BACKGROUND & AIMS: Ligation of surface IgM on B cells responding to lipopolysaccharide (LPS) suppresses terminal differentiation and high-rate Ig secretion with no effect on proliferation. As shown here, different B cell populations show characteristic mean values of ligand concentration required for 50% inhibition, with Gaussian distributions of sensitivity to IgM receptor ligation that reflect cellular heterogeneity of 'al-or-none' inhibitions in single cells. Differential sensitivity of B cell populations to IgM ligation seems to be locally determined by the cellular environment and unrelated to the 'maturity' of the responding cells. Thus, while long-lived peritoneal B cells are 3- to 5-fold more resistant than splenic B cells, there is no difference in sensitivity between short- and long-lived B cells in the spleen. Furthermore, while B cells in bone marrow and spleen differ in sensitivity by two orders of magnitude, B cells differentiated in vitro from bone marrow pre-B cells are as resistant as splenic B cells. Moreover, bone marrow cell culture supernatants restore a high level of sensitivity in such cell populations. Differential sensitivity to IgM receptor ligation is reproduced by multivalent nominal antigen, in cell populations that show identical dose-response inhibition curves to direct activation of protein kinase C by phorbol esters. We conclude that the level of sensitivity to IgM ligation is independent of the life span or maturity of the B cell, but differentially regulated in vivo by putative tissue factors.

背景与目标： 响应脂多糖（LPS）的B细胞表面IgM的连接可抑制终末分化和高速率的Ig分泌，而对增殖没有影响。如此处所示，不同的B细胞群体显示出50％抑制所需的配体浓度的特征平均值，其对IgM受体连接的敏感性的高斯分布反映了单细胞“异或无”抑制的细胞异质性。 B细胞群体对IgM连接的差异敏感性似乎是由细胞环境局部决定的，并且与响应细胞的“成熟度”无关。因此，虽然长寿腹膜B细胞的抵抗力比脾脏B细胞高3至5倍，但脾脏中短寿和长寿B细胞之间的敏感性没有差异。此外，尽管骨髓和脾脏中的B细胞在敏感性方面相差两个数量级，但体外与骨髓前B细胞分化出的B细胞与脾脏B细胞一样具有抗性。而且，骨髓细胞培养物上清液在这种细胞群体中恢复了高水平的敏感性。在表现出相同剂量反应抑制曲线以直接通过佛波醇酯激活蛋白激酶C的细胞群体中，多价名义抗原重现了对IgM受体连接的不同敏感性。我们得出的结论是，对IgM结扎的敏感性水平与B细胞的寿命或成熟度无关，但在体内受假定的组织因子的调节。

BACKGROUND & AIMS: Tn10, like several other transposons, exhibits a marked preference for integration into particular target sequences. Such sequences are referred to as integration hotspots and have been used to define a consensus target site in Tn10 transposition. We demonstrate that a Tn10 hotspot called HisG1, which was identified originally in vivo, also functions as an integration hotspot in vitro in a reaction where the HisG1 sequence is present on a short DNA oligomer. We use this in vitro system to define factors which are important for the capture of the HisG1 target site. We demonstrate that although divalent metal ions are not essential for HisG1 target capture, they greatly facilitate capture of a mutated HisG1 site. Analysis of catalytic transposase mutants further demonstrates that the DDE motif plays a critical role in 'divalent metal ion-dependent' target capture. Analysis of two other classes of transposase mutants, Exc+ Int- (which carry out transposon excision but not integration) and ATS (altered target specificity), demonstrates that while a particular ATS transposase binds HisG1 mutants better than wild-type transposase, Exc+ Int- mutants are defective in HisG1 capture, further defining the properties of these classes of mutants. Possible mechanisms for the above observations are considered.

背景与目标： 像其他几种转座子一样，Tn10表现出明显的整合特定靶序列的偏好。此类序列称为整合热点，已用于定义Tn10转座中的共有靶位点。我们证明了一个称为HisG1的Tn10热点，最初在体内被发现，在一个短DNA低聚物上存在HisG1序列的反应中，它在体外还起着整合热点的作用。我们使用这个体外系统来定义对于捕获HisG1目标位点很重要的因素。我们证明，尽管二价金属离子对于HisG1目标捕获不是必需的，但它们极大地促进了突变的HisG1位点的捕获。催化转座酶突变体的分析进一步表明，DDE基序在“二价金属离子依赖性”靶标捕获中起关键作用。分析另外两类转座酶突变体Exc Int-（进行转座子切除但不整合）和ATS（改变的靶标特异性）表明，虽然特定的ATS转座酶与HisG1突变体的结合比野生型转座酶Exc Int-突变体在HisG1捕获中存在缺陷，进一步定义了这类突变体的特性。考虑了上述观察的可能机制。

BACKGROUND & AIMS: :The final elimination step of self-reactive T cells occurs in the medulla of the thymus where a complex framework provided by stromal cells supports an optimal milieu for their selection. Here we present evidence that tight junctions (TJs) widely join medullary stromal cells of the human thymus. Occludin (OCLN) and claudin-1 (CLDN-1) of TJ-associated molecules were dominantly expressed in medullary thymic epithelial cells (mTECs), and CLDN-4 and CLDN-7 were also localized in some mTECs near Hassall's corpuscles. Interestingly, p53-like transcription factors were found to upregulate OCLN and CLDN-1 in human TEC lines, as recently suggested in the regulation of mTEC function. Furthermore, dendritic cells (DCs) of the medulla, with a major role for selection of thymocytes, expressed CLDN-1 and OCLN as well, implying that the interposition of DCs within the mTEC scaffold is also helped by TJs. Analysis of freeze-fracture replicas of the thymus revealed TJ strand structures in the vicinity of gap junction plaques through which small molecules might move, as implied by dye-transfer analysis of a medullary cell line. Thus, it is thought that p53-like molecules regulate TJ-associated interactions of medullary stromal cells and that this mechanism might be associated with an intercellular communication network, probably for preserving the medullary niches.

背景与目标： ：自我反应性T细胞的最终消除步骤发生在胸腺的髓质中，其中基质细胞提供的复杂框架为它们的选择提供了最佳环境。在这里，我们提供证据表明紧密连接（TJs）广泛加入人类胸腺的髓质基质细胞。 TJ相关分子的Occludin（OCLN）和claudin-1（CLDN-1）主要在髓样胸腺上皮细胞（mTECs）中表达，CLDN-4和CLDN-7也位于Hassall小体附近的某些mTECs中。有趣的是，正如最近在调控mTEC功能中所建议的那样，发现p53样转录因子可上调人TEC细胞系中的OCLN和CLDN-1。此外，在选择胸腺细胞中起主要作用的髓质树突状细胞（DC）也表达CLDN-1和OCLN，这暗示TJ也有助于mTEC支架内DC的插入。胸腺的冷冻断裂复制品的分析显示，在间隙连接斑块附近的TJ链结构中，小分子可能会通过间隙连接斑块移动，正如髓细胞系的染料转移分析所暗示的那样。因此，认为p53样分子调节髓质基质细胞的TJ相关相互作用，并且该机制可能与细胞间通讯网络有关，可能是为了保留髓ni。

BACKGROUND & AIMS: :With currently available combination chemotherapy regimens, the outcome of the patients newly diagnosed with aggressive non-Hodgkin's lymphoma (NHL) identified as 'high' and 'high-intermediate' risk groups according to the international prognostic index (IPI) is still unsatisfactory and a more innovative therapy is urgently required to improve the survival of the patients. The purpose of this study was to compare the efficacy of rituximab given in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and ESHAP (etoposide, methylprednisolone, high-dose Ara-C, cisplatin) vs CHOP-ESHAP and upfront high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) vs standard CHOP in patients aged < or = 65 years old newly diagnosed with 'high' and 'high-intermediate' risk aggressive lymphoma enrolled onto two consecutive treatment trials at the institute. Between May 1995 - July 2002, 84 patients, aged 15 - 65 years old, with newly diagnosed aggressive NHL and an age-adjusted IPI of 2 or 3 were enrolled. The median age of the patients was 38 years (range 15 - 65). The baseline demographic features, in particular the major prognostic variables, were similar between the treatment groups. Patients treated with rituximab-CHOP-ESHAP received eight cycles of rituximab (375 mg m(-2) on day 1 of cycles 1 - 6 and days 21 and 28 of cycle 7) plus CHOP (day 3 of cycles 1, 3 and 5) and ESHAP (day 3 of cycles 2, 4 and 6 and day 1 of cycle 7) at 21-day intervals. Patients enrolled onto the CHOP-ESHAP-HDT arm (n = 23) were treated with three courses of CHOP and then switched to two or four cycles of ESHAP followed by HDT. Patients treated with CHOP alone (n = 25) were treated with the standard eight cycles of CHOP. The rate of complete remission was significantly improved with rituximab-CHOP-ESHAP compared with either CHOP-ESHAP-HDT or CHOP alone (67% compared with 44% and 36%, respectively; p = 0.043). With a median follow-up time of 53 months, the 5-year overall survival (OS) was improved by the addition of rituximab-61% with rituximab-CHOP-ESHAP, compared with 43% for CHOP-ESHAP-HDT and 24% for CHOP alone (p = 0.088). Significant increases in failure-free survival (FFS) and disease-free survival (DFS) (61% and 96%), compared with CHOP-ESHAP-HDT (34% and 90%) and CHOP (16% and 44%; p = 0.002 and p < 0.001, respectively) were observed. Compared to CHOP, rituximab-CHOP-ESHAP yielded significantly superior OS (p = 0.014), FFS (p < 0.001) and DFS (p < 0.001). The survivals, however, were not significantly different from patients treated with CHOP-ESHAP-HDT. It is concluded that rituximab-ESHAP-CHOP is superior over standard CHOP and fares comparably to upfront HDT/ASCT in previously untreated patients with aggressive lymphoma. A prospective randomized controlled trial is warranted to confirm these results.

背景与目标： ：根据目前的联合化疗方案，根据国际预后指标（IPI），新诊断为侵袭性非霍奇金淋巴瘤（NHL）的患者的预后仍然不理想，并且迫切需要一种更具创新性的疗法来提高患者的生存率。这项研究的目的是比较利妥昔单抗与CHOP（环磷酰胺，阿霉素，长春新碱，泼尼松）和ESHAP（依托泊苷，甲基强的松龙，大剂量Ara-C，顺铂）联合使用的利妥昔单抗与CHOP-ESHAP和前期高剂量联合治疗的疗效在该研究所进行的两项连续治疗试验中，对新诊断为“高”和“高中度”风险性侵袭性淋巴瘤的年龄≤65岁的患者进行剂量治疗（HDT）和自体干细胞移植（ASCT）与标准CHOP对照。在1995年5月至2002年7月之间，纳入了84例年龄在15至65岁之间，新诊断为侵袭性NHL且年龄校正后的IPI为2或3的患者。患者的中位年龄为38岁（范围15-65）。治疗组之间的基线人口统计学特征，尤其是主要的预后变量相似。接受利妥昔单抗-CHOP-ESHAP治疗的患者接受了八个周期的利妥昔单抗（第1-6周期的第1天以及第7周期的第21和28天）（375 mg m（-2））加CHOP（第1、3和5周期的第3天） ）和ESHAP（周期2、4和6的第3天和周期7的第1天），间隔为21天。入组CHOP-ESHAP-HDT组（n = 23）的患者接受了三个疗程的CHOP治疗，然后切换到ESSHAP的两个或四个周期，然后进行HDT。单独接受CHOP治疗的患者（n = 25）接受了标准的八个CHOP周期治疗。与单独使用CHOP-ESHAP-HDT或CHOP相比，利妥昔单抗-CHOP-ESHAP的完全缓解率显着提高（分别为67％，44％和36％； p = 0.043）。中位随访时间为53个月，利妥昔单抗-CHOP-ESHAP加利妥昔单抗-61％改善了5年总生存（OS），相比之下，CHOP-ESHAP-HDT和43％改善了5年总生存率仅适用于CHOP（p = 0.088）。与CHOP-ESHAP-HDT（34％和90％）和CHOP（16％和44％）相比，无失败生存率（FFS）和无病生存率（DFS）显着增加（61％和96％）；分别观察到= 0.002和p​​ <0.001）。与CHOP相比，利妥昔单抗-CHOP-ESHAP产生显着优越的OS（p = 0.014），FFS（p <0.001）和DFS（p <0.001）。但是，其存活率与用CHOP-ESHAP-HDT治疗的患者无明显差异。结论是，对于以前未经治疗的侵袭性淋巴瘤患者，利妥昔单抗-ESHAP-CHOP优于标准CHOP，且其费用可与前期HDT / ASCT相提并论。必须进行前瞻性随机对照试验来证实这些结果。

BACKGROUND & AIMS: PURPOSE:To understand the prospective relationship between depressive symptoms and sexual risk behavior among a community sample of African American adolescents. METHODS:African American adolescents (n = 415) who participated in a larger multi-site human immunodeficiency virus (HIV) prevention program provided baseline data on demographics, psychosocial context and depressive symptoms. At six-month follow-up, data were collected regarding sexual activity in the past 90 days. Multivariate logistic regression was conducted to determine the prospective relationship between depressive symptoms and proportion of condom use while controlling for relevant demographic and contextual factors. RESULTS:The odds that African American adolescents who reported depressive symptoms at baseline would report inconsistent condom use at six-month follow-up was approximately four times greater than that of their peers who did not report depressive symptoms. Older adolescents and females were less likely to use condoms consistently and certain contextual factors, such as less pleasurable expectations about condom use, and living with a partner also heightened HIV/STI risk. CONCLUSIONS:Clinicians should assess for depression symptoms in African American adolescent patients as an indicator of future sexual risk. Prevention interventions that address depressed mood could have a significant impact on later HIV/STI sexual risk behaviors. Further research is needed to understand the effect of depressive symptoms on sexual risk among adolescents of other race/ethnicities and to examine the potential cultural forces that affect this relationship.

背景与目标： 目的：了解非裔美国青少年社区样本中抑郁症状与性危险行为之间的预期关系。
方法：参加较大的多站点人类免疫缺陷病毒（HIV）预防计划的非裔美国青少年（n = 415）提供了有关人口统计学，社会心理背景和抑郁症状的基线数据。在六个月的随访中，收集了过去90天内有关性活动的数据。进行多因素logistic回归分析以确定抑郁症状与安全套使用比例之间的预期关系，同时控制相关的人口统计学和背景因素。
结果：在基线时报告抑郁症状的非洲裔美国青少年在六个月的随访中报告使用安全套不一致的几率是未报告抑郁症状的同龄人的四倍。较大的青少年和女性不太可能一贯使用安全套，并且某些情境因素，例如对使用安全套的期望降低，以及与伴侣生活在一起，也增加了艾滋病毒/性传播疾病的风险。
结论：临床医生应评估非洲裔美国青少年患者的抑郁症状，作为未来性风险的指标。预防情绪低落的预防干预措施可能会对以后的HIV / STI性风险行为产生重大影响。需要进一步的研究来了解抑郁症状对其他种族/族裔青少年的性风险的影响，并研究影响这种关系的潜在文化力量。

BACKGROUND & AIMS: The accuracy of cervicovaginal fetal fibronectin as a predictor of preterm birth was studied in patients with increased risk for preterm delivery (according to the Creasy-score). In a prospective blind observational study the smear from the posterior fornix vaginae of 56 pregnant patients without PROM was examined using a quantitative immunoassay for the detection of fetal fibronectin. The patients who tested positively for fetal fibronectin had significantly more preterm deliveries than those with a negative result (CHI square-test, p < 0.01, RR 5.1). Overall, sensitivity, specificity, positive and negative predictive values were 56%, 87%, 45% and 91%, respectively. In patients with preterm labor these values were 75%, 87%, 60%, and 93%, respectively. No patient with a negative result delivered preterm during the following two weeks. It is concluded that performing the fetal fibronectin test in patients with preterm labor is useful for the prediction of preterm birth. Routine testing in patients at increased risk (asymptomatic patients) is not recommended for lack of effectiveness.

背景与目标： 宫颈阴道胎儿纤连蛋白作为早产预测指标的准确性已在早产风险增加的患者中进行了研究（根据Creasy评分）。在一项前瞻性盲观察研究中，使用定量免疫测定法检测了56例无PROM的孕妇的后穹vagina阴道涂片，以检测胎儿的纤连蛋白。胎儿纤连蛋白检测阳性的患者早产的结果明显高于阴性结果（CHI Square-test，p <0.01，RR 5.1）。总体而言，敏感性，特异性，阳性和阴性预测值分别为56％，87％，45％和91％。在有早产的患者中，这些值分别为75％，87％，60％和93％。在接下来的两周内，没有阴性结果的患者早产。结论是在早产患者中进行胎儿纤连蛋白测试有助于预测早产。不建议对风险较高的患者（无症状的患者）进行常规检查，因为其缺乏有效性。

BACKGROUND & AIMS: :At mammalian body temperature, the plague bacillus Yersinia pestis synthesizes lipopolysaccharide (LPS)-lipid A with poor Toll-like receptor 4 (TLR4)-stimulating activity. To address the effect of weak TLR4 stimulation on virulence, we modified Y. pestis to produce a potent TLR4-stimulating LPS. Modified Y. pestis was completely avirulent after subcutaneous infection even at high challenge doses. Resistance to disease required TLR4, the adaptor protein MyD88 and coreceptor MD-2 and was considerably enhanced by CD14 and the adaptor Mal. Both innate and adaptive responses were required for sterilizing immunity against the modified strain, and convalescent mice were protected from both subcutaneous and respiratory challenge with wild-type Y. pestis. Despite the presence of other established immune evasion mechanisms, the modified Y. pestis was unable to cause systemic disease, demonstrating that the ability to evade the LPS-induced inflammatory response is critical for Y. pestis virulence. Evading TLR4 activation by lipid A alteration may contribute to the virulence of various Gram-negative bacteria.

背景与目标： ：在哺乳动物体温下，鼠疫耶尔森菌鼠疫杆菌合成脂多糖（LPS）-脂质A，其Toll样受体4（TLR4）刺激活性较弱。为了解决弱TLR4刺激对毒力的影响，我们修饰了鼠疫耶尔森氏菌以产生有效的TLR4刺激LPS。即使在高激发剂量下，改良的鼠疫耶尔森氏菌在皮下感染后也完全无毒。对疾病的抗性需要TLR4，衔接蛋白MyD88和共受体MD-2，并且CD14和衔接蛋白Mal大大增强了抗病性。对修饰菌株的免疫力需要先天性和适应性应答，野生型鼠疫耶尔森氏菌可以保护恢复期的小鼠免受皮下和呼吸道攻击。尽管存在其他已建立的免疫逃逸机制，但经过修饰的鼠疫耶尔森氏菌不能引起全身性疾病，这表明逃避脂多糖诱导的炎症反应的能力对鼠疫耶尔森氏菌的毒力至关重要。通过脂质A改变而避免TLR4激活可能会导致多种革兰氏阴性细菌的致病性。

BACKGROUND & AIMS: :The Management Academy for Public Health is a team-based training program jointly offered by the School of Public Health and the Kenan-Flagler Business School at the University of North Carolina at Chapel Hill. This 9-month program teaches public health managers how to better manage people, information, and finances. Participants learn how to work in teams with community partners, and how to think and behave as social entrepreneurs. To practice and blend their new skills, teams develop a business plan that addresses a local public health issue. This article describes the program and explains the findings of the process evaluation, which has examined how best to structure and deploy a team-based method to create more effective, more entrepreneurial public health managers. Findings indicate that recruitment and retention are strong, program elements are relevant to learners' needs, and learners are satisfied with and value the program. Several specific benefits of the program model are identified, as well as several elements that support business plan success and skills' application on the job. On the basis of these findings, four success factors critical for developing similar programs are identified.

背景与目标： ：公共卫生管理学院是一项基于团队的培训计划，由北卡罗来纳大学教堂山分校的公共卫生学院和Kenan-Flagler商学院联合提供。这个为期9个月的课程向公共卫生经理讲授如何更好地管理人员，信息和财务。参与者学习如何与社区合作伙伴一起工作，以及如何思考和表现为社会企业家。为了练习和融合他们的新技能，团队制定了解决当地公共卫生问题的商业计划。本文介绍了该程序，并说明了过程评估的结果，该过程评估了如何最好地构建和部署基于团队的方法来创建更有效，更具创业精神的公共卫生经理。调查结果表明，招聘和留住人才的能力很强，计划要素与学习者的需求相关，学习者对计划感到满意和重视。确定了计划模型的几个特定优点，以及支持业务计划成功和技能在工作中应用的几个要素。根据这些发现，确定了开发类似程序的四个成功因素。

BACKGROUND & AIMS: BACKGROUND:Insomnia is widely reported and widely treated in general practice, yet relatively little research has focused on the natural history of the condition in primary care settings. As a result, there is at present little information to enable clinicians to assess insomnia risk, or anticipate outcomes in older general practice populations.

AIM:To estimate, using 8-year longitudinal data, the risk of insomnia onset associated with selected health and lifestyle factors.

METHOD:Survivors from a nationally representative sample (n = 1042) of elderly people originally interviewed in 1985 were reassessed in 1989 (n = 690) and 1993 (n = 410). At the first follow up in 1989, 84 new cases of insomnia were identified (a weighted incidence rate per person per year at a risk of 3.1%; 95% CI = 2.7-3.5). In logistic regression analyses controlling for age and sex, the risk of insomnia onset was then assessed in relation to the selected factors.

RESULTS:Three factors assessed in 1985 were significantly and independently related to incident insomnia: psychometric ratings consistent with depressed mood odds ratio (OR) = 4.41; 95% CI = 3.32-5.43); health index scores indicating lower physical health status (OR = 1.19; 95% CI = 1.06-1.31 per unit change in scale score); and moderate and low levels of physical activity (OR = 1.91 and 2.14; 95% CI = 1.91-3.62 and 2.14-3.64 respectively). However, although depressed mood represented a major risk factor, the most likely source of risk was physical rather than mental ill-health.

CONCLUSIONS:Psychiatric, somatic and lifestyle factors significantly and independently increase the risk of insomnia in older general practice patients. In predicting incident sleep disturbance, these factors exceed in importance the age and sex of patients.

背景与目标： 背景：失眠已被广泛报道并在一般实践中得到了广泛的治疗，但是相对较少的研究集中在初级保健机构中病情的自然史上。因此，目前尚无足够的信息可帮助临床医生评估失眠风险或预测老年全科人群的结局。

AIM ：使用8年纵向评估数据，与选定的健康和生活方式因素相关的失眠风险。

方法：对来自全国代表性样本（n = 1042）的老年人的幸存者进行了重新评估，该样本最初于1985年接受采访。在1989年（n = 690）和1993（n = 410）。在1989年的首次随访中，发现了84例新的失眠病例（加权平均每人每年的发病率，风险为3.1％； 95％CI = 2.7-3.5）。在控制年龄和性别的逻辑回归分析中，然后根据所选因素评估了失眠的风险。

结果：1985年评估的三个因素具有显着性和独立性发生失眠：心理测验评分与沮丧的情绪几率之比（OR）= 4.41； 95％CI = 3.32-5.43）；健康指数得分，表明身体健康状况较低（OR = 1.19； 95％CI =单位得分变化每单位1.06-1.31）；中度和低度的体育活动（OR分别为1.91和2.14； 95％CI分别为1.91-3.62和2.14-3.64）。但是，尽管情绪低落是主要的危险因素，但最可能的危险来源是身体而不是精神疾病。

结论：精神，躯体和生活方式因素显着且独立增加老年全科患者失眠的风险。在预测事件性睡眠障碍时，这些因素的重要性超过了患者的年龄和性别。