BACKGROUND & AIMS: Recent evidence suggests that Chlamydia trachomatis can persist in the female upper genital tract in an unculturable state. Since unsuspected C. trachomatis infection has been associated with adverse in-vitro fertilization (IVF) outcome we sought to detect further evidence of C. trachomatis in the genital tracts of women undergoing IVF. The prevalence and distribution of antibodies to the major structural proteins of C. trachomatis in paired follicular fluid and sera of women undergoing IVF were examined. Sera and follicular fluid samples from 149 women were assayed for immunoglobulin (Ig)G and IgA antibodies to two C. trachomatis antigens, the major outer membrane protein (MOMP) and a recombinant lipopolysaccharide (rLPS) fragment. Additionally, the expression of human 60 kDa heat shock protein (hsp 60) in follicular fluid was determined. All cervical and follicular fluid samples were negative for C. trachomatis by polymerase chain reaction, ligase chain reaction and DNA probe. Sera from 60% of the subjects were positive for antichlamydial rLPS IgG; 36% were positive for anti-MOMP IgG. Similarly, rLPS-directed and MOMP-directed IgA were detected in sera of 34 and 14% of the subjects respectively. IgG antibodies to MOMP and rLPS were detected in 42 and 41% of the follicular fluid examined respectively. Anti-MOMP IgA was identified in 8.7% of the follicular fluid while 27.5% were positive for anti-rLPS IgA. Human hsp 60 expression was documented in 11.6% of the follicular fluid tested. IgA antibodies to both MOMP (P = 0.03) and rLPS (P = 0.02) in follicular fluid were associated with a failure to become pregnant after embryo transfer. IgG antibodies in sera and follicular fluid and IgA antibodies in sera were unrelated to IVF outcome. Similarly only anti-MOMP IgA (P = 0.02) and anti-rLPS IgA (P = 0.04) in follicular fluid were correlated with human hsp 60 expression in follicular fluid. The unique association between IgA antibodies to two chlamydial antigens in follicular fluid and both hsp 60 expression and IVF failure provides further support for the possibility that a persistent upper genital tract chlamydial infection contributes to IVF failure in some women.

背景与目标： 最近的证据表明，沙眼衣原体可以在女性上生殖道中以无法培养的状态持续存在。由于未曾怀疑的沙眼衣原体感染与体外受精（IVF）不良结果有关，因此我们寻求在接受IVF的女性生殖道中发现沙眼衣原体的进一步证据。检查了在进行IVF的妇女的成对卵泡液和血清中沙眼衣原体主要结构蛋白的抗体的分布情况。分析了来自149名妇女的血清和卵泡液样品中针对两种沙眼衣原体抗原，主要外膜蛋白（MOMP）和重组脂多糖（rLPS）片段的免疫球蛋白（Ig）G和IgA抗体。另外，测定了人60kDa热休克蛋白（hsp 60）在卵泡液中的表达。通过聚合酶链反应，连接酶链反应和DNA探针，所有子宫颈和卵泡液样品均为沙眼衣原体阴性。 60％的受试者血清抗衣原体rLPS IgG阳性； 36％的抗MOMP IgG阳性。同样，分别在34％和14％的受试者血清中检测到了rLPS导向和MOMP导向的IgA。在分别检查的卵泡液中有42％和41％检出了针对MOMP和rLPS的IgG抗体。在8.7％的卵泡液中发现了抗MOMP IgA，而抗rLPS IgA的阳性率为27.5％。在测试的卵泡液中有11.6％记录了人类hsp 60的表达。卵泡液中针对MOMP（P = 0.03）和rLPS（P = 0.02）的IgA抗体与胚胎移植后无法怀孕有关。血清和卵泡液中的IgG抗体以及血清中的IgA抗体与IVF结果无关。同样，卵泡液中只有抗MOMP IgA（P = 0.02）和抗rLPS IgA（P = 0.04）与人hsp 60在卵泡液中的表达相关。卵泡液中两种衣原体抗原的IgA抗体与hsp 60表达和IVF衰竭之间的独特联系为某些女性持续性上生殖道衣原体感染导致IVF衰竭的可能性提供了进一步的支持。

BACKGROUND & AIMS: A 38-year-old man, blood group A+, was allotransplanted for multiple myeloma from his fully matched sister, blood group O+. Anti-A antibodies IgG and IgM titres of the donor were low. Allogeneic peripheral blood stem cells were harvested by leukapheresis after subcutaneous administration of G-CSF. Rapid engraftment occurred since 5.6 x 10(9)/l leukocytes were achieved on day +9 post-transplant. At this time a severe immune haemolytic syndrome occurred and direct antiglobulin test was positive (IgG and C3d). Elution showed an anti-A specificity. Evolution was rapidly unfavourable related to multiorgan failure. The patient died on day +20 post-transplant.

背景与目标： 一名38岁的男性，血型A，是从他完全匹配的姐姐的血型O中异位移植的，用于多发性骨髓瘤。供体的抗A抗体IgG和IgM滴度很低。皮下给药G-CSF后，通过白细胞分离术收集异体外周血干细胞。由于移植后第9天获得了5.6 x 10（9）/ l白细胞，因此发生了快速植入。这时发生了严重的免疫溶血综合症，直接抗球蛋白测试为阳性（IgG和C3d）。洗脱显示出抗A特异性。与多器官衰竭有关的进化迅速不利。该患者在移植后的第20天死亡。

BACKGROUND & AIMS: :How neutrophils (polymorphonuclear neutrophils, PMNs) damage vessels in leukocytoclastic vasculitis (LcV) mediated by immune complexes (ICs) is unclear. If degradative enzymes and oxygen radicals are released from PMNs while adhering to the inner side of the vessel wall, they could be washed away by the blood stream or neutralized by serum protease inhibitors. We investigated if in LcV PMNs could damage vessels from the tissue side after transmigration. We used CD18-deficient (CD18-/-) mice because the absence of CD18 excludes transmigration of PMNs. When eliciting the Arthus reaction in ears of CD18-/- mice, deposition of ICs was not sufficient to recruit PMNs or to induce IC-mediated LcV. Injection of PMNs intradermally in CD18-/- mice allowed us to investigate if bypassing diapedesis and placing PMNs exclusively on the abluminal side leads to vascular destruction. We found that injected PMNs gathered around perivascular ICs, but did not cause vessel damage. Only intravenous injection of wild-type PMNs could re-establish the Arthus reaction in CD18-/- mice. Thus, PMNs cause vessel damage during diapedesis from the luminal side, but not from the perivascular space. We suggest that in order to shield the cytotoxic products from the blood stream, ICs induce particularly tight interactions between them, PMNs and endothelial cells.

背景与目标： 尚不清楚：中性粒细胞（多形核中性粒细胞，PMNs）如何损害免疫复合物（ICs）介导的白细胞碎裂性血管炎（LcV）中的血管。如果降解酶和氧自由基在粘附到血管壁内侧时从PMN中释放出来，它们可能会被血流冲走或被血清蛋白酶抑制剂中和。我们调查了在LcV PMNs迁移后是否会从组织侧损害血管。我们使用CD18缺陷（CD18-/-）小鼠，因为CD18的缺失排除了PMN的迁移。当在CD18-/-小鼠的耳朵中引起Arthus反应时，IC的沉积不足以募集PMN或诱导IC介导的LcV。在CD18-/-小鼠中皮内注射PMNs使我们能够研究是否绕过了隔尿管并将PMN专门置于房外侧导致血管破坏。我们发现注射的PMN聚集在血管周围IC周围，但并未引起血管损伤。只有静脉注射野生型PMN才能在CD18-/-小鼠中重建Arthus反应。因此，PMNs在进行尿管穿刺时会从腔侧引起血管损伤，但不会引起血管周间隙损伤。我们建议，为了从血液中屏蔽细胞毒性产物，IC诱导它们，PMN和内皮细胞之间的相互作用特别紧密。

BACKGROUND & AIMS: :Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue-damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL-12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.

背景与目标： ：克罗恩病（CD）和溃疡性结肠炎（UC）是胃肠道的慢性炎性疾病，具有临床和病理学特征。最公认的假设是CD和UC均来自对肠道菌群正常成分的粘膜免疫反应失控。然而，证据表明这两种疾病的主要病理过程是不同的。在CD中，组织破坏性炎症反应是由激活的1型辅助性T细胞（Th1）驱动的，而体液反应在UC中占主导地位。一致地，在CD中可见大量的巨噬细胞积聚，使白介素（IL）-12（主要的Th1诱导因子）在CD中可见，而在UC粘膜中则未见。初步研究还表明，给予阻断IL-12 / p40亚基的单克隆抗体可用于诱导和维持CD患者的临床缓解。值得注意的是，最近描述的IL-23与IL-12共有p40亚基，从而增加了抗IL-12 / p40抗体在CD中的临床益处也可能是由于IL-23活性的中和所引起的可能性。这篇综述总结了有关CD患者和结肠炎实验模型中IL-12和IL-12相关信号通路的表达和功能作用的最新信息，从而强调了IL-12和IL-23活性在结肠炎患者中的主要差异。肠道炎症的发展。

BACKGROUND & AIMS: :Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.

背景与目标： 前哨淋巴结（SLNs）作为第一个从原发肿瘤接受淋巴结和初始肿瘤转移的优先部位的淋巴结，被强烈暴露于肿瘤细胞和其他相关细胞的生物活性产物。这使它们成为研究决定选择性组织对转移的敏感性的因素的理想选择。我们推测，肿瘤诱导的SLNs免疫调节通过抑制对原发性和转移性黑素瘤的肿瘤细胞有活性的肿瘤特异性细胞毒性T细胞的产生而促进淋巴结转移。粒细胞/巨噬细胞集落刺激因子（GM-CSF）可逆转淋巴结的免疫调节作用，这一发现对未来淋巴结转移的治疗具有重要意义。

BACKGROUND & AIMS: BACKGROUND:The purpose of this study was to investigate the fit of a hypothesized model of medical students' diagnostic or clinical reasoning skills based on their aptitude for medical school, basic science achievement, and clinical competency measures. METHOD:A total of 589 medical students who received their MD from 1994 to 2002 participated in this study. Confirmatory factor analysis was used to evaluate the fit of theoretical models of clinical reasoning using measures of basic science and clinical knowledge. RESULTS:The results provided support for a three-factor model of medical student performance (Bentler's Comparative Fit Index = .905, standardized root mean squared residual = .054, root mean squared error of approximation = .105). The clinical reasoning skills of medical students were influenced by an independent relationship between latent variables of basic science achievement and clinical competency. CONCLUSION:The findings support a theoretical model of diagnostic or clinical reasoning that treats the basic science and clinical knowledge of medical students as distinct domains.

背景与目标： 背景：本研究的目的是根据医学生对医学学校的才能，基础科学成就和临床能力测评的基础，研究假设模型对医学生诊断或临床推理能力的拟合度。
方法：1994年至2002年，共有589名医学博士获得了医学博士学位。验证性因素分析用于使用基础科学和临床知识的方法来评估临床推理理论模型的拟合度。
结果：该结果为医学学生表现的三因素模型提供了支持（Bentler比较拟合指数= .905，标准化均方根残差= .054，均方根近似误差= .105）。基础医学成就的潜在变量与临床能力之间的独立关系影响着医学生的临床推理能力。
结论：这些发现支持诊断或临床推理的理论模型，该模型将医学生的基础科学和临床知识视为不同的领域。

BACKGROUND & AIMS: The circumventricular organs (CVOs) in the brain are without a blood-brain barrier (BBB) and as such directly exposed to blood plasma constituents and blood-borne pathogens. In light of previous studies showing discrepancies regarding the immunocompetence of these organs, we initiated the present study to provide a comprehensive immunohistochemical analysis of the cellular expression of immune-associated antigens within the pineal gland, area postrema and the subfornical organ. In all CVOs, subpopulations of cells morphologically similar to complement receptor type 3 immunoreactive microglial/macrophage cells expressed major histocompatibility complex (MHC) class II antigen, leucocyte common antigen (LCA/CD45), as well as CD4 and ED1 antigen. Based on morphological criteria the MHC class II antigen expressing cells could be grouped into a major population of classical parenchymal and perivascular ramified microglial cells and a minor population presenting itself as scattered or small groups of rounded macrophage-like cells. CD4 and ED1 antigen were expressed by both cell types. CD45 was preferentially expressed by macrophage-like cells. MHC class I antigen was expressed by the vascular endothelium in both BBB-protected and BBB-deficient areas and was additionally present as a lattice-like network throughout the BBB-deficient parenchyma in all CVOs. The results suggest that the BBB-free areas of the brain besides being constantly surveyed by blood-borne macrophages, possess an intrinsic immune surveillance system based on resting and activated microglial cells, which may function as a non-endothelial, cellular barrier against blood-borne pathogens.

背景与目标： 大脑中的室间隔器官（CVO）没有血脑屏障（BBB），因此直接暴露于血浆成分和血源性病原体。鉴于先前的研究表明这些器官的免疫能力存在差异，我们发起了本研究，以提供对松果体，视网膜后区域和亚器官内免疫相关抗原的细胞表达的全面免疫组织化学分析。在所有CVO中，与补体受体3型免疫反应性小胶质细胞/巨噬细胞细胞形态相似的细胞亚群表达了主要的组织相容性复合物（MHC）II类抗原，白细胞常见抗原（LCA / CD45）以及CD4和ED1抗原。根据形态学标准，可以将表达MHC II类抗原的细胞分为经典的实质和血管周围分枝的小神经胶质细胞的主要群体，以及表现为散在的或成团的圆形巨噬细胞样细胞的少数群体。 CD4和ED1抗原通过两种细胞类型表达。 CD45优先由巨噬细胞样细胞表达。 MHC I类抗原在BBB保护的区域和BBB缺乏区域均由血管内皮表达，并在所有CVO的整个BBB缺乏实质中以格状网络形式存在。结果表明，除了大脑中无血脑屏障的区域不断被血源性巨噬细胞检查外，还具有基于静止和活化的小胶质细胞的内在免疫监视系统，该系统可能起非内皮细胞屏障的作用。传播的病原体。

BACKGROUND & AIMS: OBJECTIVE:The 24-hour creatinine clearance is the standard clinical technique for measuring kidney function; however, this measurement is cumbersome and inconvenient for patients. We hypothesized that a camera-based technetium-99m mercaptoacetyltriglycine (MAG3) clearance obtained simultaneously with a standard MAG3 scan would correlate well with the 24-hour creatinine clearance and could serve as a simple marker of kidney function. MATERIALS AND METHODS:Data were obtained from a retrospective analysis of 28 patients with varying degrees of kidney dysfunction and 85 subjects evaluated for kidney donation. The MAG3 clearance was calculated using a camera-based technique without blood or urine sampling. The creatinine clearance was measured using the plasma creatinine and a 24-hour urine collection. The MAG3 and creatinine clearances were corrected for body surface area, and clearance values in healthy subjects and patients were compared using the paired Student's t test. The linear association between the MAG3 and creatinine clearances was expressed by Pearson's correlation coefficient. RESULTS:The mean MAG3 clearance in the potential kidney donors was 321 +/- 95 mL/min/1.73 m2 (95% CI, 171-546 mL/min/1.73 m2), significantly higher than the mean creatinine clearance of 152 +/- 51 mL/min/1.73 m2 (79-278 mL/min/1.73 m2, p < 0.001). The mean MAG3 clearance in patients was 153 +/- 70 mL/min/1.73 m2 (32-316 mL/min/1.73 m2) and was also significantly higher than the mean creatinine clearance of 74 +/- 36 mL/min/1.73 m2 (21-138 mL/min/1.73 m2, p < 0.001). The ratio of the mean creatinine clearance to the mean MAG3 clearance was essentially the same for volunteers and patients, 0.47 and 0.48, respectively. The Pearson's correlation between the MAG3 and creatinine clearances was 0.80 (0.72-0.86). CONCLUSION:The camera-based 99mTc-MAG3 clearance correlates well with the 24-hour creatinine clearance and can provide a simple and convenient index of kidney function.

背景与目标： 目的：24小时肌酐清除率是衡量肾脏功能的标准临床技术。然而，这种测量对于患者而言是麻烦且不便的。我们假设与标准MAG3扫描同时获得的基于相机的tech 99m巯基乙酰基三甘氨酸（MAG3）清除率与24小时肌酐清除率相关性很好，并且可以用作肾脏功能的简单标记。
材料与方法：数据来自对28位不同程度的肾功能不全患者的回顾性分析，并对85位受试者的肾脏捐赠进行了评估。 MAG3清除率是使用基于相机的技术计算的，无需进行血液或尿液采样。使用血浆肌酐和24小时尿液收集来测量肌酐清除率。校正了MAG3和肌酐的清除率以进行表面积测定，并使用配对的Student's t检验比较了健康受试者和患者的清除率值。 MAG3和肌酐清除率之间的线性关联由皮尔逊相关系数表示。
结果：潜在肾脏供体的平均MAG3清除率为321 /-95 mL / min / 1.73 m2（95％CI，171-546 mL / min / 1.73 m2），显着高于平均肌酐清除率152 /-51 mL / min / 1.73平方米（79-278 mL / min / 1.73平方米，p <0.001）。患者的平均MAG3清除率为153 /-70 mL / min / 1.73 m2（32-316 mL / min / 1.73 m2），也显着高于平均肌酐清除率74 /-36 mL / min / 1.73 m2（ 21-138 mL / min / 1.73 m2，p <0.001）。志愿者和患者的平均肌酐清除率与平均MAG3清除率之比基本相同，分别为0.47和0.48。 MAG3和肌酐清除率之间的Pearson相关性为0.80（0.72-0.86）。
结论：基于相机的99mTc-MAG3清除率与24小时肌酐清除率相关性良好，可以提供简单便捷的肾脏功能指标。

BACKGROUND & AIMS: OBJECTIVE:To investigate renal preservation by a novel method of perfusion using an oxygenated perfluorocarbon (PFC) emulsion via retrograde access to the kidney, as preserving renal function during urological surgery has been elusive, and the recognized technique of nephron-sparing surgery has increased its application and practice in modern urology. MATERIALS AND METHODS:After institutional review and approval, 30 New Zealand White rabbits were studied. In a solitary kidney model, each rabbit had the ureter catheterized before 40 min of renal artery occlusion. Each rabbit was randomized to one retrograde perfusion group, i.e. sham, normothermic PFC, chilled PFC, normothermic saline, and chilled saline. The rabbits were maintained for 2 weeks, during which renal function, urine output, systemic blood gases, weight and serum creatinine level were measured. After death, the kidneys were individually examined and graded by one renal pathologist unaware of the treatment. RESULTS:The rabbits treated with retrograde PFC perfusion (normothermic and chilled) had less change in their creatinine clearance, at 3.6 and 4.0 mL/min per kg, than the sham group, at 7.8 mL/min per kg, while also having significantly higher systemic venous oxygenation, at 26.3 and 10.0 mmHg, than the sham group, at 0.2 mmHg. Normothermic and chilled perfusion with PFC was also associated with less histological evidence of ischaemic damage, with mean (sd) scores of 13.0 (13.5) and 8.7 (4.5), respectively, than in the sham group, at 33.3 (16.8), while favourably matching the contralateral control kidney group, at 5.5 (2.3). The rabbits treated with saline retrograde perfusion also had better outcomes than the sham cohort. There were no adverse effects in any of the study arms or with the use of PFC. CONCLUSION:Retrograde oxygen delivery to the kidney through the urinary collecting system was successful in this pilot study. Renal function, laboratory and histological data indicate a trend towards renal preservation and even systemic oxygenation in the experimental groups compared with the sham rabbits, with no adverse effects attributed to this technique.

背景与目标： 目的：研究通过使用含氧的全氟化碳（PFC）乳剂通过逆行进入肾脏的一种新的灌注方法来保护肾脏，因为在泌尿外科手术中保留肾脏功能一直是遥不可及的，而保留肾单位的手术技术已经得到了广泛应用在现代泌尿外科中的应用和实践。
材料与方法：经过机构审查和批准，对30只新西兰白兔进行了研究。在孤立的肾脏模型中，每只兔子在肾动脉闭塞40分钟之前就已经插入了输尿管。每只兔子被随机分为一个逆行灌注组，即假手术，常温PFC，冷冻PFC，常温盐水和冷冻盐水。维持兔子2周，在此期间测量肾功能，尿量，全身血气，体重和血清肌酐水平。死亡后，由一名不了解治疗方法的肾脏病理学家对肾脏进行单独检查和分级。
结果：逆行PFC灌注（常温和冷藏）处理的兔子的肌酐清除率变化较小，分别为3.6和4.0 mL / min / kg，而假手术组则为7.8 mL / min / kg，但也显着高于假手术组。全身静脉氧合分别为26.3和10.0 mmHg，而假手术组为0.2 mmHg。 PFC的常温灌注和冷灌注也与缺血性损伤的组织学证据较少相关，与假手术组相比，平均（sd）评分分别为13.0（13.5）和8.7（4.5），而有利的是匹配对侧对照肾脏组，为5.5（2.3）。盐水逆行灌注治疗的兔子也比假手术组有更好的预后。在任何研究组中或使用PFC均无不良影响。
结论：在这项初步研究中，通过尿液收集系统向肾脏逆行输氧是成功的。肾脏功能，实验室和组织学数据表明，与假兔子相比，实验组的肾脏保存趋势甚至全身性充氧都有趋势，而该技术没有任何不良反应。

BACKGROUND & AIMS: :Related outer membrane proteins, termed secretins, participate in the secretion of macromolecules across the outer membrane of many Gram-negative bacteria. In the pullulanase-secretion system, PulS, an outer membrane-associated lipoprotein, is required both for the integrity and the proper outer membrane localization of the PulD secretin. Here we show that the PulS-binding site is located within the C-terminal 65 residues of PulD. Addition of this domain to the filamentous phage secretin, pIV, or to the unrelated maltose-binding protein rendered both proteins dependent on PulS for stability. A chimeric protein composed of bacteriophage f1 pIV and the C-terminal domain of PuID required properly localized PulS to support phage assembly. An in vivo complex formed between the pIV-PulD65 chimera and PulS was detected by co-immunoprecipitation and by affinity chromatography.

背景与目标： ：相关的外膜蛋白，称为促胰液素，参与许多革兰氏阴性细菌的外膜大分子的分泌。在支链淀粉酶分泌系统中，PulS是一种与外膜相关的脂蛋白，是PulD促胰液素的完整性和正确的外膜定位所必需的。在这里，我们显示PulS结合位点位于PulD的C末端65个残基内。该结构域添加到丝状噬菌体分泌蛋白，pIV或无关的麦芽糖结合蛋白上，使得这两种蛋白都依赖于PulS进行稳定性。由噬菌体f1 pIV和PuID的C末端结构域组成的嵌合蛋白需要适当定位的PulS才能支持噬菌体装配。通过共免疫沉淀和亲和色谱法检测到了pIV-PulD65嵌合体和PulS之间形成的体内复合物。

BACKGROUND & AIMS: :Professional antigen-presenting cells (APC) are able to process and present exogenous antigen leading to the activation of T cells. Antigen-immunoglobulin (Ig)G complexes (IC) are much more efficiently processed and presented than soluble antigen. Dendritic cells (DC) are known for their ability to take up and process immune complex (IC) via FcgammaR, and they have been shown to play a crucial role in IC-processing onto major histocompatibility complex (MHC) class I as they contain a specialized cross-presenting transport system required for MHC class I antigen-processing. However, the MHC class II-antigen-processing pathway is distinct. Therefore various other professional APC, like macrophages and B cells, all displaying FcgammaR, are thought to present IC-delivered antigen in MHC class II. Nonetheless, the relative contribution of these APC in IC-facilitated antigen-presentation for MHC class II in vivo is not known. Here we show that, in mice, both macrophages and DC, but not B cells, efficiently capture IC. However, only DC, but not macrophages, efficiently activate antigen-specific MHC class II restricted CD4(+) T cells. These results indicate that mainly DC and not other professional APC, despite expressing FcgammaR and MHC class II, contribute significantly to IC-facilitated T cell activation in vivo under steady-state conditions.

背景与目标： ：专业抗原呈递细胞（APC）能够处理并呈递导致T细胞活化的外源性抗原。抗原-免疫球蛋白（Ig）G复合物（IC）比可溶性抗原的加工和呈递效率更高。树突状细胞（DC）以其通过FcgR吸收并处理免疫复合物（IC）的能力而闻名，并且由于它们包含I型树突状细胞（DC），它们在IC处理I类主要组织相容性复合物（MHC）中起着至关重要的作用。 MHC I类抗原加工所需的专业交叉展示转运系统。但是，MHC II类抗原加工途径是不同的。因此，所有其他均显示FcγR的其他专业APC（如巨噬细胞和B细胞）被认为在II类MHC中呈递IC传递的抗原。然而，尚不清楚这些APC在体内II型MHC的IC促进的抗原呈递中的相对贡献。在这里，我们表明，在小鼠中，巨噬细胞和DC都有效捕获了IC，而B细胞却没有。但是，只有DC，而不是巨噬细胞，可以有效地激活II型MHC限制性抗原特异性CD4（）T细胞。这些结果表明，尽管表达FcgammaR和II类MHC，主要还是DC，而不是其他专业APC，在稳态条件下在体内促进了IC促进的T细胞活化。

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: :We show that STAT5b is important for the in vivo accumulation of CD4+ CD25(high) T cells with regulatory cell function. A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+ CD25(high) T cells. STAT5b(A630P/A630P) CD4+ CD25(high) T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+ CD25- T cells. Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation. The impact of the STAT5b mutation was selective in that IL-2-mediated up-regulation of the common gamma-chain cytokine receptor and perforin, and activation-induced expressions of CD154 and IFN-gamma were normal. These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells.

背景与目标： ：我们表明STAT5b对于具有调节性细胞功能的CD4 CD25（high）T细胞在体内的积累很重要。一名纯合的错义A630P STAT5b突变患者表现出免疫失调和CD4 CD25（高）T细胞数量减少。 STAT5b（A630P / A630P）CD4 CD25（高）T细胞的叉头盒P3表达低，抑制CD4 CD25- T细胞增殖或杀死其的能力受损。高亲和力IL-2R的组成部分CD25的表达也响应IL-2或在体外繁殖后降低。 STAT5b突变的影响是选择性的，因为IL-2介导了共同的γ链细胞因子受体和穿孔素的上调，并且激活诱导的CD154和IFN-γ的表达是正常的。这些结果表明STAT5b传播重要的IL-2介导的信号，用于体内功能性调节性T细胞的蓄积。

BACKGROUND & AIMS: :The oncoprotein LMP1 mimics an activated CD40 receptor, yet it is not known whether constitutive CD40 signaling, like LMP1, is sufficient to transform cells. Here we demonstrate that constitutive activation of the CD40 pathway by a chimeric LMP1CD40 molecule resembles the transforming function of LMP1 in inducing loss of contact inhibition and anchorage independent growth of Rat1 fibroblasts. Rat1 transformation correlates with the expression level of LMP1CD40 and depends on its ability to oligomerize. Our data provide direct evidence for the oncogenic potential of the CD40 signaling pathway, which is also established as a model-mechanism for LMP1-induced transformation.

背景与目标： ：癌蛋白LMP1模仿激活的CD40受体，但尚不知道本构性CD40信号是否像LMP1一样足以转化细胞。在这里，我们证明了嵌合LMP1CD40分子对CD40途径的组成性激活类似于LMP1的转化功能，可诱导Rat1成纤维细胞失去接触抑制和锚定非依赖性生长。 Rat1转化与LMP1CD40的表达水平相关，并取决于其寡聚能力。我们的数据为CD40信号传导途径的致癌潜力提供了直接证据，该途径也被确立为LMP1诱导转化的模型机制。

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在75位接受800-1200 mcg布地奈德或同等水平的哮喘成年人中进行，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，FEC1的平均调整值从给药前的0.22 L（95％CI 0.19，0.35 L）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在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。