BACKGROUND & AIMS: OBJECTIVES:To characterize the naturally occurring expanded-spectrum beta-lactamase from an Escherichia coli clinical isolate and to compare it with a wild-type beta-lactamase. METHODS:The chromosome-borne ampC genes from E. coli BER and E. coli EC2 were PCR amplified, sequenced and cloned into an expression vector. Antimicrobial susceptibilities of the parental isolate and the recombinant strains were determined by agar dilution methods. Kinetic parameters were determined from purified AmpC BER and AmpC EC2. RESULTS:AmpC BER was overexpressed in its original clinical isolate because of mutations in the promoter region of its gene at positions -42 and -18. The analysis of the ampC coding sequence revealed a 6 bp insertion when compared with the wild-type sequence leading to the tandem duplication of two alanine residues inside the H-10 helix. AmpC BER-producing recombinants were resistant to ceftazidime, had reduced susceptibility to other oxyiminocephalosporins (cefotaxime and cefepime), but had a greater susceptibility to cefoxitin when compared with the recombinant expressing the wild-type beta-lactamase AmpC EC2. The affinity of AmpC BER for cephalosporins and imipenem was increased, whereas the hydrolysis rate was decreased for all these compounds. In addition, the IC50 values of clavulanic acid and tazobactam for AmpC BER were increased. CONCLUSIONS:This work sheds new light on structure-function relationships of expanded-spectrum AmpC beta-lactamases.

背景与目标： 目的：鉴定来自大肠杆菌临床分离株的天然存在的广谱β-内酰胺酶，并将其与野生型β-内酰胺酶进行比较。
方法：PCR扩增来自大肠杆菌BER和大肠杆菌EC2的染色体传播的ampC基因，测序并克隆到表达载体中。通过琼脂稀释法测定亲本分离株和重组菌株的抗药性。动力学参数由纯化的AmpC BER和AmpC EC2确定。
结果：AmpC BER在其原始临床分离株中过表达，因为其基因的启动子区域位于-42和-18位。 ampC编码序列的分析显示，与野生型序列相比，插入了6 bp，导致H-10螺旋内部两个丙氨酸残基串联重复。与表达野生型β-内酰胺酶AmpC EC2的重组体相比，产生AmpC BER的重组体对头孢他啶具有抗性，对其他氧亚氨基头孢菌素（头孢噻肟和头孢吡肟）的敏感性降低，但对头孢西丁的敏感性更高。 AmpC BER对头孢菌素和亚胺培南的亲和力增加，而所有这些化合物的水解速率均降低。此外，棒酸和他唑巴坦对AmpC BER的IC50值增加。
结论：这项工作为广谱AmpCβ-内酰胺酶的结构-功能关系提供了新的思路。

BACKGROUND & AIMS: :Mesenchymal stem cells (MSCs) have been exploited as cellular vectors to treat a wide array of diseases but the mechanisms responsible for their therapeutic effect remain indeterminate. Previously, we reported that MSCs inhibit bleomycin (BLM)-induced inflammation and fibrosis within the lungs of mice. Interrogation of the MSC transcriptome identified interleukin 1 receptor antagonist (IL1RN) as a potential mediator of this effect. Fractionation studies indicated that MSCs are the principal source of IL1RN in murine bone marrow and that its expression is restricted to a unique subpopulation of cells. Moreover, MSC-conditioned media was shown to block proliferation of an IL-1alpha-dependent T cell line and inhibit production of TNF-alpha by activated macrophages in vitro. Studies conducted in mice revealed that MSC administration was more effective than recombinant IL1RN delivered via adenoviral infection or osmotic pumps in inhibiting BLM-induced increases in TNF-alpha, IL-1alpha, and IL1RN mRNA in lung, IL1RN protein in bronchoalveolar lavage (BAL) fluid, and trafficking of lymphocytes and neutrophils into the lung. Therefore, MSCs protect lung tissue from BLM-induced injury by blocking TNF-alpha and IL-1, two fundamental proinflammatory cytokines in lung. Identification of IL1RN-expressing human MSC subpopulations may provide a novel cellular vector for treating chronic inflammatory diseases in humans.

背景与目标： 间充质干细胞（MSCs）已被用作治疗多种疾病的细胞载体，但其治疗效果的机制仍不确定。以前，我们报道了MSC抑制博来霉素（BLM）诱导的小鼠肺内炎症和纤维化。对MSC转录组的询问确定白介素1受体拮抗剂（IL1RN）是这种作用的潜在介体。分级研究表明，MSC是鼠骨髓中IL1RN的主要来源，其表达仅限于细胞的独特亚群。此外，MSC条件培养基显示在体外可阻断IL-1alpha依赖性T细胞系的增殖并抑制巨噬细胞活化TNF-α的产生。在小鼠中进行的研究表明，与通过腺病毒感染或渗透泵输送的重组IL1RN相比，MSC抑制BLM诱导的肺中TNF-α，IL-1alpha和IL1RN mRNA的增加，支气管肺泡灌洗（BAL）中的IL1RN蛋白的抑制作用更有效。液体，以及淋巴细胞和中性粒细胞向肺的运输。因此，MSC通过阻断TNF-α和IL-1（肺中两种基本的促炎细胞因子）来保护肺组织免受BLM诱导的损伤。鉴定表达IL1RN的人MSC亚群可以提供用于治疗人的慢性炎性疾病的新型细胞载体。

BACKGROUND & AIMS: BACKGROUND:Time trade-off (TTO) exercises typically present respondents with a limited time horizon, for example 10 years, thus implicitly considerably reducing remaining life expectancy for the average respondent. It is unclear how this affects health state valuations. AIM:The aim of the study is to investigate how awareness of the reduced life span implied by a 10-year TTO affects health state valuations, using an experimental design. METHODS:Two Web-based questionnaires (Q1 and Q2) were administered in a sample representative of the Dutch population. Both questionnaires contained three 10-year TTO exercises valuing three distinct health states, specified using the EQ-5D. Q1 used a TTO instruction not explicitly emphasizing the fact that remaining life expectancy was reduced to 10 years, while in Q2 respondents were explicitly made aware of this fact by emphasizing their implied age of death. Respondents answering Q1 were asked retrospectively whether they had been aware of their reduced life span due to the 10-year TTO. RESULTS:In total, 656 respondents completed the questionnaires (Q1: 339 and Q2: 317). The average age of the respondents was 43 years and 51 % of respondents were male. The average numbers of years traded off for the respondents of Q1 were for TTO1 0.443, TTO2 0.552, and TTO3 2.083 years. For the respondents of Q2, these averages were lower, i.e., TTO1 0.401 (p = 0.085 vs. Q1), TTO2: 0.546 (p = 0.036 vs. Q1), and TTO3: 1.467 years (p = 0.000 vs. Q1). Fifty-seven percent of respondents in Q1 confirmed that they were aware of the reduced life span. This spontaneous awareness had a limited and mixed influence on results. The generalized negative binomial regression analysis, explaining the time traded off showed that age, subjective life expectancy, and questionnaire Q2 (vs. Q1) were negatively associated with the years traded off, whereas education and worse health states in the TTO exercise had a significant positive impact on the years traded off. The probit model investigating the impact on the willingness to trade showed that age (-), education (+), subjective life expectancy (-), questionnaire Q2 versus Q1 (-), the interaction between Q2 and male gender (+), and worse health states in the TTO exercise (+) had a significant impact on the willingness to trade. CONCLUSION:These findings emphasize the importance of expected and implied life expectancy in TTOs.

背景与目标： 背景：时间权衡（TTO）练习通常为受访者提供有限的时间范围（例如10年），从而隐含地大大降低了平均受访者的剩余预期寿命。目前尚不清楚这如何影响健康状况评估。
目的：该研究的目的是使用实验设计，调查对10年TTO所隐含的寿命缩短的认识如何影响健康状况评估。
方法：在代表荷兰人口的样本中进行了两份基于Web的问卷（Q1和Q2）。两份问卷均包含三个为期10年的TTO演习，评估了使用EQ-5D指定的三种不同的健康状态。第一季度使用的是TTO指令，没有明确强调预期寿命会缩短至10年，而第二季度的受访者则通过强调其隐性死亡年龄来明确意识到这一事实。回顾性地回答了回答第一季度的受访者，他们是否知道由于10年的TTO而缩短了寿命。
结果：共有656名受访者完成了问卷（第一季度：339；第二季度：317）。受访者的平均年龄为43岁，而51％的受访者为男性。第一季度受访者需要权衡的平均年数为TTO1 0.443，TTO2 0.552和TTO3 2.083年。对于第二季度的受访者来说，这些平均值较低，即TTO1 0.401（p = 0.085 vs.Q1），TTO2：0.546（p = 0.036 vs.Q1）和TTO3：1.467年（p = 0.000 vs.Q1）。第一季度有57％的受访者确认他们知道寿命缩短了。这种自发的意识对结果的影响有限而又复杂。广义负二项式回归分析解释了折衷的时间，表明年龄，主观预期寿命和问卷Q2（相对于Q1）与折衷的年负相关，而TTO锻炼中的教育程度和健康状况较差对折中年的积极影响。概率模型对贸易意愿的影响进行了调查，结果显示年龄（-），教育程度（），主观预期寿命（-），调查问卷Q2与Q1（-），Q2与男性之间的相互作用（）和健康状况较差TTO演习中的州（）对贸易意愿产生了重大影响。
结论：这些发现强调了预期和隐含的预期寿命在TTO中的重要性。

BACKGROUND & AIMS: BACKGROUND:Interleukin (IL)-9 drives gut inflammation, but its role in Crohn's disease (CD) is unclear. We aimed to analyze correlations between serum IL-9 levels and disease severity and to evaluate their predictive value in relation to the clinical efficacy of infliximab (IFX) in patients with CD. METHODS:Between January 2013 and December 2015, 100 consecutive patients with active CD and 50 age- and sex-matched control individuals were recruited from a tertiary center. Their serum IL-9 levels were measured using an enzyme-linked immunosorbent assay. Correlations between the serum IL-9 levels and disease severity were examined. The serum IL-9 level was explored as a predictor of clinical remission and mucosal healing at week 30 in 50 patients for whom IFX therapy was administered. RESULTS:The serum IL-9 levels were significantly higher in the patients with active CD (22.0 pg/mL) than in the control individuals (6.3 pg/mL) (P < 0.001); they differed according to disease severity (moderate-to-severe CD: 29.1 pg/mL versus mild CD: 12.9 pg/mL) (P < 0.001), and they correlated well with the clinical activity of CD. IFX lowered the serum IL-9 level in patients who achieved efficacy at week 30. The areas under the curves for the IL-9 levels at weeks 14 and 30 that could predict clinical remission and mucosal healing at week 30 were 0.803 and 0.752 and 0.746 and 0.781, respectively. CONCLUSIONS:Serum IL-9 levels correlate with disease severity and the clinical efficacy of IFX in patients with CD, and IL-9 may be a promising novel biomarker for CD monitoring.

背景与目标： 背景：白介素（IL）-9可驱动肠道炎症，但其在克罗恩病（CD）中的作用尚不清楚。我们旨在分析血清IL-9水平与疾病严重程度之间的相关性，并评估其与英夫利昔单抗（IFX）在CD患者中的临床疗效相关的预测价值。
方法：2013年1月至2015年12月，从三级中心招募了100例连续的活动性CD患者和50例年龄和性别匹配的对照个体。使用酶联免疫吸附测定法测量其血清IL-9水平。检查血清IL-9水平与疾病严重程度之间的相关性。在接受IFX治疗的50例患者中，血清IL-9水平在30周时可作为临床缓解和粘膜愈合的预测指标。
结果：活动性CD患者的血清IL-9水平显着高于对照组（6.3 pg / mL）（22.0 pg / mL）（P <0.001）；它们根据疾病的严重程度而有所不同（中度至重度CD：29.1 pg / mL，轻度CD：12.9 pg / mL）（P <0.001），并且它们与CD的临床活性密切相关。 IFX降低了在30周时达到疗效的患者的血清IL-9水平。在14周和30周时可预测临床缓解和粘膜愈合的IL-9水平曲线下面积分别为0.803和0.752和0.746和0.781。
结论：血清IL-9水平与CD患者的疾病严重程度和IFX的临床疗效相关，并且IL-9可能是有前途的新型CD监测生物标志物。

BACKGROUND & AIMS: :Previous studies conducted in Western cultures have shown that negative emotions predict higher levels of pro-inflammatory biomarkers, specifically interleukin-6 (IL-6). This link between negative emotions and IL-6 may be specific to Western cultures where negative emotions are perceived to be problematic and thus may not extend to Eastern cultures where negative emotions are seen as acceptable and normal. Using samples of 1044 American and 382 Japanese middle-aged and older adults, we investigated whether the relationship between negative emotions and IL-6 varies by cultural context. Negative emotions predicted higher IL-6 among American adults, whereas no association was evident among Japanese adults. Furthermore, the interaction between culture and negative emotions remained even after controlling for demographic variables, psychological factors (positive emotions, neuroticism, extraversion), health behaviors (smoking status, alcohol consumption), and health status (chronic conditions, BMI). These findings highlight the role of cultural context in shaping how negative emotions affect inflammatory physiology and underscore the importance of cultural ideas and practices relevant to negative emotions for understanding of the interplay between psychology, physiology, and health.

背景与目标： ：以前在西方文化中进行的研究表明，负面情绪预示着较高的促炎性生物标志物，特别是白介素6（IL-6）。消极情绪与IL-6之间的这种联系可能特定于西方文化，在该文化中，消极情绪被认为是有问题的，因此可能不会扩展到东方文化，在东方文化中，消极情绪被视为可以接受并且是正常的。我们使用1044名美国人和382名日本中年和老年人的样本，调查了负面情绪与IL-6之间的关系是否因文化背景而异。负面情绪预示着美国成年人IL-6升高，而日本成年人却没有明显的关联。此外，即使在控制了人口统计学变量，心理因素（正性情绪，神经质，外向性），健康行为（吸烟状况，饮酒）和健康状况（慢性状况，BMI）之后，文化与负面情绪之间的相互作用仍然存在。这些发现强调了文化背景在塑造负面情绪如何影响炎症生理方面的作用，并强调了与负面情绪相关的文化观念和实践对于理解心理学，生理学和健康之间相互作用的重要性。

BACKGROUND & AIMS: :The key component in the so-called EPRI effective dose equivalent (EDE) methodology is an algorithm that utilizes two dosimeters (instead of multiple dosimeters) to predict the EDE for external photon exposures. The exposure scenarios that were previously studied in deriving the algorithm include parallel photon beams and point sources 33 cm from the body surface. The motivation for this study was the need to investigate source locations within 33 cm from the body so the method is more widely applicable. The ORNL stylized mathematical human phantoms and the MCNP code were used to calculate organ doses in this study. This paper presents the EDE data for point gamma sources at 0.3, 1.0, and 1.5 MeV, respectively, which are located at 10 cm from the surface of the body. The results and analyses show that the locations ranging from the overhead to the foot have resulted in conservative ratios except for two general regions near the front upper thigh and directly overhead. If all locations considered in this study were averaged for each photon energy, the overall ratio is on the conservative side. These data suggest that the EPRI EDE methodology is still valid for sources located 10 cm from the body, although the chance for resulting in a non-conservative estimate of the EDE has increased in comparison with the sources located at 30 cm from the body. Finally, this paper provides recommendations on how to apply the EPRI EDE methodology.

背景与目标： ：所谓的EPRI有效剂量当量（EDE）方法中的关键组件是一种算法，该算法利用两个剂量计（而不是多个剂量计）来预测外部光子暴露的EDE。先前在推导算法时曾研究过的曝光场景包括平行光子束和距体表33 cm的点光源。这项研究的动机是需要调查距人体33厘米以内的放射源位置，因此该方法更广泛地适用。在本研究中，使用了ORNL程式化的数学人体模型和MCNP代码来计算器官剂量。本文介绍了分别位于距人体表面10 cm处的0.3 MeV，1.0 MeV和1.5 MeV的点伽马源的EDE数据。结果和分析表明，从头顶到脚的位置范围导致了保守的比率，除了大腿前上方和直接头顶附近的两个一般区域。如果在本研究中考虑的所有位置均针对每种光子能量求平均值，则总体比率处于保守的一面。这些数据表明，EPRI EDE方法对于距离人体10厘米处的放射源仍然有效，尽管与位于人体30厘米处的放射源相比，导致EDE非保守估计的机会有所增加。最后，本文提供了有关如何应用EPRI EDE方法的建议。