关键词： antibody-based pharmacodelivery   F8 antibody   immunocytokines   DSS-induced colitis   interleukin-22  

摘要： Background: We have recently described the potential of the alternatively spliced extradomain A of fibronectin as a target for antibody-based pharmacodelivery applications in ulcerative colitis. Here, we report on the cloning and therapeutic properties of novel antibody-based fusion proteins, comprising the F8 antibody specific to extradomain A and murine interleukin (IL)-22, a globular cytokine belonging to the IL10 family. A protective function for IL22 in colitis has previously been described, as this cytokine induces antimicrobial, proliferative, and antiapoptotic pathways, preventing tissue damage and promoting epithelial repair. Methods: Two fusion proteins comprising IL22, fused at the N- or at the C-terminus of the F8 antibody in diabody format, were expressed in mammalian cells. The ability of radiolabeled preparations of the 2 fusion proteins to localize at sites of disease was assessed by autoradiography in a murine model of dextran sodium sulfate-induced colitis and by quantitative biodistribution analysis in a syngeneic mouse teratocarcinoma model. Therapeutic activity was assessed in mice with dextran sodium sulfate-induced colitis, which received intravenous injections of antibody-cytokine fusion proteins. Results: Both fusion proteins were able to selectively accumulate at the site of disease. The fusion protein with the cytokine moiety at the N-terminal extremity (IL22-F8) exhibited better results than the C-terminal fusion, both in terms of targeting selectivity and therapeutic efficacy. Mice treated with IL22-F8 showed a more rapid recovery from clinical symptoms compared with controls and improved macroscopic and microscopic morphology of the colon. Conclusions: IL22-F8 is a promising biopharmaceutical drug candidate for the treatment of ulcerative colitis.

关键词： Colitis   Dextran sulfate sodium   Dysbiosis   Mice   Microbiota  

摘要： The most widely used and characterized experimental model of ulcerative colitis (UC) is the epithelial erosion, dextran sulfate sodium (DSS)-induced colitis, which is developed by administration of DSS in drinking water. We investigated fecal and colonic mucosa microbial composition and functional changes in mice treated with DSS. C57Bl/6 mice received 5% DSS in drinking water for 5 days. Inflammation was evaluated clinically and by analysis of colonic tissue cytokine levels and C-reactive protein (CRP) in the serum. Colonic mucosa and fecal samples were used for DNA extraction and the V4 region of bacterial 16S rRNA gene was subjected to MiSeq Illumina sequencing. Alpha- and beta-diversities, and compositional differences at phylum and genus levels were determined, and bacterial functional pathways were predicted. DSS increased disease severity, serum CRP and cytokines IL-1 and IL-6, but decreased bacterial species richness, and shifted bacterial community composition. Bacteroides, Turicibacter, Escherichia, Clostridium, Enterobacteriaceae, Clostridiaceae, Bacteroidaceae, Bacteroidales, among other taxa were associated with DSS treatment in fecal and colonic samples. Also, DSS altered microbial functional pathways in both colonic mucosa and fecal samples. Conclusions: The development of colitis in DSS model was accompanied with reduced microbial diversity and dysbiosis of gut microbiota at lower taxonomical levels.

关键词： Dried saliva spot (DSS)   Detergent-assisted sample extraction   Ultra-high performance liquid chromatographyetandem mass spectrometry (UHPLC-MS/MS)   BMS-927711   Quantitation Pharmacokinetic study  

摘要： Dried saliva spot (DSS) sampling is a non-invasive sample collection technique for bioanalysis that can be potentially implemented at the patient's home. A UHPLC-MS/MS assay was developed using detergent-assisted sample extraction to quantify BMS-927711, a drug candidate in development for the treatment of migraines, in human DSS. By implementing DSS sampling at the patients' home, the bioanalytical sample collection for pharmacokinetic evaluation can be done at the time of the acute migraine attack without the need for clinical visits. DSS samples were prepared by spotting 15 mu L of liquid saliva onto regular Whatman FTA (TM) DMPK-C cards and verified with a UV lamp (at l 254 nm or 365 nm) during DSS punching. The 4-mm DSS punches in a 96-well plate were sonicated with 200 mu L of [C-13(2), D-4]-BMS-927711 internal standard (IS) solution in 20/80 MeOH/water for 10 min, followed by sonication with 50 mu L of 100 mM NH4OAc with 1.0% Triton-X-100 (as detergent) prior to liquid-liquid extraction with 600 mu L EtOAc/Hexane (90: 10). UHPLC-MS/MS was performed with an Aquity (R) UPLC BEH C18 Column (2.1 x 50 mm, 1.7 mm) on a Triple Quad (TM) 5500 mass spectrometer. The assay was linear with a concentration range from 2.00 to 1000 ng mL(-1) for BMS-927711 in human saliva. The intra-and inter-assay precision was within 8.8% CV, and the accuracy was within +/- 6.7% Dev of the nominal concentration values. This UHPLCeMS/MS assay has been successfully applied to determine the drug's pharmacokinetics within a clinical study. For the first time, we observed BMS-927711 exposure in human DSS, confirming the suitability of this sampling technique for migraine patients to use at home. Detergent-assisted extraction with Triton-X-100 could be very useful in DSS or other dried matrix spot (DMS) assays to overcome low or inconsistent analyte recovery issues. (C) 2016 Elsevier B.V. All rights reserved.

关键词： 医保管理   商业智能   决策支持  

摘要： 目的:通过搭建商业智能分析平台,实现对医保住院病人管理工作进行实时监控与干预。方法:通过建立医保业务数据仓库,使用商业智能(BI)分析挖掘医保病人住院期间各个方面的信息数据,建立预警监控平台、并提供多维分析平台。结论:通过应用商业智能(BI)技术,深度挖掘医保病人在住院期间的各个节点信息数据。通过预警平台监控、多维分析等技术方法,及时发现医保病人住院管理方面的存在的各种问题,从而为提升医院内涵质量建设,医院综合科学管理水平,辅助管理决策提供有效信息化手段。

摘要： Serum level of IL-21 is increased in patients with inflammatory bowel diseases (IBD), suggesting that IL-21/IL-21 receptor (IL-21R) signaling may be involved in the pathogenesis of IBD. However, the role of IL-21/IL-21 receptor signaling plays in the pathogenesis of IBD is not very clear. In this study, using IL-21R. KO mice, we tested the role of IL-21/IL-21R signaling in the regulation of T helper cell responses during intestinal inflammation. Here we found that IL-21R. KO mice were more susceptible to DSS-induced colitis as compared with C57BL/6 mice. The spontaneous inflammatory cytokines released by macrophages in LP of colon were significantly increased, and Th2, Th17 and Treg responses were down-regulated markedly. However, Th1 responses were significantly up-regulated in IL-21R. KO mice. Meanwhile, the population of CD8(+) CD44(+)IFN-gamma(+) T cells was markedly elevated in LP of inflammatory intestine of IL-21RKO mice. In vivo, after disease onset, DSS-induced intestinal inflammation was ameliorated in C57BL/6 mice treated with rIL-21. Our results demonstrate that IL-21/IL-21R signaling contributes to protection against DSS-induced acute colitis through suppression of Th1 and activation of Th2, Th17 and Treg responses in mice. Therefore, therapeutic manipulation of IL-21/IL-21R activity may allow improved immunotherapy for IBD and other inflammatory diseases associated with Th cell responses.

关键词： Biology and life sciences   Demography   Depression   Education   Educational attainment   Factor analysis   Mathematical and statistical techniques   Mathematics   Medicine and health sciences   Mental health and psychiatry   Mood disorders   Multivariate analysis   People and places   Physical sciences   Psychology   Psychometrics   Questionnaires   Research and analysis methods   Research Article   Research assessment   Research design   Research validity   Social sciences   Sociology   Statistical methods   Statistics (mathematics)   Survey research  

摘要： Background Research on depression stigma is needed to gain more insight into the underlying construct and to reduce the level of stigma in the community. However, few validated measurements of depression stigma are available in the Netherlands. Therefore, this study first sought to examine the psychometric properties of the Dutch translation of the Depression Stigma Scale (DSS). Second, we examined which demographic (gender, age, education, partner status) and other variables (anxiety and knowledge of depression) are associated with personal and perceived stigma within these samples. Methods The study population consisted of an adult convenience sample (n = 253) (study 1) and a community adult sample with elevated depressive symptoms (n = 264) (study 2). Factor structure, internal consistency, and validity were assessed. The associations between stigma, demographic variables and anxiety level were examined with regression analyses. Results Confirmatory factor analysis supported the validity and internal consistency of the DSS personal stigma scale. Internal consistency was sufficient (Cronbach's alpha = .70 (study 1) and .77 (study 2)). The results regarding the perceived stigma scale revealed no clear factor structure. Regression analyses showed that personal stigma was higher in younger people, those with no experience with depression, and those with lower education. Conclusions This study established the validity and internal consistency of the DSS personal scale in the Netherlands, in a community sample and in people with elevated depressive symptoms. However, additional research is needed to examine the factor structure of the DSS perceived scale and its use in other samples.

关键词： 药品零售   数据挖掘技术   经营决策支持   应用价值  

摘要： 目的探究在医院药房药品零售经营决策支持中应用数据挖掘技术的效果及价值。方法从我院2013年01月起,在我院药房零售经营工作中建立微软SQL Server 2010数据工作库,并且运用关联规则法对我院药品日常销售产生的数据作数据挖掘和相关分析。结果顾客购入抗眩晕及维生素药物后,再购入理血药物的可能性大;同时购入解毒消炎药及清热解毒类药物饮片后,再购入五官科用药的几率大;购入心脑血管药物、消化系统药物的顾客主要为中老年患者,再购入理血药物的可能性大;夏秋季节清热解毒类中药饮片的销售额较高,顾客在购入咽喉含片时,有较大的可能性购入清热解毒类中药饮片;购入补益药、祛风湿药物之后,再购入骨伤科用药的几率较大。结论在医院药房药品零售经营决策支持中应用数据挖掘技术,便于分析和判断顾客的购物规律和趋势,能够为完善零售经营决策方案提供有价值的信息支持。