FasL protein by HCAECs were enhanced in response to E2 treatments. CONCLUSIONS:E2 increases the apoptosis in cultured HCAECs. Enhanced Fas and FasL expressions in response to E2 suggest that activation of the Fas/FasL pathway may be a mediator of the proapoptotic effects of E2 in these cells.

背景与目标： 背景：在动物模型中，雌激素通过抑制动脉粥样硬化斑块形成的许多早期步骤来抑制动脉粥样硬化。但是，绝经后激素替代疗法缺乏心脏保护作用，并且在开始激素替代疗法后的第一年内观察到的心血管事件可能增加，这表明一旦形成斑块，雌激素可能会产生额外的作用，从而抵消其有益结果。实际上，尚未确定雌激素对斑块稳定性的作用。
目的：我们假设17β-雌二醇（E2）可能导致人冠状动脉内皮细胞（HCAEC）凋亡增加。该作用将解释对体内斑块稳定性的不利影响。
干预和主要观察指标：评估了E2对培养的HCAEC中细胞凋亡，细胞增殖以及促凋亡分子Fas和FasL配体（FasL）表达的影响。
结果：用E2处理的培养物中的HCAECs显示DNA链断裂的增加和核碎裂指示凋亡。 E2处理还诱导了HCAECs Fas mRNA和蛋白表达的浓度依赖性显着增加。而且，响应于E2处理，HCAECs的FasL mRNA的表达和FasL蛋白的分泌得到增强。
结论：E2增加了培养的HCAECs的细胞凋亡。响应E2增强的Fas和FasL表达表明Fas / FasL途径的激活可能是这些细胞中E2促凋亡作用的介质。

BACKGROUND & AIMS: :Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.

背景与目标： ：尽管在对抗胃癌方面取得了长足的进步，但它仍然是由特殊的组织学和分子特征定义的复杂致死性疾病。本研究的目的是研究pRb2 / p130，VEGF，EZH2，p53，p16（INK4A），p27（KIP1），p21（WAF1），Ki-67的表达，并分析其与临床病理因素的可能关系。通过免疫组织化学方法对47例患者的表达模式进行了检查，其中27例为肠型，20例为弥漫型，平均随访56个月，并通过Western blot检测AGS，N87，KATO-III和YCC-2 ，-3，-16个胃细胞系。总体而言，胃癌显示EZH2与高水平的p53，Ki-67和细胞质pRb2 / p130相关（分别为P <0.05和P <0.01）。在肠型中发现EZH2表达增加，并且与远处转移的风险相关（分别为P <0.05和P <0.01），表明该蛋白可能在这种类型的癌症中具有预后价值。有趣的是，观察到p27（KIP1）表达水平与晚期疾病和转移的风险之间存在强烈的负相关（P <0.05），而p21（WAF1）和低度胃癌（G1）的表达水平之间呈正相关。肿瘤（P <0.05），证实了这些肿瘤抑制基因在胃癌中的传统接受作用。最后，在核pRb2 / p130的表达水平与低度（G1）胃肿瘤的表达水平之间发现了直接相关性，具有统计学意义（P <0.05）。总之，这些数据可能有助于进一步阐明与两种主要胃癌组织学类型及其侵袭潜能有关的致病机制。

BACKGROUND & AIMS: BACKGROUND:Several studies described the benefits of the heparin-surface-modified intraocular tens (HSM IOL) with regard to the reduced inflammation in routine extracapsular cataract extractions. However, limited information is available about the advantages of the HSM IOL in patients with an intraocular inflammation. AIM:To assess the eventual benefits of the HSM IOL compared to the regular polymethylmethacrylate intraocular lens (PMMA IOL) in patients with uveitis. METHODS:A retrospective study of 43 patients with uveitis of various origins who underwent an extracapsular cataract extraction (24 with HSM, 19 with PMMA IOL). The activity of intraocular inflammation, visual acuity, eventual complications, and medications were examined. Standardized follow-up dates were used (before surgery, one and fourteen days, five and eleven months after surgery.) RESULTS:No difference in the inflammatory, activity was noted between HSM and PMMA groups; neither at short term clinical evaluation, nor at five months after surgery. Despite a slightly better visual acuity in the HSM group before surgery, no long term differences were observed. After surgery the increase in visual acuity was similar for both groups, as well as the frequency of cystoid macular oedema (CMO) and synechiae. Fewer patients in HSM group required Nd:YAG posterior capsulotomy, but the difference was not significant. CONCLUSION:No clinical advantage was found when the HSM IOL was compared with the regular PMMA IOL in 43 patients with uveitis.

背景与目标： 背景：多项研究描述了肝素表面修饰眼内张力（HSM IOL）在常规囊外白内障摘除术中减少炎症方面的益处。但是，关于眼内炎症患者中HSM IOL的优势的信息很少。
目的：评估与常规聚甲基丙烯酸甲酯人工晶状体（PMMA IOL）相比，HSM IOL在葡萄膜炎患者中的最终益处。
方法：回顾性研究43例不同来源葡萄膜炎患者的囊外白内障摘除术（HSM 24例，PMMA IOL 19例）。检查眼内炎症，视力，最终并发症和药物的活动。使用标准化的随访日期（手术前，手术后的第1天，第14天，手术后的第5个月和第11个月）。
结果：HSM和PMMA组之间在炎症，活性方面没有差异；既不进行短期临床评估，也不在术后五个月进行评估。尽管术前HSM组的视敏度稍好，但未观察到长期差异。手术后，两组的视敏度增加，囊状黄斑水肿（CMO）和粘连的发生率相似。 HSM组需要Nd：YAG后囊切开术的患者较少，但差异无统计学意义。
结论：将HSM IOL与常规PMMA IOL相比较在43例葡萄膜炎患者中未发现临床优势。

BACKGROUND & AIMS: :Tumor-infiltrating stroma cells (TISC) as well as tumors themselves are thought to be involved in tumor-related immunosuppression, which is one of the critical mechanisms of tumor escape from immune surveillance. However, preparation of TISC is difficult because of the small proportion of TISC in established tumors. Thus, the cells thought to be involved in tumor-related immunosuppression are generally prepared from spleens or draining lymph nodes in tumor-bearing mice. In this study, we developed a method for directly preparing TISC from established tumors in order to analyze their function. Using green fluorescent protein (GFP) transgenic (Tg) mice and C57BL/6 mice transplanted with bone marrow (BM) cells of GFPTg mice, we detected three subpopulations of TISC: one is compatible with immature myeloid cells (ImC) derived from BM and the two other subpopulations, CD11b(+) cells and CD11b(-) cells, do not originate from BM. The TISC including these subpopulations but not each subpopulation independently after culturing with tumors in the presence of GM-CSF could suppress T cell proliferation induced by anti-CD3. In our system, tumors did not inhibit T cell responses directly, but unknown factors from tumors affected immunosuppression by TISC.

背景与目标： ：肿瘤浸润基质细胞（TISC）以及肿瘤本身都被认为与肿瘤相关的免疫抑制有关，这是肿瘤逃避免疫监视的关键机制之一。然而，由于在已建立的肿瘤中TISC的比例很小，因此TISC的制备是困难的。因此，通常被认为与肿瘤相关的免疫抑制有关的细胞是从荷瘤小鼠的脾脏或引流淋巴结中制备的。在这项研究中，我们开发了一种从已建立的肿瘤中直接制备TISC的方法，以分析其功能。使用绿色荧光蛋白（GFP）转基因（Tg）小鼠和移植有GFPTg小鼠骨髓（BM）细胞的C57BL / 6小鼠，我们检测到TISC的三个亚群：一个与源自BM的未成熟髓样细胞（ImC）相容。其他两个亚群CD11b（）细胞和CD11b（-）细胞并非源自BM。在存在GM-CSF的情况下与肿瘤培养后，TISC包括这些亚群，但并非每个亚群独立地抑制由抗CD3诱导的T细胞增殖。在我们的系统中，肿瘤并未直接抑制T细胞反应，但来自肿瘤的未知因素影响了TISC的免疫抑制。

BACKGROUND & AIMS: :The aim of this study was to analyse the acting forces and moments induced by a special orthodontic appliance, the Pendulum K, for molar distalization in the transverse and sagittal planes. The purpose-designed test set-up (artificial maxilla with anchorage unit and two electrothermodynamic molars, an electronic measuring unit, a unit with force-moment sensor, an analogue/digital converter, and a data read-out unit) allowed simulation of in vivo conditions on the one hand and precise determination of the force systems on the other. The appliances investigated were three specimens of the Pendulum K. In vitro measurement of the resulting force systems revealed that the forces and moments in the transverse and sagittal planes remained almost constant over a 3 mm measuring increment when the distal screw was continuously activated (10 activations/mm). Without reactivation of the incorporated distal screw, however, a marked decline in the force systems was recorded. The Pendulum K allows translatory distalization of the upper molars and thus dental arch expansion, dispensing with the need for permanent teeth to be extracted, subject to a corresponding indication. This is achieved by continuous adjustment of an incorporated distal screw and by specific pre-activations of the Pendulum springs.

背景与目标： ：这项研究的目的是分析由特殊的正畸矫治器Pendulum K引起的作用力和力矩，以在横断面和矢状面上进行磨牙远侧。专门设计的测试装置（带有锚固单元和两个电热磨牙的人工上颌，一个电子测量单元，一个带有力矩传感器的单元，一个模拟/数字转换器和一个数据读出单元）允许模拟一方面是体内条件，另一方面是精确确定力系统。所研究的器具是Pendulum K的三个标本。对最终产生的力系统进行的体外测量显示，当连续激活远端螺钉（10次激活）时，横向和矢状面的力和力矩在3 mm的测量增量内几乎保持恒定。 /毫米）。然而，在没有重新激活所结合的远端螺钉的情况下，记录了力系统的显着下降。摆K允许上颌臼齿的平移远侧移动，从而使牙弓扩张，并在需要相应指示的情况下无需拔出恒牙。这是通过不断调整内置的远端螺钉并通过对摆弹簧进行特定的预激活来实现的。

BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

背景与目标： ：热休克蛋白90（HSP90）是结构折叠和维持各种蛋白质（包括与细胞信号相关的几种蛋白质）构象完整性的必需。利用HSP90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）的最新研究表明，在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向于多发性骨髓瘤（MM）患者，我们首先通过免疫荧光和流式细胞术分析了骨髓瘤细胞系（U266）和原发性骨髓瘤细胞中HSP90的表达。在证明HSP90在骨髓瘤细胞中表达后，通过免疫过氧化物酶染色分析了32例MM患者的档案样本。在所有患者中，骨髓瘤细胞在所有样品中均表现出强烈的HSP90细胞质表达，并且55％的患者还表现出并发的核免疫阳性。与未处理的对照细胞相比，用17AAG处理U266细胞和原代MM细胞可导致凋亡明显增加。分析与17-AAG孵育的MM细胞中的抗凋亡BCL2家族蛋白和akt，表明BCL-2，BCL-XL，MCL-1和akt下调。此外，尽管低浓度的硼替佐米不会导致细胞死亡，但是17AAG和硼替佐米治疗的组合显示出对U266细胞系的协同凋亡作用。这些数据表明，针对HSP90的靶向抑制可能被证明是开发MM患者未来治疗选择的有效且创新的策略。

BACKGROUND & AIMS: :Priority setting of health interventions is often ad-hoc and resources are not used to an optimal extent. Underlying problem is that multiple criteria play a role and decisions are complex. Interventions may be chosen to maximize general population health, to reduce health inequalities of disadvantaged or vulnerable groups, ad/or to respond to life-threatening situations, all with respect to practical and budgetary constraints. This is the type of problem that policy makers are typically bad at solving rationally, unaided. They tend to use heuristic or intuitive approaches to simplify complexity, and in the process, important information is ignored. Next, policy makers may select interventions for only political motives. This indicates the need for rational and transparent approaches to priority setting. Over the past decades, a number of approaches have been developed, including evidence-based medicine, burden of disease analyses, cost-effectiveness analyses, and equity analyses. However, these approaches concentrate on single criteria only, whereas in reality, policy makers need to make choices taking into account multiple criteria simultaneously. Moreover, they do not cover all criteria that are relevant to policy makers. Therefore, the development of a multi-criteria approach to priority setting is necessary, and this has indeed recently been identified as one of the most important issues in health system research. In other scientific disciplines, multi-criteria decision analysis is well developed, has gained widespread acceptance and is routinely used. This paper presents the main principles of multi-criteria decision analysis. There are only a very few applications to guide resource allocation decisions in health. We call for a shift away from present priority setting tools in health--that tend to focus on single criteria--towards transparent and systematic approaches that take into account all relevant criteria simultaneously.

背景与目标： ：卫生干预措施的优先级设置通常是临时的，资源没有得到最佳利用。潜在的问题是多个标准起着作用，并且决策很复杂。可以选择干预措施，以最大程度地提高总体人口健康，减少弱势或弱势群体的健康不平等，广告/或应对危及生命的情况，所有这些都涉及实际和预算方面的限制。这是决策者通常无助于理性解决的典型问题。他们倾向于使用启发式或直观的方法来简化复杂性，并且在此过程中，重要的信息将被忽略。接下来，政策制定者可能只出于政治动机选择干预措施。这表明需要采取合理和透明的方法来确定优先事项。在过去的几十年中，已经开发出许多方法，包括循证医学，疾病负担分析，成本效益分析和公平性分析。但是，这些方法仅集中于单个标准，而实际上，决策者需要在选择时同时考虑多个标准。此外，它们并未涵盖与决策者相关的所有标准。因此，有必要开发一种确定优先级的多标准方法，并且最近确实将其确定为卫生系统研究中最重要的问题之一。在其他科学学科中，多准则决策分析已经得到了很好的发展，已经得到了广泛的认可并被常规使用。本文介绍了多准则决策分析的主要原理。只有很少的应用程序可以指导健康状况中的资源分配决策。我们呼吁从目前卫生领域的优先重点设定工具（倾向于只关注单一标准）转变为同时考虑所有相关标准的透明，系统的方法。

BACKGROUND & AIMS: :Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+ CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.

背景与目标： 已经证明：Foxp3对于小鼠中天然产生的CD4 CD25调节性T细胞的发育和功能既必要又充分。用IPEX突变的Scurfy小鼠中的Foxp3和人类中的FOXP3突变会导致致命的早期发作的自身免疫性疾病，并证明FOXP3在维持免疫稳态方面的关键作用。 FOXP3蛋白编码几个功能域，包括C2H2锌指，亮氨酸拉链和带翼螺旋/叉头（FKH）域。先前我们已经证明FOXP3充当转录阻遏物，并抑制激活诱导的IL-2基因转录。为了表征每个预测功能结构域对FOXP3体内活性的作用，我们评估了在一大批患有免疫功能异常，多内分泌病，肠病，X连锁综合征（IPEX）的患者中鉴定出的点突变的位置，并发现它们主要聚集在FKH结构域和亮氨酸拉链中，但也存在于蛋白质的N末端定义不明确的区域。研究了每个IPEX靶向域的分子功能。我们显示FOXP3组成性地定位于原子核，并且此定位需要在其FKH域的氨基和C末端都具有序列。此外，发现FOXP3通过其亮氨酸拉链同源二聚体。我们还确定了FOXP3 N末端一半内的新型功能域，这是FOXP3介导的从组成型活性启动子和NF-AT诱导型启动子转录抑制所必需的。此外，我们证明这些域中的IPEX突变与FOXP3阻遏物功能的缺陷相关，从而证实了它们的体内相关性。

BACKGROUND & AIMS: :Activating mutations in the tyrosine kinase domain of the HER2 gene have recently been reported in lung adenocarcinomas, mainly in East Asian patients. Our study was devised to evaluate the prevalence and nature of HER2 mutations in lung adenocarcinomas from Caucasian patients. The mutational status of the HER2 gene was evaluated in 403 lung adenocarcinomas by PCR-single strand conformation polymorphism analysis and direct sequencing of Exons 19 and 20. We found HER2 mutations in 9 (2.2%) cases. Seven (78%) of the mutations were in frame duplications/insertions at codons 776-779 (YVMA), the other 2 were base substitutions resulting in aminoacid changes. The hotspot mutation at bases 776-779 was previously found to be the most frequent HER2 mutation in Asiatic patients. The distribution of mutations was significantly different between conventional lung adenocarcinomas (CLAs) and lung adenocarcinomas with bronchioloalveolar features (ABAFs). Seven (6.2%) of 113 ABAFs and 2 (0.7%) of 290 CLA were mutated (p = 0.0025). In addition, the frequency of HER2 mutations was slightly higher in females (4.1%) than in males (1.8%) and in never smokers (3.1%) than in smokers (1.9%), but differences were not statistically significant. This series of tumors was also investigated for EGFR and K-ras mutations. EGFR mutations were observed in 43 (10.7%) cases, and K-ras mutations in 110 (27.3%) cases. EGFR, HER2 and K-ras mutations were found to be mutually exclusive events. The presence of HER2 mutations in a subset of patients with lung adenocarcinoma raise hope to treat these patients with HER2 specific kinase inhibitors.

背景与目标： ：最近在肺腺癌中，主要在东亚患者中，报道了HER2基因酪氨酸激酶结构域中的活化突变。我们的研究旨在评估白人患者肺腺癌中HER2突变的发生率和性质。通过PCR单链构象多态性分析和外显子19和20的直接测序，评估了403例肺腺癌中HER2基因的突变状态。我们发现9例（2.2％）病例中存在HER2突变。突变中的七个（78％）位于776-779位密码子（YVMA）的框架重复/插入中，另外两个为碱基取代，导致氨基酸变化。先前发现在776-779碱基处的热点突变是亚洲患者中最常见的HER2突变。在传统的肺腺癌（CLA）和具有支气管肺泡特征（ABAFs）的肺腺癌之间，突变的分布显着不同。 113个ABAF中有7个（6.2％）和290个CLA中有2个（0.7％）发生了突变（p = 0.0025）。此外，HER2突变的频率在女性（4.1％）中略高于男性（1.8％），从不吸烟者（3.1％）比吸烟者（1.9％）高，但差异无统计学意义。还研究了该系列肿瘤的EGFR和K-ras突变。在43（10.7％）例中观察到EGFR突变，在110（27.3％）例中观察到K-ras突变。发现EGFR，HER2和K-ras突变是相互排斥的事件。 HER2突变在一部分肺腺癌患者中的存在增加了用HER2特异性激酶抑制剂治疗这些患者的希望。

BACKGROUND & AIMS: :The ovarian steroid hormone estrogen (E2) elicits a multiplicity of both systemic and uterotropic responses in vivo. For example, the administration of E2 to ovariectomized (Ovx) and sexually immature rodents leads to uterine-specific inflammatory infiltrates. In this study, we quantitated the number of eosinophils and BM8+, Ia+, and CD4+ cells in uteri obtained from adult Ovx control and E2-treated C57BL/6J, C3H/HeJ, and (C57BL/6J x C3H/HeJ) (B6C3) F1 hybrid mice. All three strains exhibited a significant increase in the number of uterine eosinophils and BM8+ macrophages after E2 treatment. However, C57BL/6J and B6C3 F1 hybrid mice responded with a greater number of infiltrating eosinophils and macrophages as compared with C3H/HeJ. A similar analysis of Ia+ and CD4+ cells showed that E2 treatment either down-regulates or does not affect the number of such cells in all three strains. Genome exclusion mapping using a (C57BL/6J x C3H/HeJ) x C3H/HeJ backcross population localized Est1, the major locus controlling the number of eosinophils infiltrating the uterus after E2 treatment, to chromosome 4. In addition, suggestive linkage to marker loci on chromosomes 10 and 16 was detected and evidence for locus interaction is presented. Our results conclusively demonstrate that E2-regulated/ dependent responses can be genetically controlled, indicating that the phenotypic variation observed in both the normal and pathological effects of E2 may, in part, be due to a genetic component.

背景与目标： ：卵巢类固醇激素雌激素（E2）在体内引起多种全身和子宫促反应。例如，将E2给予去卵巢（Ovx）和性不成熟的啮齿动物会导致子宫特异性炎症浸润。在这项研究中，我们量化了从成年Ovx对照和经E2处理的C57BL / 6J，C3H / HeJ和（C57BL / 6J x C3H / HeJ）（B6C3）获得的子宫中嗜酸性粒细胞和BM8，Ia和CD4细胞的数量F1杂种小鼠。在E2处理后，所有三个菌株均表现出子宫嗜酸性粒细胞和BM8巨噬细胞数量的显着增加。但是，与C3H / HeJ相比，C57BL / 6J和B6C3 F1杂种小鼠反应的浸润性嗜酸性粒细胞和巨噬细胞数量更多。对Ia和CD4细胞的类似分析显示，E2处理在所有三个菌株中均下调或不影响此类细胞的数量。使用（C57BL / 6J x C3H / HeJ）x C3H / HeJ回交群体定位的基因组排斥定位于Est1，Est1是控制E2处理后浸润子宫的嗜酸性粒细胞数量的主要基因座，并指向染色体4。检测到10号和16号染色体上的基因并提供了基因座相互作用的证据。我们的结果最终证明，E2调节/依赖性反应可以通过基因控制，这表明在E2的正常和病理效应中观察到的表型变异可能部分归因于遗传成分。

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： 免疫组织化学方法检测了定向冠状动脉粥样斑块切除术取回的59例人类冠状动脉病变中肝细胞生长因子/分散因子（HGF / SF）的表达和定位，并与转化生长因子β同工型（TGF-beta 1，-beta 2和-beta 3）。在59个样本中的21个（35.6％）中发现了类似HGF的免疫反应性（HGF-IR）。血栓形成组织中HGF免疫阳性率为45％（14/31）显着（P <0.05）分别高于7.3％（4/55），7.1％（3/42）和0％（0/14） ）分别在纤维组织，新内膜增生和粥样粥样硬化中。除了血栓形成组织外，在这些组件中，HGF的免疫反应性比TGF-β亚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中，以及在部分新血管形成的病变中的毛细血管壁之外的单核细胞/巨噬细胞。平滑肌细胞（SMCs）几乎没有表现出HGF-IR。相反，在尸检时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在可归因于人类血栓的冠状斑块形成过程中起作用。

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: STUDY DESIGN:A cross-sectional study of the spine in 40 young adults after solid organ transplantation in childhood. OBJECTIVE:To evaluate the impact of organ transplantation and long-term immunosuppressive treatment on growing spine using magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA:A review of the current literature reveals no systematic evaluation of the spine after transplantation in childhood. METHODS:A total of 40 adult patients (mean age 22.1 years, range, 16.0-27.0), who received either kidney, liver, or heart transplant as children, were evaluated. Mean follow-up after transplantation was 11.2 years (range 3.0-18.0). All patients filled in a questionnaire, underwent an interview and physical examination, as well as had MRI of the spine. Standing spinal radiographs were taken from patients with a rib hump > or = 6 degrees. RESULTS:There were 8 (20%) patients who had a history of vertebral fracture. Eleven (28%) patients reported frequent back pain at rest. There were 15 (38%) patients who had scoliosis > 10 degrees (range 10 degrees -69 degrees ). On MRI, narrowed disc spaces were noted in 32 (80%) patients, and irregular endplates were noted in 24 (60%). There were 14 (35%) patients who had at least 1 compressed or wedged vertebra (> 20%). Patients treated for acute rejection had wedged vertebrae, speckled or black disc spaces, and irregular endplates more often than patients without rejections. Males had wedged vertebrae more often than females (P = 0.0067). CONCLUSIONS:Back pain, scoliosis, wedged vertebrae, and narrowed, degenerated disc spaces are common after solid organ transplantation in childhood.

背景与目标： 研究设计：儿童实体器官移植后对40位年轻人的脊柱进行的横断面研究。
目的：利用磁共振成像（MRI）评估器官移植和长期免疫抑制治疗对生长中脊柱的影响。
背景资料摘要：对当前文献的回顾表明，儿童期移植后没有对脊柱进行系统评价。
方法：总共评估了40名成年患者（平均年龄22.1岁，范围16.0-27.0），他们从小就接受了肾脏，肝脏或心脏移植手术。移植后的平均随访时间为11.2年（范围3.0-18.0）。所有患者均填写了问卷，接受了访谈和体格检查，并对脊柱进行了MRI检查。肋骨隆起>或= 6度的患者拍摄站立式脊柱X光片。
结果：有8例（20％）有椎体骨折病史。 11名（28％）患者报告休息时经常出现背痛。脊柱侧弯> 10度（范围10度-69度）的患者为15（38％）。在MRI上，发现32例（80％）患者的椎间盘间隙变窄，发现24例（60％）的不规则端板。有14名（35％）患者至少有1块受压或楔入的椎骨（> 20％）。接受急性排斥反应的患者比没有排斥反应的患者更经常出现椎体楔形，斑点或黑色椎间盘间隙以及不规则的终板。男性比女性更经常楔住椎骨（P = 0.0067）。
结论：儿童实体器官移植后，背部疼痛，脊柱侧弯，椎骨楔形和椎间盘狭窄变窄是常见的。

BACKGROUND & AIMS: INTRODUCTION:To obtain strict glucose regulation, an accurate and feasible bedside glucometry method is essential. We evaluated three different types of point-of-care glucometry in seriously ill intensive care unit (ICU) patients. The study was performed as a single-centre, prospective, observational study in a 12-bed medical ICU of a university hospital. METHODS:Patients with an expected ICU stay of more than 48 hours were included. Because the reference laboratory delivers glucose values after approximately 30 to 60 minutes, which is too slow to use in a glucose regulation protocol and for calibration of the subcutaneous continuous glucose monitoring system (CGMS) (CGMS System Gold), we first validated the ICU-based blood gas/glucose analyser ABL715 (part 1 of the study). Subsequently, part 2 was performed: after inserting (and calibrating) the subcutaneous CGMS, heparinised arterial blood samples were drawn from an arterial line every 6 hours and analysed on both the Precision PCx point-of-care meter using test strips and on the blood gas/glucose analyser ABL715. CGMS glucose data were downloaded after 24 to 72 hours. The results of the paired measurements were analysed as a scatter plot by the method of Bland and Altman and were expressed as a correlation coefficient. RESULTS:Part 1: Four hundred and twenty-four blood samples were drawn from 45 critically ill ICU patients. The ICU-based blood gas/glucose analyser ABL715 provided a good estimate of conventional laboratory glucose assessment: the correlation coefficient was 0.95. In the Clarke error grid, 96.8% of the paired measurements were in the clinically acceptable zones A and B. Part 2: One hundred sixty-five paired samples were drawn from 19 ICU patients. The Precision PCx point-of-care meter showed a correlation coefficient of 0.89. Ninety-eight point seven percent of measurements were within zones A and B. The correlation coefficient for the subcutaneous CGMS System Gold was 0.89. One hundred percent of measurements were within zones A and B. CONCLUSION:The ICU-based blood glucose analyser ABL715 is a rapid and accurate alternative for laboratory glucose determination and can serve as a standard for ICU blood glucose measurements. The Precision PCx is a good alternative, but feasibility may be limited because of the blood sample handling. The subcutaneous CGMS System Gold is promising, but real-time glucose level reporting is necessary before it can be of clinical use in the ICU. When implementing a glucose-insulin algorithm in patient care or research, one should realise that the absolute glucose level may differ systematically among various measuring methods, influencing targeted glucose levels.

背景与目标： 简介：要获得严格的葡萄糖调节，准确，可行的床旁血糖测定方法必不可少。我们评估了重症重症监护病房（ICU）患者的三种不同的即时护理血糖仪。该研究是在大学医院的12张病床的ICU中进行的单中心，前瞻性，观察性研究。
方法：包括预期ICU超过48小时的患者。由于参考实验室在大约30至60分钟后会提供葡萄糖值，这太慢了，无法用于葡萄糖调节方案以及皮下连续葡萄糖监测系统（CGMS）（CGMS System Gold）的校准，因此我们首先验证了ICU-血气/葡萄糖分析仪ABL715（研究的第1部分）。随后，执行第2部分：插入（并校准）皮下CGMS后，每6小时从一条动脉管线中抽取肝素化的动脉血样本，并在Precision PCx即时检测仪上使用试纸条和血液进行分析气体/葡萄糖分析仪ABL715。 CGMS葡萄糖数据在24到72小时后下载。配对测量的结果通过Bland和Altman方法作为散点图进行分析，并表示为相关系数。
结果：第1部分：从45名重症ICU患者中抽取了242份血液样本。基于ICU的血气/葡萄糖分析仪ABL715提供了常规实验室葡萄糖评估的良好估计：相关系数为0.95。在Clarke误差网格中，96.8％的配对测量值在临床上可接受的区域A和B中。第2部分：从19位ICU患者中抽取了165个配对样品。 Precision PCx即时护理仪的相关系数为0.89。百分之九十八的测量值在区域A和B内。皮下CGMS系统Gold的相关系数为0.89。百分之一百的测量值在区域A和B内。
结论：基于ICU的血糖分析仪ABL715是一种快速准确的实验室葡萄糖测定方法，可作为ICU血糖测量的标准。 Precision PCx是一个很好的选择，但由于血液样本的处理，可行性可能受到限制。皮下CGMS System Gold前景看好，但在ICU中临床应用之前，必须实时报告葡萄糖水平。在患者护理或研究中实施葡萄糖-胰岛素算法时，应认识到，各种测量方法之间的绝对葡萄糖水平可能会系统地不同，从而影响目标血糖水平。