Science.gov

Sample records for atiksu ve biyokatilarinda

  1. Learning the value of VE

    SciTech Connect

    Sperling, R.B.

    1989-03-03

    Describing lessons learned from Value Engineers (VE) studies at a government-funded research laboratory reveals how project managers were encouraged to use VE and how their projects benefited from the VE savings. The five major lessons were: An officer of ''free'' VE is a low-risk incentive to encourage the use of VE; More costs savings can be identified by VE studies than cost reviews or design reviews; Large projects can benefit from repeat VE studies; VE teams can identify surprising savings when allowed to challenge all design criteria; VE programs can be costs effective even though return on investment may vary among projects. 6 tabs.

  2. The VE/CAD synergism

    SciTech Connect

    Sperling, R.B.

    1993-03-19

    Value Engineering (VE) and Computer-Aided Design (CAD) can be used synergistically to reduce costs and improve facilities designs. The cost and schedule impacts of implementing alternative design ideas developed by VE teams can be greatly reduced when the drawings have been produced with interactive CAD systems. To better understand the interrelationship between VE and CAD, the fundamentals of the VE process are explained; and example of a VE proposal is described and the way CAD drawings facilitated its implementation is illustrated.

  3. 23 CFR 627.7 - VE programs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 false VE programs. 627.7 Section 627.7 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.7 VE programs. (a) The STA shall establish and sustain a VE program under which VE analyses...

  4. 23 CFR 627.7 - VE programs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 false VE programs. 627.7 Section 627.7 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.7 VE programs. (a) The STA shall establish and sustain a VE program under which VE analyses...

  5. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  6. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  7. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  8. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Value engineering (VE). 35.926 Section... engineering (VE). (a) Value engineering proposal. All step 2 grant applications for projects having a... completion of VE analysis and submittal of VE summary reports). (b) Value engineering analysis. For...

  9. Using VE to Strategically Plan Our Future

    SciTech Connect

    Margie Jeffs; Lori Braase; Alison Conner; Darcie Martinson; Jodi Grgich

    2009-06-01

    The Value Engineering (VE) Methodology is an effective tool for business or project strategic planning. In conjunction with the “Balanced Scorecard Approach” (Drs. Robert Kaplan, PhD, and David Norton, PhD, from the Balanced Scorecard Collaborative/Palladium Group), function analysis can be used to develop strategy maps and scorecards. The FAST diagram provides an integrated approach to strategy map development by formulating a cause and effect relationship and establishing the “how” and “why” behind the strategy map. By utilizing the VE Job Plan, one is able to move from strategic thinking all the way through to execution of the strategy.

  10. JoVE: the Journal of Visualized Experiments.

    PubMed

    Vardell, Emily

    2015-01-01

    The Journal of Visualized Experiments (JoVE) is the world's first scientific video journal and is designed to communicate research and scientific methods in an innovative, intuitive way. JoVE includes a wide range of biomedical videos, from biology to immunology and bioengineering to clinical and translation medicine. This column describes the browsing and searching capabilities of JoVE, as well as its additional features (including the JoVE Scientific Education Database designed for students in scientific fields).

  11. 40 CFR 35.926 - Value engineering (VE).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... projected total step 3 grant eligible cost of $10 million or more, excluding the cost for interceptor and...) Level of VE effort; (4) VE cost estimate; (5) VE schedule in relation to project schedule (including... project officer. Rejection of any recommendation shall be on the basis of cost-effectiveness,...

  12. The veA gene is necessary for the negative regulation of the veA expression in Aspergillus nidulans.

    PubMed

    Kim, Hyoun-Young; Han, Kap-Hoon; Lee, Mimi; Oh, Miae; Kim, Hee-Seo; Zhixiong, Xie; Han, Dong-Min; Jahng, Kwang-Yeop; Kim, Jong Hwa; Chae, Keon-Sang

    2009-08-01

    The veA gene is one of the key genes in regulating sexual development of Aspergillus nidulans. During the study on the veA gene, it was observed that the veA expression level is slightly higher in a veA1 mutant than in a wild type at 37 degrees C, suggesting that the wild type veA gene is necessary for the negative regulation of the veA expression. In the veA1 mutant, the veA expression was higher than in a wild type grown at 42 degrees C but equal at 30 degrees C. Furthermore, in a veA deletion mutant having its own promoter and the N-terminus of the VeA ORF, expression of the N-terminus by the veA promoter was highly up-regulated, supporting the possibility that the veA gene is important for the negative regulation of the veA expression. Analyses of the lacZ transcript and the beta-galactosidase activity from the reporter strains in the veA1 background, which were constructed by transformation of the lacZ reporter plasmids containing the lacZ gene under the control of the intact or the truncated veA promoters from the -943 to +262 bp region, showed that the truncated promoters produced more veA transcript and higher beta-galactosidase activity than the intact one at 30 degrees C, but equal at 42 degrees C. In addition, the serial-deletion analysis of the veA promoter identified a crucial region in the promoter from -943 to -740 bp for this derepression of the veA expression. Taken together, these results indicated that the veA gene is necessary for the negative regulation of the veA expression. Moreover, the veA expression was derepressed in the light-illuminated condition, where the VeA protein is hardly transported into the nucleus.

  13. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  14. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  15. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  16. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  17. 47 CFR 97.513 - VE session manager requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false VE session manager requirements. 97.513 Section 97.513 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND SPECIAL RADIO SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.513 VE session manager requirements....

  18. 23 CFR 627.9 - Conducting a VE analysis.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.9 Conducting a VE analysis. (a) A VE analysis should be conducted as early as practicable in... that consider alternative construction materials; and (2) Be conducted based on: (i) An engineering...

  19. 23 CFR 627.9 - Conducting a VE analysis.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS VALUE ENGINEERING § 627.9 Conducting a VE analysis. (a) A VE analysis should be conducted as early as practicable in... that consider alternative construction materials; and (2) Be conducted based on: (i) An engineering...

  20. Naïve Bayes classification in R

    PubMed Central

    2016-01-01

    Naïve Bayes classification is a kind of simple probabilistic classification methods based on Bayes’ theorem with the assumption of independence between features. The model is trained on training dataset to make predictions by predict() function. This article introduces two functions naiveBayes() and train() for the performance of Naïve Bayes classification. PMID:27429967

  1. Corium Spreading Over Concrete: The Vulcano VE-U7 and VE-U8 Tests

    SciTech Connect

    Journeau, Christophe; Boccaccio, Eric; Fouquart, Pascal; Jegou, Claude; Piluso, Pascal

    2002-07-01

    Two experiments have been performed in the VULCANO facility in which prototypic corium has been spread over concrete. In the VE-U7 test, a mixture representative of what can be expected at the opening of EPR reactor-pit gate has been spread on siliceous concrete and on a reference channel in inert refractory ceramic. The spreading progression was not much affected by the presence of concrete and sparging gases. In the VE-U8 test, a UO{sub 2}-ZrO{sub 2} mixture, prototypic of in-vessel corium, has been spread over a lime-siliceous concrete. Although residual power was not simulated in this experiment, up to 2 cm of concrete have been eroded during the test. Results in terms of spreading behaviour, effects of gases, concrete erosion and thermal attack are presented and discussed. (authors)

  2. Regulation of endothelial barrier function by p120-catenin∙VE-cadherin interaction

    PubMed Central

    Garrett, Joshua P.; Lowery, Anthony M.; Adam, Alejandro P.; Kowalczyk, Andrew P.; Vincent, Peter A.

    2017-01-01

    Endothelial p120-catenin (p120) maintains the level of vascular endothelial cadherin (VE-Cad) by inhibiting VE-Cad endocytosis. Loss of p120 results in a decrease in VE-Cad levels, leading to the formation of monolayers with decreased barrier function (as assessed by transendothelial electrical resistance [TEER]), whereas overexpression of p120 increases VE-Cad levels and promotes a more restrictive monolayer. To test whether reduced endocytosis mediated by p120 is required for VE-Cad formation of a restrictive barrier, we restored VE-Cad levels using an endocytic-defective VE-Cad mutant. This endocytic-defective mutant was unable to rescue the loss of TEER associated with p120 or VE-Cad depletion. In contrast, the endocytic-defective mutant was able to prevent sprout formation in a fibrin bead assay, suggesting that p120•VE-Cad interaction regulates barrier function and angiogenic sprouting through different mechanisms. Further investigation found that depletion of p120 increases Src activity and that loss of p120 binding results in increased VE-Cad phosphorylation. In addition, expression of a Y658F–VE-Cad mutant or an endocytic-defective Y658F–VE-Cad double mutant were both able to rescue TEER independently of p120 binding. Our results show that in addition to regulating endocytosis, p120 also allows the phosphorylated form of VE-Cad to participate in the formation of a restrictive monolayer. PMID:27852896

  3. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  4. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  5. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  6. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  7. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SERVICES AMATEUR RADIO SERVICE Qualifying Examination Systems § 97.509 Administering VE requirements. (a) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... person who holds an amateur operator license of the class specified below: (i) Amateur Extra, Advanced...

  8. GloVe C++ v. 1.0

    SciTech Connect

    Cox, Jonathan A.

    2015-12-02

    This code implements the GloVe algorithm for learning word vectors from a text corpus. It uses a modern C++ approach. This algorithm is described in the open literature in the referenced paper by Pennington, Jeffrey, Richard Socher, and Christopher D. Manning.

  9. Langley VEDIT for NOS/VE usage manual

    NASA Technical Reports Server (NTRS)

    Heaney, Margaret A.

    1987-01-01

    The use of the VEDIT editor on the CDC Network Operating System/Virtual Environment (NOS/VE) is discussed. The VEDIT, a utility, allows a user to edit files line by line (line mode). How to access and the use of VEDIT are explained. The parameters and the format of the individual commands are defined. Examples are included.

  10. Isolation of a Ve homolog, mVe1, and its relationship to Verticillium wilt resistance in Mentha longifolia (L.) Huds.

    PubMed

    Vining, Kelly; Davis, Thomas

    2009-08-01

    As a step toward greater understanding of the genetics of verticillium wilt resistance in plants, we report the sequencing of a candidate wilt resistance gene, mVe1, from the mint diploid model species, Mentha longifolia (Lamiaceae). mVe1 is a putative homolog of tomato (Solanum lycopersicum L.) verticillium wilt (Ve) resistance genes. The mVe1 gene has a coding region of 3,051 bp. The predicted mVe1 protein contains a leucine-rich repeat domain, a common feature of plant disease resistance proteins. We compared 13 mVe1 alleles from three mint species. These alleles shared 96.2-99.6% nucleotide identity. We analyzed four M. longifolia populations segregating with respect to mVe1 alleles and wilt resistance versus susceptibility and found one association between mVe1 genotype and wilt phenotype. We conclude that mVe1 may play a role in mint verticillium wilt resistance, but variation for resistance in our segregating progenies is likely polygenic. Therefore, further investigations of mVe1 and identification of additional candidate genes are both warranted.

  11. Integration of APECS and VE-Suite for Data Overlay

    SciTech Connect

    McCorkel, Doug; Bivins, Gerrick; Jordan, Terry; Bryden, Mark; Zitney, S.E.; Widmann, John; Osawe, Maxwell

    2008-06-01

    In the design of advanced power generation facilities, process simulation tools are being utilized to model plant behavior and quickly analyze results. While such tools enable investigation of crucial aspects of plant design, typical commercial process simulators still do not explore some plant design information, including high-fidelity data from computational fluid dynamics (CFD) models of complex thermal and fluid flow phenomena, economics data used for policy decisions, operational data after the plant is constructed, and as-built information for use in as-designed models. Software tools must be created that allow disparate sources of information to be integrated for facilitating accurate and effective plant design. At the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL), the Advanced Process Engineering Co-Simulator (APECS) has been developed as an integrated software suite that combines process simulation (e.g., Aspen Plus®) and high-fidelity equipment simulation (e.g., FLUENT®). In this paper, the integration of the high-fidelity CFD data with overall process data in a virtual power simulation environment will be described. More specifically, we will highlight VE-Suite, an open-source virtual engineering (VE) software toolkit, and its support of Aspen Plus® Hierarchy blocks via the VE-AspenUnit.

  12. Integration of APECS and VE-Suite for data overlay

    SciTech Connect

    McCorkel, D.; Bivins, G.; Jordan, T.; Bryden, M.; Zitney, S.; Widmann, J.; Osawe, M.

    2008-01-01

    In the design of advanced power generation facilities, process simulation tools are being utilized to model plant behavior and quickly analyze results. While such tools enable investigation of crucial aspects of plant design, typical commercial process simulators still do not explore some plant design information, including high-fidelity data from computational fluid dynamics (CFD) models of complex thermal and fluid flow phenomena, economics data used for policy decisions, operational data after the plant is constructed, and as-built information for use in as-designed models. Software tools must be created that allow disparate sources of information to be integrated for facilitating accurate and effective plant design. At the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL), the Advanced Process Engineering Co-Simulator (APECS) has been developed as an integrated software suite that combines process simulation (e.g., Aspen Plus®) and high-fidelity equipment simulation (e.g., FLUENT®). In this paper, the integration of the high-fidelity CFD data with overall process data in a virtual power simulation environment will be described. More specifically, we will highlight VE-Suite, an open-source virtual engineering (VE) software toolkit, and its support of Aspen Plus® Hierarchy blocks via the VE-AspenUnit.

  13. Ectopic expression of a Ve homolog VvVe gene from Vitis vinifera enhances defense response to Verticillium dahliae infection in tobacco.

    PubMed

    Tang, Juan; Lin, Jing; Yang, Yuwen; Chen, Tianzi; Ling, Xitie; Zhang, Baolong; Chang, Youhong

    2016-01-15

    Verticillium wilt is a soil borne disease that can cause devastating losses to the production of many economically important crops. A Ve1 homologous gene responding to Verticillium dahliae infection was identified in Vitis vinifera cv. "HeiFeng" by semi-quantitative reverse transcription polymerase chain reaction and was designated as VvVe. The overexpression of VvVe in transgenic Nicotiana benthamiana plants significantly enhanced the resistance to isolate V991 of V. dahliae when compared with the wild type plants. The expressions of defense-related genes including the salicylic acid regulated gene pathogen-related 1 (PR1) but not PR2, the ethylene- and jasmonic acid-regulated genes ethylene response factor 1 (ERF1) and lipoxygenase (LOX) were significantly increased due to over expression of VvVe. And greater accumulation of active oxygen, callose and phenylalanine-ammonia lyase were observed in the leaves of transgenic VvVe tobacco plants than the wild type when under infection by V. dahliae. Moreover, the hypersensitive response mimicking cell death was exclusively occurred in the transgenic VvVe tobacco plants but not in the wild type. Taken together, the VvVe gene is a Ve1 like gene which involves in the signal cascade of salicylic acid, jasmonate, and ethylene defense pathways and enhances defense response to V. dahliae infection in the transgenic tobacco.

  14. Arctic Boreal Vulnerability Experiment (ABoVE) Science Cloud

    NASA Astrophysics Data System (ADS)

    Duffy, D.; Schnase, J. L.; McInerney, M.; Webster, W. P.; Sinno, S.; Thompson, J. H.; Griffith, P. C.; Hoy, E.; Carroll, M.

    2014-12-01

    The effects of climate change are being revealed at alarming rates in the Arctic and Boreal regions of the planet. NASA's Terrestrial Ecology Program has launched a major field campaign to study these effects over the next 5 to 8 years. The Arctic Boreal Vulnerability Experiment (ABoVE) will challenge scientists to take measurements in the field, study remote observations, and even run models to better understand the impacts of a rapidly changing climate for areas of Alaska and western Canada. The NASA Center for Climate Simulation (NCCS) at the Goddard Space Flight Center (GSFC) has partnered with the Terrestrial Ecology Program to create a science cloud designed for this field campaign - the ABoVE Science Cloud. The cloud combines traditional high performance computing with emerging technologies to create an environment specifically designed for large-scale climate analytics. The ABoVE Science Cloud utilizes (1) virtualized high-speed InfiniBand networks, (2) a combination of high-performance file systems and object storage, and (3) virtual system environments tailored for data intensive, science applications. At the center of the architecture is a large object storage environment, much like a traditional high-performance file system, that supports data proximal processing using technologies like MapReduce on a Hadoop Distributed File System (HDFS). Surrounding the storage is a cloud of high performance compute resources with many processing cores and large memory coupled to the storage through an InfiniBand network. Virtual systems can be tailored to a specific scientist and provisioned on the compute resources with extremely high-speed network connectivity to the storage and to other virtual systems. In this talk, we will present the architectural components of the science cloud and examples of how it is being used to meet the needs of the ABoVE campaign. In our experience, the science cloud approach significantly lowers the barriers and risks to organizations

  15. Relation between VE/VCO2 slope and maximum phonation time in chronic heart failure patients.

    PubMed

    Izawa, Kazuhiro P; Watanabe, Satoshi; Brubaker, Peter H; Tochimoto, Shinobu; Hirano, Yasuyuki; Matsushima, Shinya; Suzuki, Tomohiro; Oka, Koichiro; Saito, Takashi; Omori, Yutaka; Suzuki, Kengo; Osada, Naohiko; Omiya, Kazuto; Shimizu, Hiroyuki; Akashi, Yoshihiro J

    2014-12-01

    This study aimed to determine the relation between the regression slope relating minute ventilation to carbon dioxide output (VE/VCO2 slope) and maximum phonation time (MPT), and the MPT required to attain a threshold value for VE/VCO2 slope of ≤ 34 in chronic heart failure (CHF) patients. This cross-sectional study enrolled 115 CHF patients (mean age, 54.5 years; men, 84.9%). VE/VCO2 slope was assessed during cardiopulmonary exercise testing (CPX). Thereafter, patients were divided into 2 groups according to exercise capacity: VE/VCO2 slope ≤ 34 (VE/VCO2 ≤ 34 group, n = 81) and VE/VCO2 slope > 34 (VE/VCO2 > 34 group, n = 34). For MPT measurements, all patients produced a sustained vowel/a:/ for as long as possible during respiratory effort from the seated position. All subjects showed significant negative correlation between VE/VCO2 slope and MPT (r = -0.51, P < 0.001). After adjustment for clinical characteristics, MPT was significantly higher in the VE/VCO2 ≤ 34 group vs VE/VCO2 > 34 group (21.4 ± 6.4 vs 17.4 ± 4.3 s, F = 7.4, P = 0.007). The appropriate MPT cut-off value for identifying a VE/VCO2 slope ≤ 34 was 18.12 seconds. An MPT value of 18.12 seconds may be a useful target value for identifying CHF patients with a VE/VCO2 slope ≤ 34 and for risk management in these patients.

  16. Aspergillus nidulans VeA subcellular localization is dependent on the importin alpha carrier and on light.

    PubMed

    Stinnett, Suzanne M; Espeso, Eduardo A; Cobeño, Laura; Araújo-Bazán, Lidia; Calvo, Ana M

    2007-01-01

    The veA gene is a light-dependent regulator governing development and secondary metabolism in Aspergillus nidulans. We have identified a putative bipartite nuclear localization signal (NLS) motif in the A. nidulans VeA amino acid sequence and demonstrated its functionality when expressed in yeast. Furthermore, migration of VeA to the nucleus was dependent on the importin alpha. This bipartite NLS is also functional when VeA is expressed in A. nidulans. Interestingly, we found that VeA migration to the nucleus is light-dependent. While in the dark VeA is located mainly in the nuclei, under light VeA is found abundantly in the cytoplasm. The VeA1 mutant protein (lacking the first 36 amino acids at the N-terminus) was found predominantly in the cytoplasm independent of illumination. This indicates that the truncated bipartite NLS in VeA1 is not functional and fails to respond to light. These results might explain the lack of the morphological light-dependent response in strains carrying the veA1 allele. We also evaluated the effect of light on production of the mycotoxin sterigmatocystin in a veA wild-type and the veA1 mutant strains and found that the highest amount of toxin was produced by the veA+ strain growing in the dark, condition favouring accumulation of VeA in the nucleus.

  17. VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer

    PubMed Central

    Schafroth, Christian; Galván, José A.; Centeno, Irene; Koelzer, Viktor H.; Dawson, Heather E.; Sokol, Lena; Rieger, Gregor; Berger, Martin D.; Hädrich, Marion; Rosenberg, Robert; Nitsche, Ulrich; Schnüriger, Beat; Langer, Rupert; Inderbitzin, Daniel; Lugli, Alessandro; Zlobec, Inti

    2015-01-01

    Aim VE1 is a monoclonal antibody detecting mutant BRAFV600E protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients. Methods Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks). Results Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks. Conclusion VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays. PMID:26496026

  18. Building Students' Understanding of Quadratic Equation Concept Using Naïve Geometry

    ERIC Educational Resources Information Center

    Fachrudin, Achmad Dhany; Putri, Ratu Ilma Indra; Darmawijoyo

    2014-01-01

    The purpose of this research is to know how Naïve Geometry method can support students' understanding about the concept of solving quadratic equations. In this article we will discuss one activities of the four activities we developed. This activity focused on how students linking the Naïve Geometry method with the solving of the quadratic…

  19. VE-cadherin interacts with cell polarity protein Pals1 to regulate vascular lumen formation.

    PubMed

    Brinkmann, Benjamin F; Steinbacher, Tim; Hartmann, Christian; Kummer, Daniel; Pajonczyk, Denise; Mirzapourshafiyi, Fatemeh; Nakayama, Masanori; Weide, Thomas; Gerke, Volker; Ebnet, Klaus

    2016-09-15

    Blood vessel tubulogenesis requires the formation of stable cell-to-cell contacts and the establishment of apicobasal polarity of vascular endothelial cells. Cell polarity is regulated by highly conserved cell polarity protein complexes such as the Par3-aPKC-Par6 complex and the CRB3-Pals1-PATJ complex, which are expressed by many different cell types and regulate various aspects of cell polarity. Here we describe a functional interaction of VE-cadherin with the cell polarity protein Pals1. Pals1 directly interacts with VE-cadherin through a membrane-proximal motif in the cytoplasmic domain of VE-cadherin. VE-cadherin clusters Pals1 at cell-cell junctions. Mutating the Pals1-binding motif in VE-cadherin abrogates the ability of VE-cadherin to regulate apicobasal polarity and vascular lumen formation. In a similar way, deletion of the Par3-binding motif at the C-terminus of VE-cadherin impairs apicobasal polarity and vascular lumen formation. Our findings indicate that the biological activity of VE-cadherin in regulating endothelial polarity and vascular lumen formation is mediated through its interaction with the two cell polarity proteins Pals1 and Par3.

  20. Rac1 functions as a reversible tension modulator to stabilize VE-cadherin trans-interaction

    PubMed Central

    Daneshjou, Nazila; Sieracki, Nathan; van Nieuw Amerongen, Geerten P.; Conway, Daniel E.; Schwartz, Martin A.

    2015-01-01

    The role of the RhoGTPase Rac1 in stabilizing mature endothelial adherens junctions (AJs) is not well understood. In this paper, using a photoactivatable probe to control Rac1 activity at AJs, we addressed the relationship between Rac1 and the dynamics of vascular endothelial cadherin (VE-cadherin). We demonstrated that Rac1 activation reduced the rate of VE-cadherin dissociation, leading to increased density of VE-cadherin at AJs. This response was coupled to a reduction in actomyosin-dependent tension across VE-cadherin adhesion sites. We observed that inhibiting myosin II directly or through photo-release of the caged Rho kinase inhibitor also reduced the rate of VE-cadherin dissociation. Thus, Rac1 functions by stabilizing VE-cadherin trans-dimers in mature AJs by counteracting the actomyosin tension. The results suggest a new model of VE-cadherin adhesive interaction mediated by Rac1-induced reduction of mechanical tension at AJs, resulting in the stabilization of VE-cadherin adhesions. PMID:25559184

  1. VE-cadherin interacts with cell polarity protein Pals1 to regulate vascular lumen formation

    PubMed Central

    Brinkmann, Benjamin F.; Steinbacher, Tim; Hartmann, Christian; Kummer, Daniel; Pajonczyk, Denise; Mirzapourshafiyi, Fatemeh; Nakayama, Masanori; Weide, Thomas; Gerke, Volker; Ebnet, Klaus

    2016-01-01

    Blood vessel tubulogenesis requires the formation of stable cell-to-cell contacts and the establishment of apicobasal polarity of vascular endothelial cells. Cell polarity is regulated by highly conserved cell polarity protein complexes such as the Par3-aPKC-Par6 complex and the CRB3-Pals1-PATJ complex, which are expressed by many different cell types and regulate various aspects of cell polarity. Here we describe a functional interaction of VE-cadherin with the cell polarity protein Pals1. Pals1 directly interacts with VE-cadherin through a membrane-proximal motif in the cytoplasmic domain of VE-cadherin. VE-cadherin clusters Pals1 at cell–cell junctions. Mutating the Pals1-binding motif in VE-cadherin abrogates the ability of VE-cadherin to regulate apicobasal polarity and vascular lumen formation. In a similar way, deletion of the Par3-binding motif at the C-terminus of VE-cadherin impairs apicobasal polarity and vascular lumen formation. Our findings indicate that the biological activity of VE-cadherin in regulating endothelial polarity and vascular lumen formation is mediated through its interaction with the two cell polarity proteins Pals1 and Par3. PMID:27466317

  2. Genetic dissection of Verticillium wilt resistance mediated by tomato Ve1.

    PubMed

    Fradin, Emilie F; Zhang, Zhao; Juarez Ayala, Juan C; Castroverde, Christian D M; Nazar, Ross N; Robb, Jane; Liu, Chun-Ming; Thomma, Bart P H J

    2009-05-01

    Vascular wilt diseases caused by soil-borne pathogens are among the most devastating plant diseases worldwide. The Verticillium genus includes vascular wilt pathogens with a wide host range. Although V. longisporum infects various hosts belonging to the Cruciferaceae, V. dahliae and V. albo-atrum cause vascular wilt diseases in over 200 dicotyledonous species, including economically important crops. A locus responsible for resistance against race 1 strains of V. dahliae and V. albo-atrum has been cloned from tomato (Solanum lycopersicum) only. This locus, known as Ve, comprises two closely linked inversely oriented genes, Ve1 and Ve2, that encode cell surface receptor proteins of the extracellular leucine-rich repeat receptor-like protein class of disease resistance proteins. Here, we show that Ve1, but not Ve2, provides resistance in tomato against race 1 strains of V. dahliae and V. albo-atrum and not against race 2 strains. Using virus-induced gene silencing in tomato, the signaling cascade downstream of Ve1 is shown to require both EDS1 and NDR1. In addition, NRC1, ACIF, MEK2, and SERK3/BAK1 also act as positive regulators of Ve1 in tomato. In conclusion, Ve1-mediated resistance signaling only partially overlaps with signaling mediated by Cf proteins, type members of the receptor-like protein class of resistance proteins.

  3. Alternative Routes to Induce Naïve Pluripotency in Human Embryonic Stem Cells.

    PubMed

    Duggal, Galbha; Warrier, Sharat; Ghimire, Sabitri; Broekaert, Dorien; Van der Jeught, Margot; Lierman, Sylvie; Deroo, Tom; Peelman, Luc; Van Soom, Ann; Cornelissen, Ria; Menten, Björn; Mestdagh, Pieter; Vandesompele, Jo; Roost, Matthias; Slieker, Roderick C; Heijmans, Bastiaan T; Deforce, Dieter; De Sutter, Petra; De Sousa Lopes, Susana Chuva; Heindryckx, Björn

    2015-09-01

    Human embryonic stem cells (hESCs) closely resemble mouse epiblast stem cells exhibiting primed pluripotency unlike mouse ESCs (mESCs), which acquire a naïve pluripotent state. Efforts have been made to trigger naïve pluripotency in hESCs for subsequent unbiased lineage-specific differentiation, a common conundrum faced by primed pluripotent hESCs due to heterogeneity in gene expression existing within and between hESC lines. This required either ectopic expression of naïve genes such as NANOG and KLF2 or inclusion of multiple pluripotency-associated factors. We report here a novel combination of small molecules and growth factors in culture medium (2i/LIF/basic fibroblast growth factor + Ascorbic Acid + Forskolin) facilitating rapid induction of transgene-free naïve pluripotency in hESCs, as well as in mESCs, which has not been shown earlier. The converted naïve hESCs survived long-term single-cell passaging, maintained a normal karyotype, upregulated naïve pluripotency genes, and exhibited dependence on signaling pathways similar to naïve mESCs. Moreover, they undergo global DNA demethylation and show a distinctive long noncoding RNA profile. We propose that in our medium, the FGF signaling pathway via PI3K/AKT/mTORC induced the conversion of primed hESCs toward naïve pluripotency. Collectively, we demonstrate an alternate route to capture naïve pluripotency in hESCs that is fast, reproducible, supports naïve mESC derivation, and allows efficient differentiation.

  4. Mutational analysis of the Ve1 immune receptor that mediates Verticillium resistance in tomato.

    PubMed

    Zhang, Zhao; Song, Yin; Liu, Chun-Ming; Thomma, Bart P H J

    2014-01-01

    Pathogenic Verticillium species are economically important plant pathogens that cause vascular wilt diseases in hundreds of plant species. The Ve1 gene of tomato confers resistance against race 1 strains of Verticillium dahliae and V. albo-atrum. Ve1 encodes an extracellular leucine-rich repeat (eLRR) receptor-like protein (RLP) that serves as a cell surface receptor for recognition of the recently identified secreted Verticillium effector Ave1. To investigate recognition of Ave1 by Ve1, alanine scanning was performed on the solvent exposed β-strand/β-turn residues across the eLRR domain of Ve1. In addition, alanine scanning was also employed to functionally characterize motifs that putatively mediate protein-protein interactions and endocytosis in the transmembrane domain and the cytoplasmic tail of the Ve1 protein. Functionality of the mutant proteins was assessed by screening for the occurrence of a hypersensitive response upon co-expression with Ave1 upon Agrobacterium tumefaciens-mediated transient expression (agroinfiltration). In order to confirm the agroinfiltration results, constructs encoding Ve1 mutants were transformed into Arabidopsis and the transgenes were challenged with race 1 Verticillium. Our analyses identified several regions of the Ve1 protein that are required for functionality.

  5. VeA of Aspergillus niger increases spore dispersing capacity by impacting conidiophore architecture.

    PubMed

    Wang, Fengfeng; Dijksterhuis, Jan; Wyatt, Timon; Wösten, Han A B; Bleichrodt, Robert-Jan

    2015-01-01

    Aspergillus species are highly abundant fungi worldwide. Their conidia are among the most dominant fungal spores in the air. Conidia are formed in chains on the vesicle of the asexual reproductive structure called the conidiophore. Here, it is shown that the velvet protein VeA of Aspergillus niger maximizes the diameter of the vesicle and the spore chain length. The length and width of the conidiophore stalk and vesicle were reduced nearly twofold in a ΔveA strain. The latter implies a fourfold reduced surface area to develop chains of spores. Over and above this, the conidial chain length was approximately fivefold reduced. The calculated 20-fold reduction in formation of conidia by ΔveA fits the 8- to 17-fold decrease in counted spore numbers. Notably, morphology of the ΔveA conidiophores of A. niger was very similar to that of wild-type Aspergillus sydowii. This suggests that VeA is key in conidiophore architecture diversity in the fungal kingdom. The finding that biomass formation of the A. niger ΔveA strain was reduced twofold shows that VeA not only impacts dispersion capacity but also colonization capacity of A. niger.

  6. VE/VCO2 slope and its prognostic value in patients with chronic heart failure.

    PubMed

    Shen, Yuqin; Zhang, Xiaoyu; Ma, Wenlin; Song, Haoming; Gong, Zhu; Wang, Qiang; Che, Lin; Xu, Wenjun; Jiang, Jinfa; Xu, Jiahong; Yan, Wenwen; Zhou, Lin; Ni, Y I; Li, Guanghe; Zhang, Qiping; Wang, Lemin

    2015-04-01

    The minute ventilation/carbon dioxide production (VE/VCO2) slope has been widely demonstrated to have strong prognostic value in patients with chronic heart failure (CHF), and the risk of mortality is believed to increase when the VE/VCO2 slope is >32.8; however, there is little evidence concerning the prognostic value of the VE/VCO2 slope in Chinese patients. In the present study, the prognostic value of the VE/VCO2 slope was investigated in patients with CHF. A total of 258 subjects underwent symptom-limited cardiopulmonary exercise testing (CPET) and were divided into CHF (113 males and 16 females; LVEF <0.49) and control (106 males and 23 females) groups. The cardiac-related events over a median 33.7-month follow-up period subsequent to the CPET were evaluated using receiver operating characteristic curve analysis. The VE/VCO2 slope was significantly different between the CHF and control groups (P<0.001). The area under the curve (AUC) for the VE/VCO2 slope in predicting cardiac-related mortalities in the patients with CHF was 0.670 (P<0.05), and the sensitivity and specificity of the VE/VCO2 slope were 0.667 and 0.620, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related mortalities in patients with CHF was ≥39.3. The AUC for the VE/VCO2 slope in predicting cardiac-related hospitalizations in patients with CHF was 0.682 (P<0.05), and the sensitivity and specificity of the VE/VCO2 slope were 0.631 and 0.778, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related hospitalizations in patients with CHF was ≥32.9. In conclusion, ventilatory efficiency decreases in patients with CHF. The VE/VCO2 slope is a strong predictor of cardiac-related mortalities in the patients with CHF analyzed.

  7. Holographic wavefront sensor based on Karhunen-Loève decomposition

    NASA Astrophysics Data System (ADS)

    Anzuola, Esdras; Zepp, Andreas; Gladysz, Szymon; Stein, Karin

    2016-09-01

    In this paper we introduce the use of Karhunen-Loève functions as a basis set to decompose atmospheric phase aberrations in a digital holographic wavefront sensor (HWS). We show that the intermodal crosstalk when using Karhunen-Loève functions is reduced in comparison to the Zernike decomposition. Additionally, the sensor's response showed an improved linearity and better robustness to scintillation. Intermodal crosstalk remains a significant problem for this sensor but operation of an adaptive optics system based on HWS is less challenging when using Karhunen-Loève functions instead of Zernike polynomials.

  8. The interplays among technology and content, immersant and VE

    NASA Astrophysics Data System (ADS)

    Song, Meehae; Gromala, Diane; Shaw, Chris; Barnes, Steven J.

    2010-01-01

    The research program aims to explore and examine the fine balance necessary for maintaining the interplays between technology and the immersant, including identifying qualities that contribute to creating and maintaining a sense of "presence" and "immersion" in an immersive virtual reality (IVR) experience. Building upon and extending previous work, we compare sitting meditation with walking meditation in a virtual environment (VE). The Virtual Meditative Walk, a new work-in-progress, integrates VR and biofeedback technologies with a self-directed, uni-directional treadmill. As immersants learn how to meditate while walking, robust, real-time biofeedback technology continuously measures breathing, skin conductance and heart rate. The physiological states of the immersant will in turn affect the audio and stereoscopic visual media through shutter glasses. We plan to test the potential benefits and limitations of this physically active form of meditation with data from a sitting form of meditation. A mixed-methods approach to testing user outcomes parallels the knowledge bases of the collaborative team: a physician, computer scientists and artists.

  9. Deposit information in gasoline engines: Part I. Base oil effects in sequence VE deposits

    SciTech Connect

    Supp, J.A.; Kornbrekke, R.E.; Roby, S.H.

    1994-12-01

    Base oil effects on sludge and deposit formation in the ASTM Sequence VE were studied with blends made using the same American Petroleum Institute (API) SG performance package and the same viscosity improver. One percent of the dispersant was removed from the formulation to accentuate base oil effects. Nine tests on six different 100N base oils were run. Sequence VE test lubricant drain analyses show differences in insolubles, viscosity, and particle size with base stock variations. The most significant base oil factors which can be used to predict Sequence VE sludge ratings are the base oil saturate content, polar content, and volatility. While all oils studied passed the Sequence VE API SG engine varnish and piston varnish requirements, higher levels of poly-nuclear aromatics (PNA`s) are shown to increase the severity of these ratings.

  10. S-nitrosylation regulates VE-cadherin phosphorylation and internalization in microvascular permeability.

    PubMed

    Guequén, Anita; Carrasco, Rodrigo; Zamorano, Patricia; Rebolledo, Lorena; Burboa, Pia; Sarmiento, José; Boric, Mauricio P; Korayem, Adam; Durán, Walter N; Sánchez, Fabiola A

    2016-04-15

    The adherens junction complex, composed mainly of vascular endothelial (VE)-cadherin, β-catenin, p120, and γ-catenin, is the main element of the endothelial barrier in postcapillary venules.S-nitrosylation of β-catenin and p120 is an important step in proinflammatory agents-induced hyperpermeability. We investigated in vitro and in vivo whether or not VE-cadherin isS-nitrosylated using platelet-activating factor (PAF) as agonist. We report that PAF-stimulates S-nitrosylation of VE-cadherin, which disrupts its association with β-catenin. In addition, based on inhibition of nitric oxide production, our results strongly suggest that S-nitrosylation is required for VE-cadherin phosphorylation on tyrosine and for its internalization. Our results unveil an important mechanism to regulate phosphorylation of junctional proteins in association with S-nitrosylation.

  11. [Effect of dietary VE on the contents of salivary acid and MDA in RBC membrane].

    PubMed

    Wang, F; Dong, Z; Zhang, Y; Chen, Y

    1997-05-01

    Vitamin E can protect membrane from the damage of lipid peroxidation, Salivary acid is the residual of carbohydrate on the membrane. To evaluate the effect of dietary VE on salivary acid, the contents of MDA and salivary acid of erythrocyte (RBC) membrane of rats were measured. The rats were fed with different amounts of dietary VE and stayed at different temperatures. The results revealed that the content of salivary acid of RBC membrane reduced markly (P < 0.01) and the content of MDA of RBC membrane was stable (P > 0.05) after the rats were exposed to cold for 10 days. High dietary VE intake increased the content of salivary acid of RBC membrane (P < 0.01). There was no correlation between the content of salivary acid and MDA of RBC membrane. It suggested that dietary VE could raise the content of salivary acid in RBC membrane, but it can not be explained by the reduction of LPO.

  12. Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium

    PubMed Central

    Yang, Junjun; Yao, Wei; Qian, Guisheng; Wei, Zhenghua

    2016-01-01

    The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation. PMID:26112597

  13. Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium.

    PubMed

    Yang, Junjun; Yao, Wei; Qian, Guisheng; Wei, Zhenghua; Wu, Guangyu; Wang, Guansong

    2015-12-01

    The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation.

  14. Discrimination of Stem Cell Status after Subjecting Cynomolgus Monkey Pluripotent Stem Cells to Naïve Conversion

    PubMed Central

    Honda, Arata; Kawano, Yoshihiro; Izu, Haruna; Choijookhuu, Narantsog; Honsho, Kimiko; Nakamura, Tomonori; Yabuta, Yukihiro; Yamamoto, Takuya; Takashima, Yasuhiro; Hirose, Michiko; Sankai, Tadashi; Hishikawa, Yoshitaka; Ogura, Atsuo; Saitou, Mitinori

    2017-01-01

    Experimental animal models have played an indispensable role in the development of human induced pluripotent stem cell (iPSC) research. The derivation of high-quality (so-called “true naïve state”) iPSCs of non-human primates enhances their application and safety for human regenerative medicine. Although several attempts have been made to convert human and non-human primate PSCs into a truly naïve state, it is unclear which evaluation methods can discriminate them as being truly naïve. Here we attempted to derive naïve cynomolgus monkey (Cm) (Macaca fascicularis) embryonic stem cells (ESCs) and iPSCs. Several characteristics of naïve Cm ESCs including colony morphology, appearance of naïve-related mRNAs and proteins, leukaemia inhibitory factor dependency, and mitochondrial respiration were confirmed. Next, we generated Cm iPSCs and converted them to a naïve state. Transcriptomic comparison of PSCs with early Cm embryos elucidated the partial achievement (termed naïve-like) of their conversion. When these were subjected to in vitro neural differentiation, enhanced differentiating capacities were observed after naïve-like conversion, but some lines exhibited heterogeneity. The difficulty of achieving contribution to chimeric mouse embryos was also demonstrated. These results suggest that Cm PSCs could ameliorate their in vitro neural differentiation potential even though they could not display true naïve characteristics. PMID:28349944

  15. VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers

    PubMed Central

    Bartolomé, Rubén A.; Torres, Sofía; de Val, Soledad Isern; Escudero-Paniagua, Beatriz; Calviño, Eva; Teixidó, Joaquín; Casal, J. Ignacio

    2017-01-01

    We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers. PMID:27966446

  16. Structure of artificial and natural VE-cadherin-based adherens junctions.

    PubMed

    Taveau, Jean-Christophe; Dubois, Mathilde; Le Bihan, Olivier; Trépout, Sylvain; Almagro, Sébastien; Hewat, Elizabeth; Durmort, Claire; Heyraud, Stéphanie; Gulino-Debrac, Danielle; Lambert, Olivier

    2008-04-01

    In vascular endothelium, adherens junctions between endothelial cells are composed of VE-cadherin (vascular endothelial cadherin), an adhesive receptor that is crucial for the proper assembly of vascular structures and the maintenance of vascular integrity. As a classical cadherin, VE-cadherin links endothelial cells together by homophilic interactions mediated by its extracellular part and associates intracellularly with the actin cytoskeleton via catenins. Although, from structural crystallographic data, a dimeric structure arranged in a trans orientation has emerged as a potential mechanism of cell-cell adhesion, the cadherin organization within adherens junctions remains controversial. Concerning VE-cadherin, its extracellular part possesses the capacity to self-associate in solution as hexamers consisting of three antiparallel cadherin dimers. VE-cadherin-based adherens junctions were reconstituted in vitro by assembly of a VE-cadherin EC (extracellular repeat) 1-EC4 hexamer at the surfaces of liposomes. The artificial adherens junctions revealed by cryoelectron microscopy appear as a two-dimensional self-assembly of hexameric structures. This cadherin organization is reminiscent of that found in native desmosomal junctions. Further structural studies performed on native VE-cadherin junctions would provide a better understanding of the cadherin organization within adherens junctions. Homophilic interactions between cadherins are strengthened intracellularly by connection to the actin cytoskeleton. Recently, we have discovered that annexin 2, an actin-binding protein connects the VE-cadherin-catenin complex to the actin cytoskeleton. This novel link is labile and promotes the endothelial cell switch from a quiescent to an angiogenic state.

  17. Establishment and Maintenance of the Human Naïve CD4+ T-Cell Compartment

    PubMed Central

    Silva, Susana L.; Sousa, Ana E.

    2016-01-01

    The naïve CD4+ T-cell compartment is considered essential to guarantee immune competence throughout life. Its replenishment with naïve cells with broad diverse receptor repertoire, albeit with reduced self-reactivity, is ensured by the thymus. Nevertheless, cumulative data support a major requirement of post-thymic proliferation both for the establishment of the human peripheral naïve compartment during the accelerated somatic growth of childhood, as well as for its lifelong maintenance. Additionally, a dynamic equilibrium is operating at the cell level to fine-tune the T-cell receptor threshold to activation and survival cues, in order to counteract the continuous naïve cell loss by death or conversion into memory/effector cells. The main players in these processes are low-affinity self-peptide/MHC and cytokines, particularly IL-7. Moreover, although naïve CD4+ T-cells are usually seen as a homogeneous population regarding stage of maturation and cell differentiation, increasing evidence points to a variety of phenotypic and functional subsets with distinct homeostatic requirements. The paradigm of cells committed to a distinct lineage in the thymus are the naïve regulatory T-cells, but other functional subpopulations have been identified based on their time span after thymic egress, phenotypic markers, such as CD31, or cytokine production, namely IL-8. Understanding the regulation of these processes is of utmost importance to promote immune reconstitution in several clinical settings, namely transplantation, persistent infections, and aging. In this mini review, we provide an overview of the mechanisms underlying human naïve CD4+ T-cell homeostasis, combining clinical data, experimental studies, and modeling approaches. PMID:27843891

  18. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.

    PubMed

    Geula, Shay; Moshitch-Moshkovitz, Sharon; Dominissini, Dan; Mansour, Abed AlFatah; Kol, Nitzan; Salmon-Divon, Mali; Hershkovitz, Vera; Peer, Eyal; Mor, Nofar; Manor, Yair S; Ben-Haim, Moshe Shay; Eyal, Eran; Yunger, Sharon; Pinto, Yishay; Jaitin, Diego Adhemar; Viukov, Sergey; Rais, Yoach; Krupalnik, Vladislav; Chomsky, Elad; Zerbib, Mirie; Maza, Itay; Rechavi, Yoav; Massarwa, Rada; Hanna, Suhair; Amit, Ido; Levanon, Erez Y; Amariglio, Ninette; Stern-Ginossar, Noam; Novershtern, Noa; Rechavi, Gideon; Hanna, Jacob H

    2015-02-27

    Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner.

  19. Establishment of cell-cell junctions depends on the oligomeric states of VE-cadherin

    PubMed Central

    Bibert, Stéphanie; Ayari, Hélène; Riveline, Daniel; Concord, Evelyne; Hermant, Bastien; Vernet, Thierry; Gulino-Debrac, Danièle

    2008-01-01

    Specifically expressed at intercellular adherens junctions of endothelial cells, VE-cadherin is a receptor that exhibits particular self-association properties. Indeed, in vitro studies demonstrated that the extracellular part of VE-cadherin elaborates Ca++-dependent hexameric structures. We hypothesized that this assembly could be at the basis of a new cadherin-mediated cell-cell adhesion mechanism. To verify this assumption, we first demonstrated that VE-cadherin can elaborate hexamers at the cell surface of confluent endothelial cells. Second, mutations were introduced within the extracellular part of VE-cadherin to destabilize the hexamer. Following an in vitro screening, three mutants were selected, among which, one is able to elaborate only dimers. The selected mutations were expressed as C-terminal Green Fluorescent Protein fusions in CHO cells. Despite their capacity to elaborate nascent cell-cell contacts, the mutants seem to be rapidly degraded and or internalized. Altogether, our results suggest that the formation of VE-cadherin hexamers protects this receptor and might allow the elaboration of mature endothelial cell-cell junctions. PMID:18343874

  20. Optimum Vehicle Component Integration with InVeST (Integrated Vehicle Simulation Testbed)

    SciTech Connect

    Ng, W; Paddack, E; Aceves, S

    2001-12-27

    We have developed an Integrated Vehicle Simulation Testbed (InVeST). InVeST is based on the concept of Co-simulation, and it allows the development of virtual vehicles that can be analyzed and optimized as an overall integrated system. The virtual vehicle is defined by selecting different vehicle components from a component library. Vehicle component models can be written in multiple programming languages running on different computer platforms. At the same time, InVeST provides full protection for proprietary models. Co-simulation is a cost-effective alternative to competing methodologies, such as developing a translator or selecting a single programming language for all vehicle components. InVeST has been recently demonstrated using a transmission model and a transmission controller model. The transmission model was written in SABER and ran on a Sun/Solaris workstation, while the transmission controller was written in MATRIXx and ran on a PC running Windows NT. The demonstration was successfully performed. Future plans include the applicability of Co-simulation and InVeST to analysis and optimization of multiple complex systems, including those of Intelligent Transportation Systems.

  1. Stüve-Wiedemann Syndrome: Update on Clinical and Genetic Aspects

    PubMed Central

    Romeo Bertola, Débora; Honjo, Rachel S.; Baratela, Wagner A.R.

    2016-01-01

    Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions. Since the first cases in 1971, much has been learned about this condition, including its molecular basis - mutations in the leukemia inhibitory factor receptor gene (LIFR) -, natural history and management possibilities. This review aims to highlight the clinical aspects, radiological features, molecular findings, and management strategies in Stüve-Wiedemann syndrome. PMID:27194968

  2. Lessons about Virtual-Environment Software Systems from 20 years of VE building

    PubMed Central

    Taylor, Russell M.; Jerald, Jason; VanderKnyff, Chris; Wendt, Jeremy; Borland, David; Marshburn, David; Sherman, William R.; Whitton, Mary C.

    2010-01-01

    What are desirable and undesirable features of virtual-environment (VE) software architectures? What should be present (and absent) from such systems if they are to be optimally useful? How should they be structured? To help answer these questions we present experience from application designers, toolkit designers, and VE system architects along with examples of useful features from existing systems. Topics are organized under the major headings of: 3D space management, supporting display hardware, interaction, event management, time management, computation, portability, and the observation that less can be better. Lessons learned are presented as discussion of the issues, field experiences, nuggets of knowledge, and case studies. PMID:20567602

  3. Virtual endoscopy (VE) of the basal cisterns: its value in planning the neurosurgical approach.

    PubMed

    Boor, S; Resch, K M; Perneczky, A; Stoeter, P

    1998-12-01

    Virtual endoscopy (VE) is a postprocessing technique based on a diverging ray casting algorithm to create perspective 3 D-images from computed tomographic angiography (CTA) and high resolution magnetic resonance imaging (MR) data. By applying VE to aneurysms, tumors, and vascular compression syndromes within the basal cisterns, endoscopic-like views of these structures are achieved from an intracisternal point above the cranial base. These views closely simulate the surgeon's impression during intraoperative endoscopy or microscopy and facilitate preoperative planning of different approaches.

  4. 76 FR 24883 - DNB Exports LLC, and AFI Elektromekanikanik Ve Elektronik San. Tic. Ltd. Sti. v. Barsan Global...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-03

    ... From the Federal Register Online via the Government Publishing Office FEDERAL MARITIME COMMISSION DNB Exports LLC, and AFI Elektromekanikanik Ve Elektronik San. Tic. Ltd. Sti. v. Barsan Global... Commission (``Commission'') by DNB Exports LLC (``DNB''), and AFI Elektromekanikanik Ve Elektronik San....

  5. Broad taxonomic characterization of Verticillium wilt resistance genes reveals an ancient origin of the tomato Ve1 immune receptor.

    PubMed

    Song, Yin; Zhang, Zhao; Seidl, Michael F; Majer, Aljaz; Jakse, Jernej; Javornik, Branka; Thomma, Bart P H J

    2017-02-01

    Plant-pathogenic microbes secrete effector molecules to establish themselves on their hosts, whereas plants use immune receptors to try and intercept such effectors in order to prevent pathogen colonization. The tomato cell surface-localized receptor Ve1 confers race-specific resistance against race 1 strains of the soil-borne vascular wilt fungus Verticillium dahliae which secrete the Ave1 effector. Here, we describe the cloning and characterization of Ve1 homologues from tobacco (Nicotiana glutinosa), potato (Solanum tuberosum), wild eggplant (Solanum torvum) and hop (Humulus lupulus), and demonstrate that particular Ve1 homologues govern resistance against V. dahliae race 1 strains through the recognition of the Ave1 effector. Phylogenetic analysis shows that Ve1 homologues are widely distributed in land plants. Thus, our study suggests an ancient origin of the Ve1 immune receptor in the plant kingdom.

  6. Informed and Uninformed Naïve Assessment Constructors' Strategies for Item Selection

    ERIC Educational Resources Information Center

    Fives, Helenrose; Barnes, Nicole

    2017-01-01

    We present a descriptive analysis of 53 naïve assessment constructors' explanations for selecting test items to include on a summative assessment. We randomly assigned participants to an informed and uninformed condition (i.e., informed participants read an article describing a Table of Specifications). Through recursive thematic analyses of…

  7. Naïve prey exhibit reduced antipredator behavior and survivorship

    PubMed Central

    2014-01-01

    Prey naiveté has been hypothesized to be one of the major driving forces behind population declines following the introduction of novel predators or release of inexperienced prey into predator rich environments. In these cases, naïve prey may lack sufficient antipredator behavior and, as a result, suffer increased mortality. Despite this, some evidence suggests that many prey utilize a generalized response to predators. Here, the naiveté hypothesis is tested using a predator–prey pair sharing an evolutionary history: the red swamp crayfish (Procambarus clarkii Girard, 1852) and largemouth bass (Micropterus salmoides Lacépède, 1802). Using farm-reared, naïve crayfish and wild-caught, experienced individuals, laboratory experiments demonstrated that naïve, farmed crayfish lack behavioral responses to chemical cues from bass, both in terms of movement and use of structural refuge. In contrast, experienced crayfish responded strongly to the same cues. In a subsequent field tethering experiment, these naïve individuals suffered a three-fold increase in predation rate. Based on these results, recognition of predators may not be innate in all prey, and previous experience and learning likely play a key role in the development of antipredator behavior. PMID:25392763

  8. First-Year Medical Students' Naïve Beliefs about Respiratory Physiology

    ERIC Educational Resources Information Center

    Badenhorst, Elmi; Mamede, Silvia; Abrahams, Amaal; Bugarith, Kishor; Friedling, Jacqui; Gunston, Geney; Kelly-Laubscher, Roisin; Schmidt, Henk G.

    2016-01-01

    The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader…

  9. Behaviour of equine influenza virus in a naïve population: a practitioner's perspective.

    PubMed

    Major, D A; Jones, B

    2011-07-01

    We describe the behaviour of equine influenza (EI) virus infection in a naïve population as observed by equine veterinary practitioners. The clinical signs displayed by infected horses and the highly contagious nature of the disease are discussed, as well as the treatment and management of infected horses.

  10. The Karhunen-Loève Transform for bioastronomy and SETI

    NASA Astrophysics Data System (ADS)

    Maccone, C.

    2006-02-01

    I present here a short description of the Karhunen-Loève Transform (KLT) used to detect very weak radio signals over narrow-band and wide-band extraterrestrial telecommunications out of the cosmic background noise. It appears that the KLT is more appropriate than the well known Fourier Transform (FT).

  11. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature

    PubMed Central

    Shen, Jikui; Frye, Maike; Lee, Bonnie L.; Reinardy, Jessica L.; McClung, Joseph M.; Ding, Kun; Kojima, Masashi; Xia, Huiming; Seidel, Christopher; Silva, Raquel Lima e; Dong, Aling; Hackett, Sean F.; Wang, Jiangxia; Howard, Brian W.; Vestweber, Dietmar; Kontos, Christopher D.; Peters, Kevin G.; Campochiaro, Peter A.

    2014-01-01

    Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti–VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. Ischemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases PMID:25180601

  12. "You've Got the Power": Documentary Film as a Tool of Environmental Adult Education

    ERIC Educational Resources Information Center

    Clover, Darlene E.

    2011-01-01

    Educators call for more creative means to combat the moribund narratives of contemporary environmentalism. Using visual methodology and environmental adult education theory, this article discusses how a documentary film titled "You've Got the Power" works to pose questions about complex environmental issues and develop critical thinking…

  13. HIV integrase variability and genetic barrier in antiretroviral naïve and experienced patients

    PubMed Central

    2011-01-01

    Background HIV-1 integrase (IN) variability in treatment naïve patients with different HIV-1 subtypes is a major issue. In fact, the effect of previous exposure to antiretrovirals other than IN inhibitors (INI) on IN variability has not been satisfactorily defined. In addition, the genetic barrier for specific INI resistance mutations remains to be calculated. Methods IN variability was analyzed and compared with reverse transcriptase (RT) and protease (PR) variability in 41 treatment naïve and 54 RT inhibitor (RTI) and protease inhibitor (PRI) experienced patients from subjects infected with subtype B and non-B strains. In addition, four HIV-2 strains were analyzed in parallel. Frequency and distribution of IN mutations were compared between HAART-naïve and RTI/PI-experienced patients; the genetic barrier for 27 amino acid positions related to INI susceptibility was calculated as well. Results Primary mutations associated with resistance to INI were not detected in patients not previously treated with this class of drug. However, some secondary mutations which have been shown to contribute to INI resistance were found. Only limited differences in codon usage distribution between patient groups were found. HIV-2 strains from INI naïve patients showed the presence of both primary and secondary resistance mutations. Conclusion Exposure to antivirals other than INI does not seem to significantly influence the emergence of mutations implicated in INI resistance. HIV-2 strain might have reduced susceptibility to INI. PMID:21453487

  14. Human α(2)β(1)(HI) CD133(+VE) epithelial prostate stem cells express low levels of active androgen receptor.

    PubMed

    Williamson, Stuart C; Hepburn, Anastasia C; Wilson, Laura; Coffey, Kelly; Ryan-Munden, Claudia A; Pal, Deepali; Leung, Hing Y; Robson, Craig N; Heer, Rakesh

    2012-01-01

    Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis.

  15. Treated and Treatment-Naïve Alcoholics Come From Different Populations

    PubMed Central

    Fein, George; Landman, Bennett

    2007-01-01

    Most research on alcoholism uses convenience samples of individuals who have been in some type of treatment; Berkson’s fallacy results when the associations found in studies of select samples are incorrectly presumed to apply to all alcoholics (i.e. including untreated alcoholics in the general population). This study examines whether treated and untreated alcoholics have similar early alcohol use histories by comparing abstinent alcoholics (treated and sober at least 6 months) to treatment-naïve alcoholics (active drinkers). We studied fourteen pairs of women and twenty-five pairs of men matched on the age at which they first met criteria for heavy alcohol use (80 drinks/month for women and 100 drinks/month for men). The timeline follow-back interview methodology was used to gather retrospective alcohol use information. Alcohol dose and duration was then computed for two intervals: the time between the person’s first drink and the date at which they met criteria for heavy drinking, and the period between meeting criteria for heavy drinking and the current age of the treatment-naïve person from each pair. During the period prior to meeting the matching ‘heavy drinking’ criteria, alcohol dose did not differ between groups. In the period after meeting criteria for heavy alcohol use, the treated alcoholics had higher average and peak alcohol doses than the treatment naïve alcoholics. We rejected the hypothesis that the treatment naïve alcoholics and the treated alcoholics have similar alcohol use trajectories over time, with the treatment naïve sample simply being observed earlier in their alcohol use histories. Instead we concluded that the two groups come from different populations with regard to alcohol use (in fact, the treated alcoholics had alcohol doses over 50% higher than treatment-naïve alcoholics in the years just after they began drinking heavily). This suggests that results from studies of alcoholics in treatment or post-treatment (i

  16. Balance deficits and ADHD symptoms in medication-naïve school-aged boys

    PubMed Central

    Konicarova, Jana; Bob, Petr; Raboch, Jiri

    2014-01-01

    Background and objectives Functional disturbances developed early in life include balance deficits which are linked to dysfunctions of higher levels of cognitive and motor integration. According to our knowledge, there are only a few studies suggesting that balance deficits are related to behavioral disturbances in attention-deficit/hyperactivity disorder (ADHD). Methods We tested the extent to which balance deficits were related to ADHD symptoms in 35 medication-naïve boys of school age (8–11 years) and compared the results with a control group of 30 boys of the same age. Results ADHD symptoms in medication-naïve boys had specific relationships to disturbances of postural and gait balance. Conclusion To our knowledge, this study provides the first evidence in the medical literature for a direct relationship between ADHD symptoms and balance deficits, that cannot be attributed to medication and the presence of any neurological disease. PMID:24476629

  17. Abacavir-Reactive Memory T Cells Are Present in Drug Naïve Individuals

    PubMed Central

    Lucas, Andrew; Lucas, Michaela; Strhyn, Anette; Keane, Niamh M.; McKinnon, Elizabeth; Pavlos, Rebecca; Moran, Ellen M.; Meyer-Pannwitt, Viola; Gaudieri, Silvana; D’Orsogna, Lloyd; Kalams, Spyros; Ostrov, David A.; Buus, Søren; Peters, Bjoern; Mallal, Simon; Phillips, Elizabeth

    2015-01-01

    Background Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population. Methods To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling. Results Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells. Conclusions We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection. PMID:25674793

  18. The challenging definition of naïve patient for biological drug use.

    PubMed

    Biggioggero, Martina; Danova, Marco; Genovese, Umberto; Locatelli, Francesco; Meroni, Pier Luigi; Pane, Fabrizio; Scaglione, Francesco

    2015-06-01

    Biosimilar is defined by The European Medical Agency as a biological medicinal product, which is similar but not identical to the biological drug already authorized. The biosimilar and its reference product are expected to display the same safety and efficacy profile and are generally used to treat the same conditions. The Italian Medicines Agency considers biosimilars as a valid therapeutic option with an economic advantage, especially in primary naïve patients with no previous exposure to the originator or with a sufficiently long wash-out period ("secondary naïve"). The identification of "secondary naïve" is not well defined and can be subjected to different variables, mainly the drug biologic effect and its immunogenicity. The first one depends on the type of biologics and on their mechanism of action. The second one is related to the fact that biologicals may be immunogenic and can trigger an anti-drug antibody response (ADA). ADA may behave as neutralizing antibodies blocking the active site of the biological but can also recognize other epitopes favoring the formation of immune-complexes that eventually affect the pharmacodynamics. Moreover, the concomitant immune-suppressive treatment can affect the immunogenicity, even if the exact mechanism remains unknown. In conclusion, the development and use of biosimilars represent a tool for increasing health system sustainability. However it is of paramount importance to distinguish between the pharmacodynamics of a given drug and its immunogenicity being the two aspects unrelated. Thus a detailed definition of "secondary naïve" patients is challenging, and may be related to both the two parameters.

  19. Gender differences in non-motor symptoms in early, drug naïve Parkinson's disease.

    PubMed

    Picillo, Marina; Amboni, Marianna; Erro, Roberto; Longo, Katia; Vitale, Carmine; Moccia, Marcello; Pierro, Angela; Santangelo, Gabriella; De Rosa, Anna; De Michele, Giuseppe; Santoro, Lucio; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa

    2013-11-01

    Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the χ (2) exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naïve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients.

  20. Naïve realism: folk fallacies in the design and use of visual displays.

    PubMed

    Smallman, Harvey S; Cook, Maia B

    2011-07-01

    Often implicit in visual display design and development is a gold standard of photorealism. By approximating direct perception, photorealism appeals to users and designers by being both attractive and apparently effortless. The vexing result from numerous performance evaluations, though, is that increasing realism often impairs performance. Smallman and St. John (2005) labeled misplaced faith in realistic information display Naïve Realism and theorized it resulted from a triplet of folk fallacies about perception. Here, we illustrate issues associated with the wider trend towards realism by focusing on a specific current trend for high-fidelity perspective view (3D) geospatial displays. In two experiments, we validated Naïve Realism for different terrain understanding tasks, explored whether certain individuals are particularly prone to Naïve Realism, and determined the ability of task feedback to mitigate Naïve Realism. Performance was measured for laying and judging a concealed route across realistic terrain shown in different display formats. Task feedback was either implicit, in Experiment 1, or explicit in Experiment 2. Prospective and retrospective intuitions about the best display formats for the tasks were recorded and then related to task performance and participant spatial ability. Participants generally intuited they would perform tasks better with more realism than they actually required. For example, counter to intuitions, lowering fidelity of the terrain display revealed the gross scene layout needed to lay a well-concealed route. Individuals of high spatial ability calibrated their intuitions with only implicit task feedback, whereas those of low spatial ability required salient, explicit feedback to calibrate their intuitions about display realism. Results are discussed in the wider context of applying perceptual science to display design, and combating folk fallacies.

  1. Feature weighted naïve Bayes algorithm for information retrieval of enterprise systems

    NASA Astrophysics Data System (ADS)

    Wang, Li; Ji, Ping; Qi, Jing; Shan, Siqing; Bi, Zhuming; Deng, Weiguo; Zhang, Naijing

    2014-01-01

    Automated information retrieval is critical for enterprise information systems to acquire knowledge from the vast amount of data sets. One challenge in information retrieval is text classification. Current practices rely heavily on the classical naïve Bayes algorithm due to its simplicity and robustness. However, results from this algorithm are not always satisfactory. In this article, the limitations of the naïve Bayes algorithm are discussed, and it is found that the assumption on the independence of terms is the main reason for an unsatisfactory classification in many real-world applications. To overcome the limitations, the dependent factors are considered by integrating a term frequency-inverse document frequency (TF-IDF) weighting algorithm in the naïve Bayes classification. Moreover, the TF-IDF algorithm itself is improved so that both frequencies and distribution information are taken into consideration. To illustrate the effectiveness of the proposed method, two simulation experiments were conducted, and the comparisons with other classification methods have shown that the proposed method has outperformed other existing algorithms in terms of precision and index recall rate.

  2. Diesel Exhaust Particle Exposure Causes Redistribution of Endothelial Tube VE-Cadherin

    PubMed Central

    Chao, Ming-Wei; Kozlosky, John; Po, Iris P.; Strickland, Pamela Ohman; Svoboda, Kathy K. H.; Cooper, Keith; Laumbach, Robert; Gordon, Marion K.

    2010-01-01

    Whether diesel exhaust particles (DEPs) potentially have a direct effect on capillary endothelia was examined by following the adherens junction component, vascular endothelial cell cadherin (VE-cadherin). This molecule is incorporated into endothelial adherens junctions at the cell surface, where it forms homodimeric associations with adjacent cells and contributes to the barrier function of the vasculature (Dejana et al., 2008; Venkiteswaran et al., 2002; Villasante et al., 2007). Human umbilical vein endothelial cells (HUVECs) that were pre-formed into capillary-like tube networks in vitro were exposed to DEPs for 24 hr. After exposure, the integrity of VE-cadherin in adherens junctions was assessed by immunofluorescence analysis, and demonstrated that increasing concentrations of DEPs caused increasing redistribution of VE-cadherin away from the cell-cell junctions toward intracellular locations. Since HUVEC tube networks are three-dimensional structures, whether particles entered the endothelial cells or tubular lumens was also examined. The data indicate that translocation of the particles does occur. The results, obtained in a setting that removes the confounding effects of inflammatory cells or blood components, suggest that if DEPs encounter alveolar capillaries in vivo, they may be able to directly affect the endothelial cell-cell junctions. PMID:20887764

  3. A Multilayer Naïve Bayes Model for Analyzing User's Retweeting Sentiment Tendency

    PubMed Central

    Wang, Mengmeng; Zuo, Wanli; Wang, Ying

    2015-01-01

    Today microblogging has increasingly become a means of information diffusion via user's retweeting behavior. Since retweeting content, as context information of microblogging, is an understanding of microblogging, hence, user's retweeting sentiment tendency analysis has gradually become a hot research topic. Targeted at online microblogging, a dynamic social network, we investigate how to exploit dynamic retweeting sentiment features in retweeting sentiment tendency analysis. On the basis of time series of user's network structure information and published text information, we first model dynamic retweeting sentiment features. Then we build Naïve Bayes models from profile-, relationship-, and emotion-based dimensions, respectively. Finally, we build a multilayer Naïve Bayes model based on multidimensional Naïve Bayes models to analyze user's retweeting sentiment tendency towards a microblog. Experiments on real-world dataset demonstrate the effectiveness of the proposed framework. Further experiments are conducted to understand the importance of dynamic retweeting sentiment features and temporal information in retweeting sentiment tendency analysis. What is more, we provide a new train of thought for retweeting sentiment tendency analysis in dynamic social networks. PMID:26417367

  4. Determining the extent and dynamics of surface water for the ABoVE field campaign

    NASA Astrophysics Data System (ADS)

    Carroll, M.; Sohlberg, R. A.; Townshend, J. R.; DiMiceli, C.

    2013-12-01

    The proposed Arctic and Boreal Vulnerability Experiment (ABoVE) will conduct multi-disciplinary studies to explore and quantify the linkages between all of the individual components of the ecosystem. One common thread identified in the final report for the scoping study for ABoVE is the need for maps of the location, extent and dynamics of surface water to connect the different disciplines. Water represents a transport vehicle for nutrients and other solutes, provides habitat for flora and fauna, and has a controlling effect on surface energy exchange yet it remains one of the least characterized features of the study region. We have been selected to develop a new dataset to represent surface water in the ABoVE study region at 30m spatial resolution for 3 epochs (1991, 2001, 2011). These data will be used to identify and quantify the change in surface water over the past 2 decades in the North American High Arctic. In this presentation we will describe the project and give the status of processing as well as early results from select locations.

  5. Dopamine transporter availability in motor subtypes of de novo drug-naïve Parkinson's disease.

    PubMed

    Moccia, Marcello; Pappatà, Sabina; Picillo, Marina; Erro, Roberto; Coda, Anna Rita Daniela; Longo, Katia; Vitale, Carmine; Amboni, Marianna; Brunetti, Arturo; Capo, Giuseppe; Salvatore, Marco; Barone, Paolo; Pellecchia, Maria Teresa

    2014-11-01

    Tremor dominant (TD) and akinetic-rigid type (ART) are two motor subtypes of Parkinson's disease associated with different disease progression and neurochemical/neuropathological features. The role of presynaptic nigrostriatal dopaminergic damage is still controversial, poorly explored, and only assessed in medicated patients. In this study, we investigated with FP-CIT SPECT the striatal dopamine transporter (DAT) availability in drug-naïve PD patients with ART and TD phenotypes. Fifty-one de novo, drug-naïve patients with PD underwent FP-CIT SPECT studies. Patients were evaluated with Unified Parkinson's Disease Rating Scale (UPDRS) part III and Hoehn and Yahr scale (H&Y) and divided into ART (24/51) and TD (27/51) according to UPDRS part III. ART and TD patients were not different with regard to age, gender, and disease duration. However, compared to TD, ART patients presented higher UPDRS part III (p = 0.01) and H&Y (p = 0.02) and lower DAT availability in affected and unaffected putamen (p = 0.008 and p = 0.007, respectively), whereas no differences were found in caudate. Moreover, in the whole group of patients, rigidity and bradykinesia, but not tremor scores of UPDRS part III were significantly related to FP-CIT binding in the putamen. These results suggest that in newly diagnosed drug-naïve PD patients DAT availability might be different between ART and TD in relation to different disease severity.

  6. A Ve homologous gene from Gossypium barbadense, Gbvdr3, enhances the defense response against Verticillium dahliae.

    PubMed

    Chen, Tianzi; Kan, Jialiang; Yang, Yuwen; Ling, Xitie; Chang, Youhong; Zhang, Baolong

    2016-01-01

    The tomato Ve1 gene and several Ve1 homologues are involved in the resistance to Verticillium dahliae. Here, we report on another Ve homologous gene, Gbvdr3, from a Verticillium wilt-resistant cotton cultivar, Gossypium barbadense Hai7124, which has a 3207-bp region that encodes a predicted receptor-like protein. Transient expression analyses indicated that Gbvdr3 is localized in the plasma membrane, and virus-induced gene silencing of Gbvdr3 compromised the resistance of Hai7124 cotton to a defoliating strain of V. dahliae, V991, but not to a non-defoliating strain, BP2. This resistance pattern was further confirmed by over-expression of Gbvdr3 in transgenic Arabidopsis, which significantly elevated the expression of the ethylene-regulated gene GST2, the ethylene- and jasmonic acid-regulated defense-related genes PR3 and PDF1.2, and the salicylic acid-regulated genes PR1 and PR5, but not the PR2 gene. It also triggered the accumulation of hydrogen peroxide and callose at early time points during infection by the V991 defoliating strain. In contrast, elevated accumulation of hydrogen peroxide or callose in Gbvdr3-expressed Arabidopsis leaves was not apparent under infection by the non-defoliating strain, BP2. These results suggested that Gbvdr3 is involved in the resistance to a unique spectrum of defoliating V. dahliae strains.

  7. VE-cadherin trans-interactions modulate Rac activation and enhancement of lung endothelial barrier by iloprost.

    PubMed

    Birukova, Anna A; Tian, Yufeng; Dubrovskyi, Oleksii; Zebda, Noureddine; Sarich, Nicolene; Tian, Xinyong; Wang, Yingxiao; Birukov, Konstantin G

    2012-10-01

    Small GTPase Rac is important regulator of endothelial cell (EC) barrier enhancement by prostacyclin characterized by increased peripheral actin cytoskeleton and increased interactions between VE-cadherin and other adherens junction (AJ) proteins. This study utilized complementary approaches including siRNA knockdown, culturing in Ca(2+) -free medium, and VE-cadherin blocking antibody to alter VE-cadherin extracellular interactions to investigate the role of VE-cadherin outside-in signaling in modulation of Rac activation and EC barrier regulation by prostacyclin analog iloprost. Spatial analysis of Rac activation in pulmonary EC by FRET revealed additional spike in iloprost-induced Rac activity at the sites of newly formed cell-cell junctions. In contrast, disruption of VE-cadherin extracellular trans-interactions suppressed iloprost-activated Rac signaling and attenuated EC barrier enhancement and cytoskeletal remodeling. These inhibitory effects were associated with decreased membrane accumulation and activation of Rac-specific guanine nucleotide exchange factors (GEFs) Tiam1 and Vav2. Conversely, plating of pulmonary EC on surfaces coated with extracellular VE-cadherin domain further promoted iloprost-induced Rac signaling. In the model of thrombin-induced EC barrier recovery, blocking of VE-cadherin trans-interactions attenuated activation of Rac pathway during recovery phase and delayed suppression of Rho signaling and restoration of EC barrier properties. These results suggest that VE-cadherin outside-in signaling controls locally Rac activity stimulated by barrier protective agonists. This control is essential for maximal EC barrier enhancement and accelerated barrier recovery.

  8. Transgenerational soil-mediated differences between plants experienced or naïve to a grass invasion

    PubMed Central

    Deck, Anna; Muir, Adrianna; Strauss, Sharon

    2013-01-01

    Invasive species may undergo rapid change as they invade. Native species persisting in invaded areas may also experience rapid change over this short timescale relative to native populations in uninvaded areas. We investigated the response of the native Achillea millefolium to soil from Holcus lanatus-invaded and uninvaded areas, and we sought to determine whether differential responses between A. millefolium from invaded (invader experienced) and uninvaded (invader naïve) areas were mediated by soil community changes. Plants grown from seed from experienced and naïve areas responded differently to invaded and uninvaded soil with respect to germination time, biomass, and height. Overall, experienced plants grew faster and taller than their naïve counterparts. Naïve native plants showed negative feedbacks with their home soil and positive feedbacks with invaded soil; experienced plants were less responsive to soil differences. Our results suggest that native plants naïve to invasion may be more sensitive to soil communities than experienced plants, consistent with recent studies. While differences between naïve and experienced plants are transgenerational, our design cannot differentiate between differences that are genetically based, plastic, or both. Regardless, our results highlight the importance of seed source and population history in restoration, emphasizing the restoration potential of experienced seed sources. PMID:24198931

  9. Transgenerational soil-mediated differences between plants experienced or naïve to a grass invasion.

    PubMed

    Deck, Anna; Muir, Adrianna; Strauss, Sharon

    2013-10-01

    Invasive species may undergo rapid change as they invade. Native species persisting in invaded areas may also experience rapid change over this short timescale relative to native populations in uninvaded areas. We investigated the response of the native Achillea millefolium to soil from Holcus lanatus-invaded and uninvaded areas, and we sought to determine whether differential responses between A. millefolium from invaded (invader experienced) and uninvaded (invader naïve) areas were mediated by soil community changes. Plants grown from seed from experienced and naïve areas responded differently to invaded and uninvaded soil with respect to germination time, biomass, and height. Overall, experienced plants grew faster and taller than their naïve counterparts. Naïve native plants showed negative feedbacks with their home soil and positive feedbacks with invaded soil; experienced plants were less responsive to soil differences. Our results suggest that native plants naïve to invasion may be more sensitive to soil communities than experienced plants, consistent with recent studies. While differences between naïve and experienced plants are transgenerational, our design cannot differentiate between differences that are genetically based, plastic, or both. Regardless, our results highlight the importance of seed source and population history in restoration, emphasizing the restoration potential of experienced seed sources.

  10. VE-cadherin Y685F knock-in mouse is sensitive to vascular permeability in recurrent angiogenic organs.

    PubMed

    Sidibé, Adama; Polena, Helena; Pernet-Gallay, Karin; Razanajatovo, Jeremy; Mannic, Tiphaine; Chaumontel, Nicolas; Bama, Soumalamaya; Maréchal, Irène; Huber, Philippe; Gulino-Debrac, Danielle; Bouillet, Laurence; Vilgrain, Isabelle

    2014-08-01

    Covalent modifications such as tyrosine phosphorylation are associated with the breakdown of endothelial cell junctions and increased vascular permeability. We previously showed that vascular endothelial (VE)-cadherin was tyrosine phosphorylated in vivo in the mouse reproductive tract and that Y685 was a target site for Src in response to vascular endothelial growth factor in vitro. In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 mo old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells, and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (wild-type, 11.5 ± 0.3, n = 78; and VE-Y685F, 12.48 ± 0.3, n = 65; P = 0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or vascular endothelial growth factor-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary

  11. Fixed bimonthly aflibercept in naïve and switched neovascular age-related macular degeneration patients: one year outcomes

    PubMed Central

    Warwick, Alasdair N; Leaver, Hannah H; Lotery, Andrew J; Goverdhan, Srini V

    2016-01-01

    AIM To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bimonthly fixed dosing aflibercept regimen. METHODS This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (<15 letters loss) at 12mo was also evaluated. RESULTS Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (P<0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16 µm in the switched group and -35.36 µm in the naïve group (P<0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year. CONCLUSION Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes. PMID:27588271

  12. Effects of Risperidone on Cytokine Profile in Drug-Naïve First-Episode Psychosis

    PubMed Central

    Noto, Cristiano; Ota, Vanessa Kiyomi; Gouvea, Eduardo S.; Rizzo, Lucas B.; Spindola, Leticia M. N.; Honda, Pedro H. S.; Cordeiro, Quirino; Belangero, Sintia Iole; Bressan, Rodrigo Affonseca; Gadelha, Ary; Maes, Michael

    2015-01-01

    Background: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. Methods: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. Results: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms. Conclusions: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions. PMID:25522386

  13. Towards the Integration of APECS with VE-Suite to Create a Comprehensive Virtual Engineering Environment

    SciTech Connect

    McCorkle, D.; Yang, C.; Jordan, T.; Swensen, D.; Zitney, S.E.; Bryden, M.

    2007-06-01

    Modeling and simulation tools are becoming pervasive in the process engineering practice of designing advanced power generation facilities. These tools enable engineers to explore many what-if scenarios before cutting metal or constructing a pilot scale facility. While such tools enable investigation of crucial plant design aspects, typical commercial process simulation tools such as Aspen Plus®, gPROMS®, and HYSYS® still do not explore some plant design information, including computational fluid dynamics (CFD) models for complex thermal and fluid flow phenomena, economics models for policy decisions, operational data after the plant is constructed, and as-built information for use in as-designed models. Software tools must be created that allow disparate sources of information to be integrated if environments are to be constructed where process simulation information can be accessed. At the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL), the Advanced Process Engineering Co-Simulator (APECS) has been developed as an integrated software suite that combines process simulation (e.g., Aspen Plus) and high-fidelity equipment simulation (e.g., Fluent® CFD), together with advanced analysis capabilities including case studies, sensitivity analysis, stochastic simulation for risk/uncertainty analysis, and multi-objective optimization. In this paper, we discuss the initial phases of integrating APECS with the immersive and interactive virtual engineering software, VE-Suite, developed at Iowa State University and Ames Laboratory. VE-Suite utilizes the ActiveX (OLE Automation) controls in Aspen Plus wrapped by the CASI library developed by Reaction Engineering International to run the process simulation and query for unit operation results. This integration permits any application that uses the VE-Open interface to integrate with APECS co-simulations, enabling construction of the comprehensive virtual engineering environment needed for the

  14. Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation

    PubMed Central

    Lee, Choon-Soo; Kim, Yun Gi; Cho, Hyun-Jai; Park, Jonghanne; Jeong, Heewon; Lee, Sang-Eun; Lee, Seung-Pyo; Kang, Hyun-Jae; Kim, Hyo-Soo

    2016-01-01

    The inhibitors of CD26 (dipeptidyl peptidase-4; DPP4) have been widely prescribed to control glucose level in diabetic patients. DPP4-inhibitors, however, accumulate stromal cell-derived factor-1α (SDF-1α), a well-known inducer of vascular leakage and angiogenesis both of which are fundamental pathophysiology of diabetic retinopathy. The aim of this study was to investigate the effects of DPP4-inhibitors on vascular permeability and diabetic retinopathy. DPP4-inhibitor (diprotin A or sitagliptin) increased the phosphorylation of Src and vascular endothelial-cadherin (VE-cadherin) in human endothelial cells and disrupted endothelial cell-to-cell junctions, which were attenuated by CXCR4 (receptor of SDF-1α)-blocker or Src-inhibitor. Disruption of endothelial cell-to-cell junctions in the immuno-fluorescence images correlated with the actual leakage of the endothelial monolayer in the transwell endothelial permeability assay. In the Miles assay, vascular leakage was observed in the ears into which SDF-1α was injected, and this effect was aggravated by DPP4-inhibitor. In the model of retinopathy of prematurity, DPP4-inhibitor increased not only retinal vascularity but also leakage. Additionally, in the murine diabetic retinopathy model, DPP4-inhibitor increased the phosphorylation of Src and VE-cadherin and aggravated vascular leakage in the retinas. Collectively, DPP4-inhibitor induced vascular leakage by augmenting the SDF-1α/CXCR4/Src/VE-cadherin signaling pathway. These data highlight safety issues associated with the use of DPP4-inhibitors. PMID:27381080

  15. Serum uric acid is associated with apathy in early, drug-naïve Parkinson's disease.

    PubMed

    Picillo, Marina; Santangelo, Gabriella; Moccia, Marcello; Erro, Roberto; Amboni, Marianna; Prestipino, Elio; Longo, Katia; Vitale, Carmine; Spina, Emanuele; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa

    2016-04-01

    Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson's disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-naïve PD patients. Forty-nine early, drug-naïve PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA ≤ 4.8 mg/dl; Group 2 serum UA > 4.8 mg/dl). The cohort was followed for the first 2 years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-naïve PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis.

  16. Aluminum-Oxide Temperatures on the Mark VB, VE, VR, 15, and Mark 25 Assemblies

    SciTech Connect

    Aleman, S.E.

    2001-07-17

    The task was to compute the maximum aluminum-oxide and oxide-coolant temperatures of assemblies cladded in 99 plus percent aluminum. The assemblies considered were the Mark VB, VE, V5, 15 and 25. These assemblies consist of nested slug columns with individual uranium slugs cladded in aluminum cans. The CREDIT code was modified to calculate the oxide film thickness and the aluminum-oxide temperature at each axial increment. The information in this report will be used to evaluate the potential for cladding corrosion of the Mark 25 assembly.

  17. Hepatitis B virus reverse transcriptase mutations in treatment Naïve chronic hepatitis B patients.

    PubMed

    Singla, Bhupesh; Chakraborti, Anuradha; Sharma, Bal Krishan; Kapil, Shweta; Chawla, Yogesh K; Arora, Sunil K; Das, Ashim; Dhiman, Radha K; Duseja, Ajay

    2013-07-01

    Mutations in the reverse transcriptase (RT) region of the hepatitis B virus (HBV) genome lead to decreased susceptibility to nucleos(t)ide analogs approved for treatment of HBV infection. The aim of this study was to detect and analyze pre-existing HBV RT mutations in treatment naïve patients with chronic hepatitis B. Seventy one chronic HBV treatment naïve patients were enrolled from January 2009 to June 2011. HBV RT sequence analysis was done by using direct bidirectional sequencing of semi-nested PCR products. HBV genotypes were determined by multiplex PCR. Genotype D was found in 64 patients (90.1%) followed by genotype C and A which were present in 5 (7.0%) and 2 (2.8%) patients respectively. The results of the RT sequence analysis showed mutations in 34 (47.9%) patients. The rtH248N mutation was the most common mutation, accounting for 47.1% patients. Other common mutations included rtD263E/S, rtM129L, rtF122L/V/I, rtS135Y/H, rtQ149K, rtL91I, rtH126R, rtC256S/G, rtY257W, rtS259T and rtE271D, which were present in 26.5% (9/34), 29.4% (10/34), 20.6% (7/34), 20.6% (7/34), 20.6% (7/34), 17.6% (6/34), 14.7% (5/34), 14.7% (5/34), 11.8% (4/34), 11.8% (4/34) and 11.8% (4/34) patients respectively. The known primary drug resistance mutations were found in 3 (8.8%) patients. The present study shows the presence of RT amino acid substitutions in treatment-naïve patients with chronic hepatitis B, which may decrease susceptibility to available oral antiviral drugs. On the basis of the finding of this study, genotypic testing is recommended before the start of therapy in naïve patients, so that suitable antiviral drugs can be prescribed.

  18. Endocrine therapy for hormone treatment-naïve advanced breast cancer.

    PubMed

    Martin, Miguel; Lopez-Tarruella, Sara; Gilarranz, Yolanda Jerez

    2016-08-01

    A proportion of patients with hormone receptor-positive locally advanced or metastatic breast cancer will not have received prior endocrine therapy. However, there are limited clinical data specifically in these patients. We conducted a review of randomized phase II and III clinical studies of anastrozole, letrozole, exemestane, palbociclib, and fulvestrant to determine the evidence base supporting use of specific endocrine therapies in this patient population. From our findings, there is a paucity of clinical studies in patients with endocrine therapy-naïve disease; however, it appears that first-line treatment effects are consistent between patients who have and have not received prior endocrine treatment.

  19. Aluminum-Oxide Temperatures on the Mark VB, VE, VR, 15, and Mark 25 Assemblies

    SciTech Connect

    Aleman, S.E.

    2001-07-17

    The task was to compute the maximum aluminum-oxide and oxide-coolant temperatures of assemblies cladded in 99+ percent aluminum. The assemblies considered were the Mark VB, VE, V5, 15 and 25. These assemblies consist of nested slug columns with individual uranium slugs cladded in aluminum cans. The CREDIT code was modified to calculate the oxide film thickness and the aluminum-oxide temperature at each axial increment. This information in this report will be used to evaluate the potential for cladding corrosion of the Mark 25 assembly.

  20. Aspergillus fumigatus spore proteomics and genetics reveal that VeA represses DefA-mediated DNA damage response.

    PubMed

    Shin, Kwang-Soo; Park, Hee-Soo; Kim, Young; Heo, In-Beom; Kim, Young Hwan; Yu, Jae-Hyuk

    2016-10-04

    Aspergillus fumigatus reproduces and infects host by forming a high number of small asexual spores (conidia). The velvet proteins are global transcriptional regulators governing the complex process of conidiogenesis in this fungus. Here, to further understand the velvet-mediated regulation, we carried out comparative proteomic analyses of conidia of wild type (WT) and three velvet mutants (ΔveA, ΔvelB and ΔvosA). Cluster analysis of 184 protein spots showing at least 1.5-fold differential accumulation between WT and mutants reveal the clustering of WT- ΔveA and ΔvelB-ΔvosA. Among 43 proteins identified by Nano-LC-ESI-MS/MS, 23 including several heat shock proteins showed more than two-fold reduction in both the ∆velB and ∆vosA conidia. On the contrary, three proteins exhibited more than five-fold increase in ∆veA only, including the putative RNA polymerase II degradation factor DefA. The deletion of defA resulted in a reduced number of conidia and restricted colony growth. In addition, the defA deletion mutant conidia showed hypersensitivity against the DNA damaging agents NQO and MMS, while the ΔveA mutant conidia were more resistant against to NQO. Taken together, we propose that VeA controls protein level of DefA in conidia, which are dormant and equipped with multiple layers of protection against environmental cues.

  1. VE-cadherin is a critical molecule for trophoblast-endothelial cell interaction in decidual spiral arteries

    SciTech Connect

    Bulla, Roberta; Villa, Antonello; Bossi, Fleur; Cassetti, Arianna; Radillo, Oriano; Spessotto, Paola; De Seta, Francesco; Guaschino, Secondo; Tedesco, Francesco . E-mail: tedesco@univ.trieste.it

    2005-02-01

    Fetal cytotrophoblasts colonize the decidual spiral arteries during pregnancy and partially replace the endothelium by an as yet unknown mechanism. To clarify this issue, we cocultured trophoblast cells (TCs) and decidual endothelial cells (DECs) isolated from first trimester placentae and found by electron microscopic analysis that TCs adhered to DECs and migrated through the interendothelial junctions within 24 h. Since extravillous TCs were shown by FACS analysis to express vascular-endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM)-1, we investigated the role of these junctional molecules in TC adhesion to DECs and transendothelial migration of cytotrophoblasts. Both VE-cadherin and PECAM-1 were present at the contact sites between TCs and DECs in decidual sections. TC adhesion and migration were markedly inhibited by mAbs to VE-cadherin and marginally by mAb to PECAM-1. Increased expression of VE-cadherin was observed at the contact areas between TCs and DECs, whereas PECAM-1 was found to be redistributed from intercellular junctions. The induction of apoptosis of DECs by TCs, as the mechanism responsible for their replacement, was ruled out by the negative staining with TUNEL of DECs cocultured with TCs and the absence of DNA fragmentation. In conclusion, VE-cadherin is involved in transendothelial migration of TCs, and replacement of DECs by TCs is not the result of apoptosis.

  2. Dephosphorylation of Y685-VE-Cadherin Involved in Pulmonary Microvascular Endothelial Barrier Injury Induced by Angiotensin II.

    PubMed

    Wu, Zhiyong; Wang, Zhiwei; Dai, Feifeng; Liu, Huagang; Ren, Wei; Chang, Jinxing; Li, Bowen

    2016-01-01

    Angiotensin II (AngII) caused pulmonary microvascular endothelial barrier injury, which induced acute aortic dissection (AAD) combined with acute lung injury (ALI). However, the exact mechanism is unclear. We investigated the role of dephosphorylation of Y685-VE-cadherin in the AngII induced pulmonary microvascular endothelial barrier injury. Mice or pulmonary microvascular endothelial cells (PMVECs) were divided into control group, AngII group, AngII+PP2 (Src kinase inhibitor) group, and PP2 group. PP2 was used to inhibit the phosphorylation of Y685-VE-cadherin. Pathological changes, infiltration of macrophages and neutrophils, and pulmonary microvascular permeability were used to determine the pulmonary microvascular endothelial barrier function. Flow cytometry was used to determine the apoptosis of PMVECs, and immunofluorescence was used to determine the skeletal arrangement. Transendothelial resistance was used to detect the permeability of endothelial barrier. Phosphorylation of Y685-VE-cadherin was significantly reduced after AngII stimulation (P < 0.05), together with skeletal rearrangement, and elevation of endothelial permeability which finally induced endothelial barrier injury. After PP2 interference, the phosphorylation of Y685-VE-cadherin was further reduced and the endothelial permeability was further elevated. These data indicated that AngII could induce pulmonary injury by triggering endothelial barrier injury, and such process may be related to the dephosphorylation of Y685-VE-cadherin and the endothelial skeletal rearrangement.

  3. Dephosphorylation of Y685-VE-Cadherin Involved in Pulmonary Microvascular Endothelial Barrier Injury Induced by Angiotensin II

    PubMed Central

    Wang, Zhiwei; Dai, Feifeng; Liu, Huagang; Ren, Wei; Chang, Jinxing; Li, Bowen

    2016-01-01

    Angiotensin II (AngII) caused pulmonary microvascular endothelial barrier injury, which induced acute aortic dissection (AAD) combined with acute lung injury (ALI). However, the exact mechanism is unclear. We investigated the role of dephosphorylation of Y685-VE-cadherin in the AngII induced pulmonary microvascular endothelial barrier injury. Mice or pulmonary microvascular endothelial cells (PMVECs) were divided into control group, AngII group, AngII+PP2 (Src kinase inhibitor) group, and PP2 group. PP2 was used to inhibit the phosphorylation of Y685-VE-cadherin. Pathological changes, infiltration of macrophages and neutrophils, and pulmonary microvascular permeability were used to determine the pulmonary microvascular endothelial barrier function. Flow cytometry was used to determine the apoptosis of PMVECs, and immunofluorescence was used to determine the skeletal arrangement. Transendothelial resistance was used to detect the permeability of endothelial barrier. Phosphorylation of Y685-VE-cadherin was significantly reduced after AngII stimulation (P < 0.05), together with skeletal rearrangement, and elevation of endothelial permeability which finally induced endothelial barrier injury. After PP2 interference, the phosphorylation of Y685-VE-cadherin was further reduced and the endothelial permeability was further elevated. These data indicated that AngII could induce pulmonary injury by triggering endothelial barrier injury, and such process may be related to the dephosphorylation of Y685-VE-cadherin and the endothelial skeletal rearrangement. PMID:28119542

  4. Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7.

    PubMed

    Silva, Susana L; Albuquerque, Adriana S; Serra-Caetano, Ana; Foxall, Russell B; Pires, Ana R; Matoso, Paula; Fernandes, Susana M; Ferreira, João; Cheynier, Rémi; Victorino, Rui M M; Caramalho, Iris; Barata, João T; Sousa, Ana E

    2016-03-15

    Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.

  5. The Late-Type Extension to MoVeRS (LaTE-MoVeRS): Proper Motion Verified Low-mass Stars and Brown Dwarfs from SDSS, 2MASS, and WISE

    NASA Astrophysics Data System (ADS)

    Theissen, Christopher A.; West, Andrew A.; Shippee, Guillaume; Burgasser, Adam J.; Schmidt, Sarah J.

    2017-03-01

    We present the Late-Type Extension to the Motion Verified Red Stars (LaTE-MoVeRS) catalog, containing 46,463 photometric late-type (>M5) dwarfs within the Sloan Digital Sky Survey (SDSS) footprint. Proper motions were computed for objects combining astrometry from the SDSS Data Release 12 (DR12), the Two-micron All-Sky Survey (2MASS) Point Source Catalog, and the Wide-field Infrared Survey Explorer (WISE) AllWISE data sets. LaTE-MoVeRS objects were required to have significant proper motion ({μ }{tot}≥slant 2{σ }{μ {tot}}). Using the LaTE-MoVeRS sample and Gaia Data Release 1, we estimate Gaia will be ∼64% complete for very low-mass objects (>M5) in comparison to the combined SDSS+2MASS+WISE data set (i< 21.3). We computed photometric distances and estimated stellar effective temperatures for the LaTE-MoVeRS catalog. The majority of the dwarfs in the sample have distances < 150 pc and {T}{eff}< 3000 K. Thirteen objects that have not been previously identified as nearby objects were identified within LaTE-MoVeRS with estimated photometric distances within 25 pc. We also identified one new object that has not been previously identified with a large amount of excess mid-infrared flux (2MASS J11151597+1937266). This object appears to be an L2γ at ∼50 pc showing spectroscopic signs of a flaring event (e.g., strong hydrogen Balmer emission lines). This object does not exhibit kinematics similar to any known kinematic association. The LaTE-MoVeRS catalog is available through SDSS CasJobs and VizieR.

  6. Predicting drug-induced liver injury in human with Naïve Bayes classifier approach

    NASA Astrophysics Data System (ADS)

    Zhang, Hui; Ding, Lan; Zou, Yi; Hu, Shui-Qing; Huang, Hai-Guo; Kong, Wei-Bao; Zhang, Ji

    2016-10-01

    Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.

  7. Morbidity and nutrition status of rural drug-naïve Kenyan women living with HIV.

    PubMed

    Neumann, Charlotte G; Nyandiko, Winstone; Siika, Abraham; Drorbaugh, Natalie; Samari, Goleen; Ettyang, Grace; Ernst, Judith A

    2016-09-01

    This paper describes morbidity in a group of HIV-positive drug-naïve rural women in western Kenya. A total of 226 drug-naïve HIV-positive women were evaluated for baseline morbidity, immune function, and anthropometry before a food-based nutrition intervention. Kenyan nurses visited women in their homes and conducted semi-structured interviews regarding symptoms and physical signs experienced at the time of the visit and during the previous week and physical inspection. Blood and urine samples were examined for determination of immune function (CD4, CD8, and total lymphocyte counts), anaemia, malaria, and pregnancy status. Intradermal skin testing with tuberculin (PPD), candida, and tetanus toxoid antigens was also performed to evaluate cell-mediated immunity. Anthropometry was measured, and body mass index (BMI) was calculated. Seventy-six per cent of the women reported being sick on the day of the interview or within the previous week. Illnesses considered serious were reported by 13.7% of women. The most frequent morbidity episodes reported were upper respiratory tract infections (13.3%), suspected malaria (5.85%), skeletal pain (4.87%), and stomach pain (4.42%). The most common morbidity signs on physical inspection were respiratory symptoms, most commonly rhinorrhea and coughing. Confirmed malaria and severe diarrhea were significantly associated with a higher BMI.

  8. Towards the Integration of APECS and VE-Suite for Virtual Power Plant Co-Simulation

    SciTech Connect

    Zitney, S.E.; McCorkle, D.; Yang, C.; Jordan, T.; Swensen, D.; Bryden, M.

    2007-05-01

    Process modeling and simulation tools are widely used for the design and operation of advanced power generation systems. These tools enable engineers to solve the critical process systems engineering problems that arise throughout the lifecycle of a power plant, such as designing a new process, troubleshooting a process unit or optimizing operations of the full process. To analyze the impact of complex thermal and fluid flow phenomena on overall power plant performance, the Department of Energy’s (DOE) National Energy Technology Laboratory (NETL) has developed the Advanced Process Engineering Co-Simulator (APECS). The APECS system is an integrated software suite that combines process simulation (e.g., Aspen Plus) and high-fidelity equipment simulations such as those based on computational fluid dynamics (CFD), together with advanced analysis capabilities including case studies, sensitivity analysis, stochastic simulation for risk/uncertainty analysis, and multi-objective optimization. In this paper we discuss the initial phases of the integration of the APECS system with the immersive and interactive virtual engineering software, VE-Suite, developed at Iowa State University and Ames Laboratory. VE-Suite uses the ActiveX (OLE Automation) controls in the Aspen Plus process simulator wrapped by the CASI library developed by Reaction Engineering International to run process/CFD co-simulations and query for results. This integration represents a necessary step in the development of virtual power plant co-simulations that will ultimately reduce the time, cost, and technical risk of developing advanced power generation systems.

  9. The metabolome regulates the epigenetic landscape during naïve to primed human embryonic stem cell transition

    PubMed Central

    Sperber, Henrik; Mathieu, Julie; Wang, Yuliang; Ferreccio, Amy; Hesson, Jennifer; Xu, Zhuojin; Fischer, Karin A.; Devi, Arikketh; Detraux, Damien; Gu, Haiwei; Battle, Stephanie L.; Showalter, Megan; Valensisi, Cristina; Bielas, Jason H.; Ericson, Nolan G.; Margaretha, Lilyana; Robitaille, Aaron M.; Margineantu, Daciana; Fiehn, Oliver; Hockenbery, David; Blau, C. Anthony; Raftery, Daniel; Margolin, Adam; Hawkins, R. David; Moon, Randall T.; Ware, Carol B.; Ruohola-Baker, Hannele

    2015-01-01

    For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans display two stable yet epigenetically distinct states of pluripotency, naïve and primed. We now show that nicotinamide-N-methyl transferase (NNMT) and metabolic state regulate pluripotency in hESCs. Specifically, in naïve hESCs NNMT and its enzymatic product 1-methylnicotinamide (1-MNA) are highly upregulated, and NNMT is required for low SAM levels and H3K27me3 repressive state. NNMT consumes SAM in naïve cells, making it unavailable for histone methylation that represses Wnt and activates HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development. PMID:26571212

  10. [Efficacy of dolutegravir in treatment-naïve patients. The SPRING-1, SPRING-2, SINGLE and FLAMINGO trials].

    PubMed

    Bernardino, José I; Antela, Antonio

    2015-03-01

    The efficacy of dolutegravir (DTG) in treatment-naïve patients has been analyzed in the SPRING 1 and 2, SINGLE and FLAMINGO trials, which compared dolutegravir with the agents currently recommended as the drugs of choice in clinical practice guidelines in treatment-naïve patients: efavirenz, raltegravir and darunavir/ritonavir. These trials confirmed the superiority (SINGLE and FLAMINGO) or the non-inferiority (SPRING-2) of dolutegravir. More than 2,000 patients were included in these 4 studies, lending value to their results and reinforcing the view of dolutegravir as the drug of choice in treatment-naïve patients, accompanied either by abacavir/lamivudine (Kivexa(®)) or tenofovir/emtricitabine (Truvada®).

  11. miRNA Profiling of Naïve, Effector and Memory CD8 T Cells

    PubMed Central

    Wu, Haoquan; Neilson, Joel R.; Kumar, Priti; Manocha, Monika; Shankar, Premlata; Sharp, Phillip A.; Manjunath, N.

    2007-01-01

    microRNAs have recently emerged as master regulators of gene expression during development and cell differentiation. Although profound changes in gene expression also occur during antigen-induced T cell differentiation, the role of miRNAs in the process is not known. We compared the miRNA expression profiles between antigen-specific naïve, effector and memory CD8+ T cells using 3 different methods-small RNA cloning, miRNA microarray analysis and real-time PCR. Although many miRNAs were expressed in all the T cell subsets, the frequency of 7 miRNAs (miR-16, miR-21, miR-142-3p, miR-142-5p, miR-150, miR-15b and let-7f) alone accounted for ∼60% of all miRNAs, and their expression was several fold higher than the other expressed miRNAs. Global downregulation of miRNAs (including 6/7 dominantly expressed miRNAs) was observed in effector T cells compared to naïve cells and the miRNA expression levels tended to come back up in memory T cells. However, a few miRNAs, notably miR-21 were higher in effector and memory T cells compared to naïve T cells. These results suggest that concomitant with profound changes in gene expression, miRNA profile also changes dynamically during T cell differentiation. Sequence analysis of the cloned mature miRNAs revealed an extensive degree of end polymorphism. While 3′end polymorphisms dominated, heterogeneity at both ends, resembling drosha/dicer processing shift was also seen in miR-142, suggesting a possible novel mechanism to generate new miRNA and/or to diversify miRNA target selection. Overall, our results suggest that dynamic changes in the expression of miRNAs may be important for the regulation of gene expression during antigen-induced T cell differentiation. Our study also suggests possible novel mechanisms for miRNA biogenesis and function. PMID:17925868

  12. Alterations in Polysomnographic (PSG) profile in drug-naïve Parkinson's disease

    PubMed Central

    Joy, Sanju P.; Sinha, Sanjib; Pal, Pramod Kumar; Panda, Samhita; Philip, Mariamma; Taly, Arun B.

    2014-01-01

    Objective: We studied the changes in Polysomnographic (PSG) profile in drug-naïve patients of Parkinson's disease (PD) who underwent evaluation with sleep overnight PSG. Materials and Methods: This prospective study included 30 with newly diagnosed levodopa-naïve patients with PD, fulfilling the UK-PD society brain bank clinical diagnostic criteria (M:F = 25:5; age: 57.2 ± 10.7 years). The disease severity scales and sleep related questionnaires were administered, and then patients were subjected to overnight PSG. Results: The mean duration of illness was 9.7 ± 9.5 months. The mean Hoehn and Yahr stage was 1.8 ± 0.4. The mean Unified Parkinson's Disease Rating Scale (UPDRS) motor score improved from 27.7 ± 9.2 to 17.5 ± 8.9 with sustained usage of levodopa. Nocturnal sleep as assessed by Pittsburgh Sleep Quality Index (PSQI) was impaired in 10 (33.3%) patients (mean PSQI score: 5.1 ± 3.1). Excessive day time somnolence was recorded in three patients with Epworth Sleepiness Scale (ESS) score ≥ 10 (mean ESS score: 4.0 ± 3.4). PSG analysis revealed that poor sleep efficiency of <85% was present in 86.7% of patients (mean: 68.3 ± 21.3%). The latencies to sleep onset (mean: 49.8 ± 67.0 minutes) and stage 2 sleep (36.5 ± 13.1%) were prolonged while slow wave sleep was shortened. Respiration during sleep was significantly impaired in which 43.3% had impaired apnoea hyperpnoea index (AHI) ≥5, mean AHI: 8.3 ± 12.1). Apnoeic episodes were predominantly obstructive (obstructive sleep apnea, OSA index = 2.2 ± 5.1). These patients had periodic leg movement (PLM) disorder (56.7% had PLM index of 5 or more, mean PLMI: 27.53 ± 4 9.05) that resulted in excessive daytime somnolence. Conclusions: To conclude, sleep macro-architecture is altered in frequently and variably in levodopa-naïve patients of PD and the alterations are possibly due to disease process per se. PMID:25221397

  13. p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma–associated ubiquitin ligase K5

    PubMed Central

    Nanes, Benjamin A.; Grimsley-Myers, Cynthia M.; Cadwell, Chantel M.; Robinson, Brian S.; Lowery, Anthony M.; Vincent, Peter A.; Mosunjac, Marina; Früh, Klaus; Kowalczyk, Andrew P.

    2017-01-01

    Vascular endothelial (VE)-cadherin undergoes constitutive internalization driven by a unique endocytic motif that also serves as a p120-catenin (p120) binding site. p120 binding masks the motif, stabilizing the cadherin at cell junctions. This mechanism allows constitutive VE-cadherin endocytosis and recycling to contribute to adherens junction dynamics without resulting in junction disassembly. Here we identify an additional motif that drives VE-cadherin endocytosis and pathological junction disassembly associated with the endothelial-derived tumor Kaposi sarcoma. Human herpesvirus 8, which causes Kaposi sarcoma, expresses the MARCH family ubiquitin ligase K5. We report that K5 targets two membrane-proximal VE-cadherin lysine residues for ubiquitination, driving endocytosis and down-regulation of the cadherin. K5-induced VE-cadherin endocytosis does not require the constitutive endocytic motif. However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5. Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability. PMID:27798235

  14. p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma-associated ubiquitin ligase K5.

    PubMed

    Nanes, Benjamin A; Grimsley-Myers, Cynthia M; Cadwell, Chantel M; Robinson, Brian S; Lowery, Anthony M; Vincent, Peter A; Mosunjac, Marina; Früh, Klaus; Kowalczyk, Andrew P

    2017-01-01

    Vascular endothelial (VE)-cadherin undergoes constitutive internalization driven by a unique endocytic motif that also serves as a p120-catenin (p120) binding site. p120 binding masks the motif, stabilizing the cadherin at cell junctions. This mechanism allows constitutive VE-cadherin endocytosis and recycling to contribute to adherens junction dynamics without resulting in junction disassembly. Here we identify an additional motif that drives VE-cadherin endocytosis and pathological junction disassembly associated with the endothelial-derived tumor Kaposi sarcoma. Human herpesvirus 8, which causes Kaposi sarcoma, expresses the MARCH family ubiquitin ligase K5. We report that K5 targets two membrane-proximal VE-cadherin lysine residues for ubiquitination, driving endocytosis and down-regulation of the cadherin. K5-induced VE-cadherin endocytosis does not require the constitutive endocytic motif. However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5. Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability.

  15. You've Written a Cool Astronomy Code! Now What Do You Do with It?

    NASA Astrophysics Data System (ADS)

    Allen, Alice; Accomazzi, A.; Berriman, G. B.; DuPrie, K.; Hanisch, R. J.; Mink, J. D.; Nemiroff, R. J.; Shamir, L.; Shortridge, K.; Taylor, M. B.; Teuben, P. J.; Wallin, J. F.

    2014-01-01

    Now that you've written a useful astronomy code for your soon-to-be-published research, you have to figure out what you want to do with it. Our suggestion? Share it! This presentation highlights the means and benefits of sharing your code. Make your code citable -- submit it to the Astrophysics Source Code Library and have it indexed by ADS! The Astrophysics Source Code Library (ASCL) is a free online registry of source codes of interest to astronomers and astrophysicists. With over 700 codes, it is continuing its rapid growth, with an average of 17 new codes a month. The editors seek out codes for inclusion; indexing by ADS improves the discoverability of codes and provides a way to cite codes as separate entries, especially codes without papers that describe them.

  16. Influenza-Like Illness Surveillance on Twitter through Automated Learning of Naïve Language

    PubMed Central

    Gesualdo, Francesco; Stilo, Giovanni; Agricola, Eleonora; Gonfiantini, Michaela V.; Pandolfi, Elisabetta; Velardi, Paola; Tozzi, Alberto E.

    2013-01-01

    Twitter has the potential to be a timely and cost-effective source of data for syndromic surveillance. When speaking of an illness, Twitter users often report a combination of symptoms, rather than a suspected or final diagnosis, using naïve, everyday language. We developed a minimally trained algorithm that exploits the abundance of health-related web pages to identify all jargon expressions related to a specific technical term. We then translated an influenza case definition into a Boolean query, each symptom being described by a technical term and all related jargon expressions, as identified by the algorithm. Subsequently, we monitored all tweets that reported a combination of symptoms satisfying the case definition query. In order to geolocalize messages, we defined 3 localization strategies based on codes associated with each tweet. We found a high correlation coefficient between the trend of our influenza-positive tweets and ILI trends identified by US traditional surveillance systems. PMID:24324799

  17. Influenza-like illness surveillance on Twitter through automated learning of naïve language.

    PubMed

    Gesualdo, Francesco; Stilo, Giovanni; Agricola, Eleonora; Gonfiantini, Michaela V; Pandolfi, Elisabetta; Velardi, Paola; Tozzi, Alberto E

    2013-01-01

    Twitter has the potential to be a timely and cost-effective source of data for syndromic surveillance. When speaking of an illness, Twitter users often report a combination of symptoms, rather than a suspected or final diagnosis, using naïve, everyday language. We developed a minimally trained algorithm that exploits the abundance of health-related web pages to identify all jargon expressions related to a specific technical term. We then translated an influenza case definition into a Boolean query, each symptom being described by a technical term and all related jargon expressions, as identified by the algorithm. Subsequently, we monitored all tweets that reported a combination of symptoms satisfying the case definition query. In order to geolocalize messages, we defined 3 localization strategies based on codes associated with each tweet. We found a high correlation coefficient between the trend of our influenza-positive tweets and ILI trends identified by US traditional surveillance systems.

  18. Safety and efficacy of fingolimod in treatment-naïve multiple sclerosis patients.

    PubMed

    Marriott, James J

    2011-01-01

    Fingolimod was recently approved for use in the United States after two phase III trials confirmed its effectiveness in reducing disease activity in relapsing-remitting multiple sclerosis. These positive results, coupled with the important fact that this is the first oral disease-modifying therapy, has lead to considerable enthusiasm amongst physicians and patients. However, fingolimod is associated with rare but serious adverse events. In addition, unlike conventional disease-modifying therapies, cardiopulmonary, ophthalmological and dermatological safety monitoring unfamiliar to both neurologists and patients is required before and during treatment. This paper will discuss these issues from the perspective of using fingolimod as a first-line disease-modifying therapy in treatment-naïve relapsing-remitting multiple sclerosis patients.

  19. Learning accurate and concise naïve Bayes classifiers from attribute value taxonomies and data

    PubMed Central

    Kang, D.-K.; Silvescu, A.; Honavar, V.

    2009-01-01

    In many application domains, there is a need for learning algorithms that can effectively exploit attribute value taxonomies (AVT)—hierarchical groupings of attribute values—to learn compact, comprehensible and accurate classifiers from data—including data that are partially specified. This paper describes AVT-NBL, a natural generalization of the naïve Bayes learner (NBL), for learning classifiers from AVT and data. Our experimental results show that AVT-NBL is able to generate classifiers that are substantially more compact and more accurate than those produced by NBL on a broad range of data sets with different percentages of partially specified values. We also show that AVT-NBL is more efficient in its use of training data: AVT-NBL produces classifiers that outperform those produced by NBL using substantially fewer training examples. PMID:20351793

  20. Investigation of Blue Bedding in Cages Housing Treatment-Naïve Hamsters.

    PubMed

    Shah, Vishal D; Walton, Betsy J; Culp, Amanda G; Castellino, Stephen

    2015-11-01

    During the acclimation phase of a preclinical safety study involving Syrian golden hamsters, some of the cages of treatment-naïve animals were noted to contain blue-tinged bedding; the urine of these hamsters was not discolored. We sought to understand the underlying cause of this unusual finding to ensure that the study animals were healthy and free from factors that might confound the interpretation of the study. Analysis of extracts from the blue bedding by using HPLC with inline UV detection and high-resolution mass spectrometry indicated that the color was due to the presence of indigo blue. Furthermore, the indigo blue likely was formed through a series of biochemical events initiated by the intestinal metabolism of tryptophan to an indoxyl metabolite. We offer 2 hypotheses regarding the fate of the indoxyl metabolite: indigo blue formation through oxidative coupling in the liver or through urinary bacterial metabolism.

  1. Naïve conceptions about multimedia learning: a study on primary school textbooks

    PubMed Central

    Colombo, Barbara; Antonietti, Alessandro

    2013-01-01

    HIGHLIGHTS This interview study explores beliefs about the instructional role of illustrationsWe compared illustrators', teachers', students' and common people's ideasParticipants' responses were internally coherent and close to multimedia learning theoryWe propose and discuss an integrated multimedia learning model An interview study, based on specific pictures taken from textbooks used in primary schools, was carried out to investigate illustrators', teachers', students', and common people's beliefs about the role that illustrations play in facilitating learning. Participants' responses were internally coherent, indicating a systematic nature of the underlying naïve conceptions. Findings disprove Mayer's pessimistic claim that laypersons' conceptions of multimedia learning fail to match experimentally supported principles and theories. On the contrary, interviewees spontaneously came very close to the multimedia learning theory, which states that students learn better from pictures, which fit specific cognitive principles. Implications for school instruction are highlighted. PMID:23908636

  2. sLORETA intracortical lagged coherence during breath counting in meditation-naïve participants

    PubMed Central

    Milz, Patricia; Faber, Pascal L.; Lehmann, Dietrich; Kochi, Kieko; Pascual-Marqui, Roberto D.

    2013-01-01

    We investigated brain functional connectivity comparing no-task resting to breath counting (a meditation exercise but given as task without referring to meditation). Functional connectivity computed as EEG coherence between head-surface data suffers from localization ambiguity, reference dependence, and overestimation due to volume conduction. Lagged coherence between intracortical model sources addresses these criticisms. With this analysis approach, experienced meditators reportedly showed reduced coherence during meditation, meditation-naïve participants have not yet been investigated. 58-channel EEG from 23 healthy, right-handed, meditation-naïve males during resting [3 runs] and breath counting [2 runs] was computed into sLORETA time series of intracortical electrical activity in 19 regions of interest (ROI) corresponding to the cortex underlying 19 scalp electrode sites, for each of the eight independent EEG frequency bands covering 1.5–44 Hz. Intracortical lagged coherences and head-surface conventional coherences were computed between the 19 regions/sites. During breath counting compared to resting, paired t-tests corrected for multiple testing revealed four significantly lower intracortical lagged coherences, but four significantly higher head-surface conventional coherences. Lowered intracortical lagged coherences involved left BA 10 and right BAs 3, 10, 17, 40. In conclusion, intracortical lagged coherence can yield results that are inverted to those of head-surface conventional coherence. The lowered functional connectivity between cognitive control areas and sensory perception areas during meditation-type breath counting compared to resting conceivably reflects the attention to a bodily percept without cognitive reasoning. The reductions in functional connectivity were similar but not as widespread as the reductions reported during meditation in experienced meditators. PMID:24860483

  3. Lung Microbiome Analysis in Steroid-Naїve Asthma Patients by Using Whole Sputum

    PubMed Central

    Jung, Jae-Woo; Choi, Jae-Chol; Shin, Jong-Wook; Kim, Jae-Yeol; Park, In-Won; Choi, Byoung Whui; Park, Heung-Woo; Cho, Sang-Heon

    2016-01-01

    Background Although recent metagenomic approaches have characterized the distinguished microbial compositions in airways of asthmatics, these results did not reach a consensus due to the small sample size, non-standardization of specimens and medication status. We conducted a metagenomics approach by using terminal restriction fragment length polymorphism (T-RFLP) analysis of the induced whole sputum representing both the cellular and fluid phases in a relative large number of steroid naïve asthmatics. Methods Induced whole sputum samples obtained from 36 healthy subjects and 89 steroid-naїve asthma patients were analyzed through T-RFLP analysis. Results In contrast to previous reports about microbiota in the asthmatic airways, the diversity of microbial composition was not significantly different between the controls and asthma patients (p=0.937). In an analysis of similarities, the global R-value showed a statistically significant difference but a very low separation (0.148, p=0.002). The dissimilarity in the bacterial communities between groups was 28.74%, and operational taxonomic units (OTUs) contributing to this difference were as follows: OTU 789 (Lachnospiraceae), 517 (Comamonadaceae, Acetobacteraceae , and Chloroplast), 633 (Prevotella), 645 (Actinobacteria and Propionibacterium acnes), 607 (Lactobacillus buchneri, Lactobacillus otakiensis, Lactobacillus sunkii, and Rhodobacteraceae), and 661 (Acinetobacter, Pseudomonas, and Leptotrichiaceae), and they were significantly more prevalent in the sputum of asthma patients than in the sputum of the controls. Conclusion Before starting anti-asthmatic treatment, the microbiota in the whole sputum of patients with asthma showed a marginal difference from the microbiota in the whole sputum of the controls. PMID:27433177

  4. Predicting drug-induced liver injury in human with Naïve Bayes classifier approach.

    PubMed

    Zhang, Hui; Ding, Lan; Zou, Yi; Hu, Shui-Qing; Huang, Hai-Guo; Kong, Wei-Bao; Zhang, Ji

    2016-10-01

    Drug-induced liver injury (DILI) is one of the major safety concerns in drug development. Although various toxicological studies assessing DILI risk have been developed, these methods were not sufficient in predicting DILI in humans. Thus, developing new tools and approaches to better predict DILI risk in humans has become an important and urgent task. In this study, we aimed to develop a computational model for assessment of the DILI risk with using a larger scale human dataset and Naïve Bayes classifier. The established Naïve Bayes prediction model was evaluated by 5-fold cross validation and an external test set. For the training set, the overall prediction accuracy of the 5-fold cross validation was 94.0 %. The sensitivity, specificity, positive predictive value and negative predictive value were 97.1, 89.2, 93.5 and 95.1 %, respectively. The test set with the concordance of 72.6 %, sensitivity of 72.5 %, specificity of 72.7 %, positive predictive value of 80.4 %, negative predictive value of 63.2 %. Furthermore, some important molecular descriptors related to DILI risk and some toxic/non-toxic fragments were identified. Thus, we hope the prediction model established here would be employed for the assessment of human DILI risk, and the obtained molecular descriptors and substructures should be taken into consideration in the design of new candidate compounds to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.

  5. Bayesian estimation of Karhunen-Loève expansions; A random subspace approach

    NASA Astrophysics Data System (ADS)

    Chowdhary, Kenny; Najm, Habib N.

    2016-08-01

    One of the most widely-used procedures for dimensionality reduction of high dimensional data is Principal Component Analysis (PCA). More broadly, low-dimensional stochastic representation of random fields with finite variance is provided via the well known Karhunen-Loève expansion (KLE). The KLE is analogous to a Fourier series expansion for a random process, where the goal is to find an orthogonal transformation for the data such that the projection of the data onto this orthogonal subspace is optimal in the L2 sense, i.e., which minimizes the mean square error. In practice, this orthogonal transformation is determined by performing an SVD (Singular Value Decomposition) on the sample covariance matrix or on the data matrix itself. Sampling error is typically ignored when quantifying the principal components, or, equivalently, basis functions of the KLE. Furthermore, it is exacerbated when the sample size is much smaller than the dimension of the random field. In this paper, we introduce a Bayesian KLE procedure, allowing one to obtain a probabilistic model on the principal components, which can account for inaccuracies due to limited sample size. The probabilistic model is built via Bayesian inference, from which the posterior becomes the matrix Bingham density over the space of orthonormal matrices. We use a modified Gibbs sampling procedure to sample on this space and then build probabilistic Karhunen-Loève expansions over random subspaces to obtain a set of low-dimensional surrogates of the stochastic process. We illustrate this probabilistic procedure with a finite dimensional stochastic process inspired by Brownian motion.

  6. Heterodimeric protein complex identification by naïve Bayes classifiers

    PubMed Central

    2013-01-01

    Background Protein complexes are basic cellular entities that carry out the functions of their components. It can be found that in databases of protein complexes of yeast like CYC2008, the major type of known protein complexes is heterodimeric complexes. Although a number of methods for trying to predict sets of proteins that form arbitrary types of protein complexes simultaneously have been proposed, it can be found that they often fail to predict heterodimeric complexes. Results In this paper, we have designed several features characterizing heterodimeric protein complexes based on genomic data sets, and proposed a supervised-learning method for the prediction of heterodimeric protein complexes. This method learns the parameters of the features, which are embedded in the naïve Bayes classifier. The log-likelihood ratio derived from the naïve Bayes classifier with the parameter values obtained by maximum likelihood estimation gives the score of a given pair of proteins to predict whether the pair is a heterodimeric complex or not. A five-fold cross-validation shows good performance on yeast. The trained classifiers also show higher predictability than various existing algorithms on yeast data sets with approximate and exact matching criteria. Conclusions Heterodimeric protein complex prediction is a rather harder problem than heteromeric protein complex prediction because heterodimeric protein complex is topologically simpler. However, it turns out that by designing features specialized for heterodimeric protein complexes, predictability of them can be improved. Thus, the design of more sophisticate features for heterodimeric protein complexes as well as the accumulation of more accurate and useful genome-wide data sets will lead to higher predictability of heterodimeric protein complexes. Our tool can be downloaded from http://imi.kyushu-u.ac.jp/~om/. PMID:24299017

  7. Abnormalities of cingulate cortex in antipsychotic-naïve chronic schizophrenia.

    PubMed

    Liu, Xiaoyi; Wang, Xijin; Lai, Yunyao; Hao, Chuanxi; Chen, Lei; Zhou, Zhenyu; Yu, Xin; Hong, Nan

    2016-05-01

    While several morphometric studies have postulated a critical contribution of the cingulate cortex (CC) to the pathophysiology of schizophrenia based on abnormalities in CC volume, other studies have been inconclusive. Most such studies have focused only on changes in cortical volume, whereas other morphometric parameters such as surface area and cortical thickness could be more relevant and possibly account for these discrepancies. Furthermore, factors such as antipsychotic drug use and treatment duration may also influence cortical morphology. To clarify the association between schizophrenia and CC deficits, we investigated morphometric abnormalities of the CC in antipsychotic drug (AD)-naïve chronic schizophrenia patients by comparing T1-weighted magnetic resonance images (T1WI-MRI) from patients (n=17) to healthy controls (n=17) using the surface-based morphometry program FreeSurfer. Partial correlations were examined between abnormal morphometric measures and both clinical variables and cognitive performance scores. Compared to healthy controls, drug-naïve schizophrenia patients exhibited significantly lower volumes in both left rostral anterior CC (rACC) and left posterior CC (PCC). These reductions in CC volume resulted from reduced surface area rather than reduced cortical thickness. There was also a significant relationship between left PCC volume and working memory in patients. No significant correlations were observed between CC volume and clinical variables. The results suggest that abnormalities in the CC as manifested by reduced surface area may contribute to cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled SI: PSC and the brain.

  8. Characterization of bovine embryos cultured under conditions appropriate for sustaining human naïve pluripotency

    PubMed Central

    van Tol, Helena T. A.; Groot Koerkamp, Marian J. A.; Wubbolts, Richard W.; Haagsman, Henk P.; Roelen, Bernard A. J.

    2017-01-01

    In mammalian preimplantation development, pluripotent cells are set aside from cells that contribute to extra-embryonic tissues. Although the pluripotent cell population of mouse and human embryos can be cultured as embryonic stem cells, little is known about the pathways involved in formation of a bovine pluripotent cell population, nor how to maintain these cells in vitro. The objective of this study was to determine the transcriptomic profile related to bovine pluripotency. Therefore, in vitro derived embryos were cultured in various culture media that recently have been reported capable of maintaining the naïve pluripotent state of human embryonic cells. Gene expression profiles of embryos cultured in these media were compared using microarray analysis and quantitative RT-PCR. Compared to standard culture conditions, embryo culture in ‘naïve’ media reduced mRNA expression levels of the key pluripotency markers NANOG and POU5F1. A relatively high percentage of genes with differential expression levels were located on the X-chromosome. In addition, reduced XIST expression was detected in embryos cultured in naïve media and female embryos contained fewer cells with H3K27me3 foci, indicating a delay in X-chromosome inactivation. Whole embryos cultured in one of the media, 5iLA, could be maintained until 23 days post fertilization. Together these data indicate that ‘naïve’ conditions do not lead to altered expression of known genes involved in pluripotency. Interestingly, X-chromosome inactivation and development of bovine embryos were dependent on the culture conditions. PMID:28241084

  9. Evaluation of acute effects of melatonin on ethanol drinking in ethanol naïve rats

    PubMed Central

    Rather, Zahoor Ahmad; Chowta, Mukta N.; Bolumbu, Ganaraja; Rakesh, K. B.

    2015-01-01

    Objective: The objective was to evaluate the acute effect of melatonin on ethanol drinking in ethanol naïve rats and to determine the specificity of the effect of melatonin on ethanol intake as compared to an intake of plain tap water or sugar water. Materials and Methods: A total of three experiments (2 weeks duration each) using different drinking solutions (ethanol, plain tap water, sugar water) was conducted in individually housed male wistar rats of 5 weeks age. Each animal had access to bottles containing drinking solutions for 2 h a day. In each experiment, on day 1, day 2, day 4, day 5, day 8, day 9, day 11, day 12 rats received drinking solutions. Each individual rat received single doses of saline, melatonin (50 mg and 100 mg/kg), and naltrexone on day 2, 5, 9, and 12, 1-h before receiving drinking solution. The order of drug administration is permuted such a way that each animal received the drugs in a different order in different experiments. Results: Melatonin has significantly decreased ethanol consumption by the rats and effect is dose-dependent. Naltrexone also has caused a significant reduction in the ethanol consumption. The maximum reduction in ethanol consumption was seen with melatonin 100 mg/kg dose compared to melatonin 50 mg/kg and naltrexone. There was no statistically significant effect of melatonin on plain water and sugar solution intake. Conclusions: Melatonin decreases ethanol consumption in ethanol naïve rats. The effect of melatonin is similar to naltrexone affecting selectively ethanol consumption, but not plain water and sugar water consumption. PMID:26288469

  10. HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Naïve Patients

    PubMed Central

    Valcour, Victor G.; Ananworanich, Jintanat; Agsalda, Melissa; Sailasuta, Napapon; Chalermchai, Thep; Schuetz, Alexandra; Shikuma, Cecilia; Liang, Chin-Yuan; Jirajariyavej, Supunee; Sithinamsuwan, Pasiri; Tipsuk, Somporn; Clifford, David B.; Paul, Robert; Fletcher, James L. K.; Marovich, Mary A.; Slike, Bonnie M.; DeGruttola, Victor; Shiramizu, Bruce

    2013-01-01

    Objectives Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury. Methods We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). Results The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. Interpretation Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. PMID:23936155

  11. Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

    PubMed Central

    Takahashi, Tetsuya; Cho, Raymond Y.; Mizuno, Tomoyuki; Kikuchi, Mitsuru; Murata, Tetsuhito; Takahashi, Koichi; Wada, Yuji

    2010-01-01

    Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics. PMID:20149880

  12. Differential effects of modafinil on memory in naïve and memory-impaired rats.

    PubMed

    Garcia, Vanessa Athaíde; Souza de Freitas, Betânia; Busato, Stefano Boemler; D'avila Portal, Bernardo Chaves; Piazza, Francisco Correa; Schröder, Nadja

    2013-12-01

    Modafinil is a wake-promoting drug and has been approved for the treatment of excessive daytime sleepiness in narcolepsy and obstructive sleep apnea. Modafinil was shown to improve learning and memory in rodents, and to reverse memory deficits induced by sleep deprivation or stress. However, depending on the memory paradigm used, modafinil might also impair memory. We aimed to investigate the effects of modafinil on memory consolidation and retrieval for object recognition and inhibitory avoidance in naïve adult rats. We also investigated whether acute or chronic administration of modafinil would reverse memory deficits induced by iron overload, a model of memory impairment related to neurodegenerative disorders. Adult naïve rats received modafinil (0.0, 0.75, 7.5 or 75 mg/kg) either immediately after training or 1 h prior to testing in object recognition or inhibitory avoidance. Iron-treated rats received modafinil immediately after training in object recognition. In order to investigate the effects of chronic modafinil, iron-treated rats received daily injections of modafinil for 17 days, and 24 h later they were trained in object recognition or inhibitory avoidance. Acute modafinil does not affect memory consolidation or retrieval in naive rats. A single injection of modafinil at the highest dose was able to recover recognition memory in iron-treated rats. Chronic modafinil completely recovered iron-induced recognition memory and emotional memory deficits. Additional preclinical and clinical studies are necessary in order to support the applicability of modafinil in recovering memory impairment associated with neurodegenerative disorders.

  13. Is Tetranychus urticae suitable prey for development and reproduction of naïve Coleomegilla maculata?

    PubMed

    Riddick, Eric W; Wu, Zhixin; Rojas, M Guadalupe

    2014-02-01

    The lady beetle Coleomegilla maculata De Geer is an omnivorous predator that could help suppress aphid and spider mite populations on plants in greenhouses, plantscapes or interiorscapes. We are assessing the nutritional requirements and feeding behavior of C. maculata on target prey (spider mites) and factitious (unnatural) food. Our ultimate goal is to develop an efficacious diet to mass produce C. maculata. In this study, we tested the hypothesis that Tetranychus urticae Koch (two-spotted spider mite) is not suitable prey for development and reproduction of naïve C. maculata (i.e., with no prior exposure to T. urticae). Our objectives were to (i) provide baseline data on the effects of consuming T. urticae on C. maculata life history, (ii) to compare the effects of consuming all stages of T. urticae versus eggs of Musca domestica L. (common housefly), and (iii) to determine if the consumption of plant products was beneficial. We used C. maculata from a colony reared only on Ephestia kuehniella Zeller (Mediterranean flour moth) eggs. In experiments, C. maculata larvae were reared from the first instar to adult stage with prey/food in replicated arenas; adult females were paired with a single male with prey/food. The results showed that naïve C. maculata readily attacked and consumed T. urticae. Nevertheless, T. urticae was less suitable than M. domestica eggs for C. maculata development and reproduction. Applying a synthetic pollen-Chlorella alga powder (SPCA) in arenas containing T. urticae appeared to boost C. maculata female development and reproduction.

  14. Antibody Profiling in Naïve and Semi-immune Individuals Experimentally Challenged with Plasmodium vivax Sporozoites

    PubMed Central

    Arévalo-Herrera, Myriam; Lopez-Perez, Mary; Dotsey, Emmanuel; Jain, Aarti; Rubiano, Kelly; Felgner, Philip L.; Davies, D. Huw; Herrera, Sócrates

    2016-01-01

    Background Acquisition of malaria immunity in low transmission areas usually occurs after relatively few exposures to the parasite. A recent Plasmodium vivax experimental challenge trial in malaria naïve and semi-immune volunteers from Colombia showed that all naïve individuals developed malaria symptoms, whereas semi-immune subjects were asymptomatic or displayed attenuated symptoms. Sera from these individuals were analyzed by protein microarray to identify antibodies associated with clinical protection. Methodology/Principal Findings Serum samples from naïve (n = 7) and semi-immune (n = 9) volunteers exposed to P. vivax sporozoite-infected mosquito bites were probed against a custom protein microarray displaying 515 P. vivax antigens. The array revealed higher serological responses in semi-immune individuals before the challenge, although malaria naïve individuals also had pre-existing antibodies, which were higher in Colombians than US adults (control group). In both experimental groups the response to the P. vivax challenge peaked at day 45 and returned to near baseline at day 145. Additional analysis indicated that semi-immune volunteers without fever displayed a lower response to the challenge, but recognized new antigens afterwards. Conclusion Clinical protection against experimental challenge in volunteers with previous P. vivax exposure was associated with elevated pre-existing antibodies, an attenuated serological response to the challenge and reactivity to new antigens. PMID:27014875

  15. The Communication of Naïve Theories of the Social World in Parent-Child Conversation

    ERIC Educational Resources Information Center

    Chalik, Lisa; Rhodes, Marjorie

    2015-01-01

    Three studies examined the communication of naïve theories of social groups in conversations between parents and their 4-year-old children (N = 48). Parent-child dyads read and discussed a storybook in which they either explained why past social interactions had occurred (Study 1) or evaluated whether future social interactions should occur…

  16. DNA methylation-associated colonic mucosal immune and defense responses in treatment-naïve pediatric ulcerative colitis.

    PubMed

    Harris, R Alan; Nagy-Szakal, Dorottya; Mir, Sabina A V; Frank, Eibe; Szigeti, Reka; Kaplan, Jess L; Bronsky, Jiri; Opekun, Antone; Ferry, George D; Winter, Harland; Kellermayer, Richard

    2014-08-01

    Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naïve patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn's disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naïve UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naïve UC separated from control. One-hundred-and-twenty genes with significant expression change in UC (> 2-fold, P<0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naïve UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD.

  17. The Public's View of Agricultural Education: We've Come a Long Way--Or Have We?

    ERIC Educational Resources Information Center

    Krueger, David E.; And Others

    1995-01-01

    Includes "We've Come a Long Way--Or Have We?" (Krueger); "If Agricultural Education Were a Coca-Cola" (Doerfert); "Agriculture Is Taught? In High School?" (Elliot); "Let's Tell Our Story" (Davis); "Perception, Reality or Idealism" (Powers, Bull); "Agricultural Education under the Bright Lights" (Foster); and "The Changing Face of Agricultural…

  18. Tomato immune receptor Ve1 recognizes effector of multiple fungal pathogens uncovered by genome and RNA sequencing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fungal plant pathogens secrete effector molecules to establish disease on their hosts, while plants in turn utilize immune receptors to intercept these effectors. The tomato immune receptor Ve1 governs resistance to race 1 strains of the soil-borne vascular wilt fungi Verticillium dahliae and V. alb...

  19. Feeding preferences of experienced and naïve goats and sheep for the toxic plant Ipomoea carnea subsp. fistulosa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ipomoea carnea is a toxic plant that grazing goats and cattle may learn to ingest with repeated exposure. The objective of this study was to evaluate the feeding preferences of experienced and non-experienced (naïve) goats and sheep for I. carnea. The study used 3 groups of 5 goats (Group 1, experi...

  20. Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse.

    PubMed

    Taylor, J J; Laudenbach, M; Tucker, A M; Jenkins, M K; Pravetoni, M

    2014-03-01

    Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naïve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naïve B cells exhibited relatively higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naïve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naïve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naïve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules.

  1. A new mechanism shapes the naïve CD8(+) T cell repertoire: the selection for full diversity.

    PubMed

    Gonçalves, Pedro; Ferrarini, Marco; Molina-Paris, Carmen; Lythe, Grant; Vasseur, Florence; Lim, Annik; Rocha, Benedita; Azogui, Orly

    2017-05-01

    During thymic T cell differentiation, TCR repertoires are shaped by negative, positive and agonist selection. In the thymus and in the periphery, repertoires are also shaped by strong inter-clonal and intra-clonal competition to survive death by neglect. Understanding the impact of these events on the T cell repertoire requires direct evaluation of TCR expression in peripheral naïve T cells. Several studies have evaluated TCR diversity, with contradictory results. Some of these studies had intrinsic technical limitations since they used material obtained from T cell pools, preventing the direct evaluation of clonal sizes. Indeed with these approaches, identical TCRs may correspond to different cells expressing the same receptor, or to several amplicons from the same T cell. We here overcame this limitation by evaluating TCRB expression in individual naïve CD8(+) T cells. Of the 2269 Tcrb sequences we obtained from 13 mice, 99% were unique. Mathematical analysis of the data showed that the average number of naïve peripheral CD8(+) T cells expressing the same TCRB is 1.1 cell. Since TCRA co-expression studies could only increase repertoire diversity, these results reveal that the number of naïve T cells with unique TCRs approaches the number of naïve cells. Since thymocytes undergo multiple rounds of divisions after TCRB rearrangement and 3-5% of thymocytes survive thymic selection events the number of cells expressing the same TCRB was expected to be much higher. Thus, these results suggest a new repertoire selection mechanism, which strongly selects for full TCRB diversity.

  2. Decreased Cardiac Vagal Control in Drug-Naïve Patients with Posttraumatic Stress Disorder

    PubMed Central

    Chang, Hsin-An; Chang, Chuan-Chia; Tzeng, Nian-Sheng; Kuo, Terry BJ; Lu, Ru-Band

    2013-01-01

    Objective Decreased cardiac vagal control (CVC) has been proposed in posttraumatic stress disorder (PTSD), but the results are mixed. Analyses with larger sample sizes and better methodology are needed. Methods Thirty-two drug-naïve survivors with current PTSD, 32 survivors without PTSD and 192 matched controls were recruited for a case-control analysis. We used the PTSD checklist-civilian version (PCL-C) to assess posttraumatic symptoms severity. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters. Frequency-domain indices of HRV were obtained. The obtained results were evaluated in association with personality traits assessed by the Tridimensional Personality Questionnaire (TPQ). Results PTSD patients exhibited decreased LF-HRV and HF-HRV as compared to survivors without PTSD and to matched controls. The PTSD symptoms severity was associated with reduced mean RR intervals, Var-HRV, LF-HRV and HF-HRV. The harm avoidance score (which has been suggested to be associated with serotonergic activity) was negatively correlated with Var-HRV, LF-HRV and HF-HRV. Conclusion These data suggest that PTSD is accompanied by decreased CVC, highlighting the importance of assessing HRV in PTSD patients. In view of the increased risk for cardiovascular diseases in these vulnerable individuals, one might consider the treatment to restore their autonomic function while reducing PTSD symptoms. PMID:23798959

  3. Follower ants in a tandem pair are not always naïve

    PubMed Central

    Schultheiss, Patrick; Raderschall, Chloé A; Narendra, Ajay

    2015-01-01

    In addition to foraging individually several species of ants guide nestmates to a goal by tandem running. We found that the Australian ant, Camponotus consobrinus, forages both individually and by tandem running to head to the same goal, nest-specific native Australian trees on which they forage. While paths of solitary foragers and initial paths of tandem followers showed no differences in heading directions or straightness, tandem followers moved at about half the speed of solitary runs. When leaders were experimentally removed, follower ants initially engaged in a systematic search around the point of interruption, following which they either (a) headed directly towards and successfully reached the foraging trees, or (b) continued searching or (c) returned to the nest. The high incidence of followers that successfully navigated towards the foraging trees on their own provides strong evidence that many tandem followers are in fact experienced foragers. Detailed analysis of the searching behaviour revealed that even seemingly lost followers displayed a directional bias towards the foraging trees in their search path. Our results show that in a foraging context follower ants in a tandem pair are not always naïve. PMID:26021611

  4. A Pairwise Naïve Bayes Approach to Bayesian Classification

    PubMed Central

    Betensky, Rebecca A.

    2016-01-01

    Despite the relatively high accuracy of the naïve Bayes (NB) classifier, there may be several instances where it is not optimal, i.e. does not have the same classification performance as the Bayes classifier utilizing the joint distribution of the examined attributes. However, the Bayes classifier can be computationally intractable due to its required knowledge of the joint distribution. Therefore, we introduce a “pairwise naïve” Bayes (PNB) classifier that incorporates all pairwise relationships among the examined attributes, but does not require specification of the joint distribution. In this paper, we first describe the necessary and sufficient conditions under which the PNB classifier is optimal. We then discuss sufficient conditions for which the PNB classifier, and not NB, is optimal for normal attributes. Through simulation and actual studies, we evaluate the performance of our proposed classifier relative to the Bayes and NB classifiers, along with the HNB, AODE, LBR and TAN classifiers, using normal density and empirical estimation methods. Our applications show that the PNB classifier using normal density estimation yields the highest accuracy for data sets containing continuous attributes. We conclude that it offers a useful compromise between the Bayes and NB classifiers. PMID:27087730

  5. Categorization of Natural Whistled Vowels by Naïve Listeners of Different Language Background

    PubMed Central

    Meyer, Julien; Dentel, Laure; Meunier, Fanny

    2017-01-01

    Whistled speech in a non-tonal language consists of the natural emulation of vocalic and consonantal qualities in a simple modulated whistled signal. This special speech register represents a natural telecommunication system that enables high levels of sentence intelligibility by trained speakers and is not directly intelligible to naïve listeners. Yet, it is easily learned by speakers of the language that is being whistled, as attested by the current efforts of the revitalization of whistled Spanish in the Canary Islands. To better understand the relation between whistled and spoken speech perception, we look herein at how Spanish, French, and Standard Chinese native speakers, knowing nothing about whistled speech, categorized four Spanish whistled vowels. The results show that the listeners categorized differently depending on their native language. The Standard Chinese speakers demonstrated the worst performance on this task but were still able to associate a tonal whistle to vowel categories. Spanish speakers were the most accurate, and both Spanish and French participants were able to categorize the four vowels, although not as accurately as an expert whistler. These results attest that whistled speech can be used as a natural laboratory to test the perceptual processes of language. PMID:28174545

  6. Reduced anterior cingulate gray matter volume in treatment-naïve clinically depressed adolescents☆

    PubMed Central

    Pannekoek, Justine Nienke; van der Werff, Steven J.A.; van den Bulk, Bianca G.; van Lang, Natasja D.J.; Rombouts, Serge A.R.B.; van Buchem, Mark A.; Vermeiren, Robert R.J.M.; van der Wee, Nic J.A.

    2014-01-01

    Adolescent depression is associated with increased risk for suicidality, social and educational impairment, smoking, substance use, obesity, and depression in adulthood. It is of relevance to further our insight in the neurobiological mechanisms underlying this disorder in the developing brain, as this may be essential to optimize treatment and prevention of adolescent depression and its negative clinical trajectories. The equivocal findings of the limited number of studies on neural abnormalities in depressed youth stress the need for further neurobiological investigation of adolescent depression. We therefore performed a voxel-based morphometry study of the hippocampus, amygdala, superior temporal gyrus, and anterior cingulate cortex (ACC) in 26 treatment-naïve, clinically depressed adolescents and 26 pair-wise matched healthy controls. Additionally, an exploratory whole-brain analysis was performed. Clinically depressed adolescents showed a volume reduction of the bilateral dorsal ACC compared to healthy controls. However, no association was found between gray matter volume of the ACC and clinical severity scores for depression or anxiety. Our finding of a smaller ACC in clinically depressed adolescents is consistent with literature on depressed adults. Future research is needed to investigate if gray matter abnormalities precede or follow clinical depression in adolescents. PMID:24501702

  7. Movement imagery classification in EMOTIV cap based system by Naïve Bayes.

    PubMed

    Stock, Vinicius N; Balbinot, Alexandre

    2016-08-01

    Brain-computer interfaces (BCI) provide means of communications and control, in assistive technology, which do not require motor activity from the user. The goal of this study is to promote classification of two types of imaginary movements, left and right hands, in an EMOTIV cap based system, using the Naïve Bayes classifier. A preliminary analysis with respect to results obtained by other experiments in this field is also conducted. Processing of the electroencephalography (EEG) signals is done applying Common Spatial Pattern filters. The EPOC electrodes cap is used for EEG acquisition, in two test subjects, for two distinct trial formats. The channels picked are FC5, FC6, P7 and P8 of the 10-20 system, and a discussion about the differences of using C3, C4, P3 and P4 positions is proposed. Dataset 3 of the BCI Competition II is also analyzed using the implemented algorithms. The maximum classification results for the proposed experiment and for the BCI Competition dataset were, respectively, 79% and 85% The conclusion of this study is that the picked positions for electrodes may be applied for BCI systems with satisfactory classification rates.

  8. Normal Performance on a Simulated Gambling Task in Treatment-Naïve Alcohol Dependent Individuals

    PubMed Central

    Fein, George; McGillivray, Shannon; Finn, Peter

    2007-01-01

    Background Research suggests that substance abusers make more disadvantageous decisions on the simulated gambling task (SGT); such decisions are associated with deviance proneness and antisocial symptoms. This study examines decision-making on the SGT in young adults with alcohol dependence that are treatment-naïve (TxN). Methods 116 subjects (58 controls, 58 TxNs) were tested on the SGT, where participants choose cards from 4 different decks that vary in terms of the magnitude of the immediate gain (large/small) and the magnitude of long-term loss (larger/smaller). Participants also were assessed on measures of externalizing symptoms, personality traits reflecting social deviance, neuropsychological function, and the density of the family history of alcoholism. Results TxNs did not differ from controls on measures of SGT decision-making. SGT performance was not associated with externalizing symptoms, social deviance proneness, or a familial density of alcoholism. Although, TxNs had higher levels of externalizing symptoms, social deviance and familial density of alcoholism compared with controls, these variables were only modestly elevated compared with previous samples of long-term abstinent alcohol dependent individuals who showed decision-making deficits on the SGT. Conclusions The results suggest that our sample of young adult TxN adults with alcohol dependence do not have global deficits in decision-making as measured by the SGT, and that their poor decisions regarding their alcohol consumption are more specific to drinking. PMID:16737453

  9. Categorization of Natural Whistled Vowels by Naïve Listeners of Different Language Background.

    PubMed

    Meyer, Julien; Dentel, Laure; Meunier, Fanny

    2017-01-01

    Whistled speech in a non-tonal language consists of the natural emulation of vocalic and consonantal qualities in a simple modulated whistled signal. This special speech register represents a natural telecommunication system that enables high levels of sentence intelligibility by trained speakers and is not directly intelligible to naïve listeners. Yet, it is easily learned by speakers of the language that is being whistled, as attested by the current efforts of the revitalization of whistled Spanish in the Canary Islands. To better understand the relation between whistled and spoken speech perception, we look herein at how Spanish, French, and Standard Chinese native speakers, knowing nothing about whistled speech, categorized four Spanish whistled vowels. The results show that the listeners categorized differently depending on their native language. The Standard Chinese speakers demonstrated the worst performance on this task but were still able to associate a tonal whistle to vowel categories. Spanish speakers were the most accurate, and both Spanish and French participants were able to categorize the four vowels, although not as accurately as an expert whistler. These results attest that whistled speech can be used as a natural laboratory to test the perceptual processes of language.

  10. Meditation-Based Treatment Yielding Immediate Relief for Meditation-Naïve Migraineurs

    PubMed Central

    Tonelli, Makenzie E.; Wachholtz, Amy B.

    2014-01-01

    Meditation is gaining popularity as an effective means of managing and attenuating pain and has been particularly effective for migraines. Meditation additionally addresses the negative emotional states known to exist with migraines. The purpose of this study was to evaluate the effectiveness of meditation as an immediate intervention for reducing migraine pain as well as alleviating emotional tension, examined herein as a negative affect hypothesized to be correlated with pain. Twenty-seven migraineurs, with two to ten migraines per month, reported migraine-related pain and emotional tension ratings on a Likert scale (ranging from 0 to 10) before and after exposure to a brief meditation-based treatment. All participants were meditation-naïve, and attended one 20-minute guided meditation session based on the Buddhist “loving kindness” approach. After the session, participants reported a 33% decrease in pain and a 43% decrease in emotional tension. The data suggest that a single exposure to a brief meditative technique can significantly reduce pain and tension, as well as offer several clinical implications. It can be concluded that single exposure to a meditative technique can significantly reduce pain and tension. The effectiveness and immediacy of this intervention offers several implications for nurses. PMID:24602422

  11. Optimized suppression of coherent noise from seismic data using the Karhunen-Loève transform.

    PubMed

    Montagne, Raúl; Vasconcelos, Giovani L

    2006-07-01

    Signals obtained in land seismic surveys are usually contaminated with coherent noise, among which the ground roll (Rayleigh surface waves) is of major concern for it can severely degrade the quality of the information obtained from the seismic record. This paper presents an optimized filter based on the Karhunen-Loève transform for processing seismic images contaminated with ground roll. In this method, the contaminated region of the seismic record, to be processed by the filter, is selected in such way as to correspond to the maximum of a properly defined coherence index. The main advantages of the method are that the ground roll is suppressed with negligible distortion of the remnant reflection signals and that the filtering procedure can be automated. The image processing technique described in this study should also be relevant for other applications where coherent structures embedded in a complex spatiotemporal pattern need to be identified in a more refined way. In particular, it is argued that the method is appropriate for processing optical coherence tomography images whose quality is often degraded by coherent noise (speckle).

  12. Social isolation prompts maternal behavior in sexually naïve male ddN mice.

    PubMed

    Orikasa, Chitose; Nagaoka, Kentaro; Katsumata, Harumi; Sato, Manami; Kondo, Yasuhiko; Minami, Shiro; Sakuma, Yasuo

    2015-11-01

    Maternal behavior in mice is considered to be sexually dimorphic; that is, females show maternal care for their offspring, whereas this behavior is rarely shown in males. Here, we examined how social isolation affects the interaction of adult male mice with pups. Three weeks of isolation during puberty (5-8 weeks old) induced retrieving and crouching when exposed to pups, while males with 1 week isolation (7-8 weeks old) also showed such maternal care, but were less responsive to pups. We also examined the effect of isolation during young adulthood (8-11 weeks old), and found an induction of maternal behavior comparable to that in younger male mice. This effect was blocked by exposure to chemosensory and auditory social signals derived from males in an attached compartment separated by doubled opaque barriers. These results demonstrate that social isolation in both puberty and postpuberty facilitates male maternal behavior in sexually naïve mice. The results also indicate that air-borne chemicals and/or sounds of male conspecifics, including ultrasonic vocalization and noise by their movement may be sufficient to interfere with the isolation effect on induction of maternal behavior in male mice.

  13. SHG-specificity of cellular Rootletin filaments enables naïve imaging with universal conservation

    PubMed Central

    Akiyama, Toshihiro; Inoko, Akihito; Kaji, Yuichi; Yonemura, Shigenobu; Kakiguchi, Kisa; Segawa, Hiroki; Ishitsuka, Kei; Yoshida, Masaki; Numata, Osamu; Leproux, Philippe; Couderc, Vincent; Oshika, Tetsuro; Kano, Hideaki

    2017-01-01

    Despite growing demand for truly naïve imaging, label-free observation of cilium-related structure remains challenging, and validation of the pertinent molecules is correspondingly difficult. In this study, in retinas and cultured cells, we distinctively visualized Rootletin filaments in rootlets in the second harmonic generation (SHG) channel, integrated in custom coherent nonlinear optical microscopy (CNOM) with a simple, compact, and ultra-broadband supercontinuum light source. This SHG signal was primarily detected on rootlets of connecting cilia in the retinal photoreceptor and was validated by colocalization with anti-Rootletin staining. Transfection of cells with Rootletin fragments revealed that the SHG signal can be ascribed to filaments assembled from the R234 domain, but not to cross-striations assembled from the R123 domain. Consistent with this, Rootletin-depleted cells lacked SHG signal expected as centrosome linker. As a proof of concept, we confirmed that similar fibrous SHG was observed even in unicellular ciliates. These findings have potential for broad applications in clinical diagnosis and biophysical experiments with various organisms. PMID:28059168

  14. Reactions to small pox vaccine in naïve and previously-vaccinated individuals.

    PubMed

    Auckland, Cressida; Cowlishaw, Alexandra; Morgan, Dilys; Miller, Elizabeth

    2005-07-14

    Two hundred health care workers in England and Wales were vaccinated with the Lister/Elstree strain of the vaccinia virus, and completed health diaries for 21 days or until the lesion had scabbed over. Pain and temperature were measured daily, and all other symptoms recorded freehand by the vaccinee. One hundred and forty two (71%) vaccinees reported pain, of which 25% considered it to be moderate or severe; 32 vaccinees (16%) recorded a temperature of >37.7 degrees C, two of which exceeded 39 degrees C. Other, mainly trivial, adverse events were common; itch was reported in 72%, erythema in 27%, axillary pain or lymphadenopathy in 38%, malaise or flu-like symptoms in 40% and headache in 23%. The incidences of minor adverse events were lower in re-vaccinees, compared with naïve vaccine recipients, significantly so in the case of erythema and general malaise (p=0.001 and 0.006, respectively), perhaps reflecting pre-existing immunity. Major adverse events occurred in two vaccinees (hospital admission, one with cellulitis and one with headache and possible encephalitis), and a further five were treated with antibiotics for local cellulitis. This is the first study to report results derived from active follow-up by diaries in recipients of the Lister/Elstree strain of vaccinia, and to document reductions in trivial adverse events in re-vaccinees.

  15. Strong lensing probability in TeVeS (tensor-vector-scalar) theory

    SciTech Connect

    Chen Daming

    2008-01-15

    We recalculate the strong lensing probability as a function of the image separation in TeVeS (tensor-vector-scalar) cosmology, which is a relativistic version of MOND (MOdified Newtonian Dynamics). The lens is modeled by the Hernquist profile. We assume an open cosmology with {Omega}{sub b} = 0.04 and {Omega}{sub {Lambda}} = 0.5 and three different kinds of interpolating functions. Two different galaxy stellar mass functions (GSMF) are adopted: PHJ (Panter, Heavens and Jimenez 2004 Mon. Not. R. Astron. Soc. 355 764) determined from SDSS data release 1 and Fontana (Fontana et al 2006 Astron. Astrophys. 459 745) from GOODS-MUSIC catalog. We compare our results with both the predicted probabilities for lenses from singular isothermal sphere galaxy halos in LCDM (Lambda cold dark matter) with a Schechter-fit velocity function, and the observational results for the well defined combined sample of the Cosmic Lens All-Sky Survey (CLASS) and Jodrell Bank/Very Large Array Astrometric Survey (JVAS). It turns out that the interpolating function {mu}(x) = x/(1+x) combined with Fontana GSMF matches the results from CLASS/JVAS quite well.

  16. SHG-specificity of cellular Rootletin filaments enables naïve imaging with universal conservation

    NASA Astrophysics Data System (ADS)

    Akiyama, Toshihiro; Inoko, Akihito; Kaji, Yuichi; Yonemura, Shigenobu; Kakiguchi, Kisa; Segawa, Hiroki; Ishitsuka, Kei; Yoshida, Masaki; Numata, Osamu; Leproux, Philippe; Couderc, Vincent; Oshika, Tetsuro; Kano, Hideaki

    2017-01-01

    Despite growing demand for truly naïve imaging, label-free observation of cilium-related structure remains challenging, and validation of the pertinent molecules is correspondingly difficult. In this study, in retinas and cultured cells, we distinctively visualized Rootletin filaments in rootlets in the second harmonic generation (SHG) channel, integrated in custom coherent nonlinear optical microscopy (CNOM) with a simple, compact, and ultra-broadband supercontinuum light source. This SHG signal was primarily detected on rootlets of connecting cilia in the retinal photoreceptor and was validated by colocalization with anti-Rootletin staining. Transfection of cells with Rootletin fragments revealed that the SHG signal can be ascribed to filaments assembled from the R234 domain, but not to cross-striations assembled from the R123 domain. Consistent with this, Rootletin-depleted cells lacked SHG signal expected as centrosome linker. As a proof of concept, we confirmed that similar fibrous SHG was observed even in unicellular ciliates. These findings have potential for broad applications in clinical diagnosis and biophysical experiments with various organisms.

  17. Meditation-based treatment yielding immediate relief for meditation-naïve migraineurs.

    PubMed

    Tonelli, Makenzie E; Wachholtz, Amy B

    2014-03-01

    Meditation is gaining popularity as an effective means of managing and attenuating pain and has been particularly effective for migraines. Meditation additionally addresses the negative emotional states known to exist with migraines. The purpose of this study was to evaluate the effectiveness of meditation as an immediate intervention for reducing migraine pain as well as alleviating emotional tension, examined herein as a negative affect hypothesized to be correlated with pain. Twenty-seven migraineurs, with two to ten migraines per month, reported migraine-related pain and emotional tension ratings on a Likert scale (ranging from 0 to 10) before and after exposure to a brief meditation-based treatment. All participants were meditation- naïve, and attended one 20-minute guided meditation session based on the Buddhist "loving kindness" approach. After the session, participants reported a 33% decrease in pain and a 43% decrease in emotional tension. The data suggest that a single exposure to a brief meditative technique can significantly reduce pain and tension, as well as offer several clinical implications. It can be concluded that single exposure to a meditative technique can significantly reduce pain and tension. The effectiveness and immediacy of this intervention offers several implications for nurses.

  18. Management of treatment-naïve limited-stage small cell esophagus carcinoma

    PubMed Central

    Tao, Haitao; Li, Fangfang; Wang, Jinliang; Dong, Weiwei; Gao, Jie; Jiao, Shunchang; Hu, Yi

    2015-01-01

    Objectives: To identify the problems and principles of treatment decisions in treatment-naïve limited-stage small cell esophagus carcinoma (LD-SCEC). Methods: Clinical data from 39 patients with LD-SCEC treated in the Chinese People’s Liberation Army General Hospital, Beijing, China between 2000 and 2013 were retrospectively collected with regard to pathologic characteristics, overall survival (OS), and relevant prognostic factors. Results: The median OS was 21.1 months (95% confidence interval [CI]: 12.4-29.7 months). The one-year OS was 76%, 3-year was 25%, and the 5-year OS was 8%. Depth of invasion, lymph metastasis status, and chemotherapy were independent prognostic factors. Of the 39 cases, only 38.4% (15 cases) were diagnosed as SCEC by the biopsy specimen. Eight of the 15 patients (group A) received chemotherapy and/or radiotherapy, while the remaining 7 patients (group B) and the other 24 patients (group C) received surgery as initial treatment. The one-year survival of group A was 87%, of group B was 69%, and of group C was 74% (p=0.037). The accuracy of the biopsy diagnosis influenced the treatment decisions and prognosis. Conclusion: Small cell esophagus carcinoma is a systemic disease, with depth of invasion, lymph metastasis status, and chemotherapy as independent prognostic factors. Systemic therapy based on chemotherapy is recommended. The top priority is to improve the accuracy of diagnosis before deciding on the initial treatment option. PMID:25737171

  19. The Effect of Orthopedic Advertising and Self-Promotion on a Naïve Population.

    PubMed

    Mohney, Stephen; Lee, Daniel J; Elfar, John C

    2016-01-01

    There has been a marked increase in the number of physicians marketing themselves directly to patients and consumers. However, it is unclear how different promotional styles affect patients' perceptions of their physicians. We hypothesized that self-promoting orthopedic surgeons enjoy a more positive impact on nonphysician patients as compared to non-self-promoting surgeons, as well as a corresponding negative impact on their peer-surgeons. Surgeon websites were selected from the 5 largest population centers in the United States. Subjects with varying degrees of familiarity with orthopedic surgery evaluated Internet profiles of surgeons on a forced choice Likert scale to measure the amount of self-promotion. The naïve subjects judged self-promoting surgeons more favorably than the orthopedic surgeons. In contrast, board-certified orthopedic surgeons viewed self-promoting surgeons more negatively than did their nonphysician counterparts. In summary, the present study revealed that the potential for self-promotion to unduly influence potential patients is real and should be a considerable concern to surgeons, patients, and the profession.

  20. Neural correlates of performance monitoring in chronic cannabis users and cannabis-naïve controls

    PubMed Central

    Fridberg, Daniel J; Skosnik, Patrick D; Hetrick, William P; O’Donnell, Brian F

    2014-01-01

    Chronic cannabis use is associated with residual negative effects on measures of executive functioning. However, little previous work has focused specifically on executive processes involved in performance monitoring in frequent cannabis users. The present study investigated event-related potential (ERP) correlates of performance monitoring in chronic cannabis users. The error-related negativity (ERN) and error positivity (Pe), ERPs sensitive to performance monitoring, were recorded from 30 frequent cannabis users (mean usage=5.52 days/week) and 32 cannabis-naïve control participants during a speeded stimulus discrimination task. The “oddball” P3 ERP was recorded as well. Users and controls did not differ on the amplitude or latency of the ERN; however, Pe amplitude was larger among users. Users also showed increased amplitude and reduced latency of the P3 in response to infrequent stimuli presented during the task. Among users, urinary cannabinoid metabolite levels at testing were unrelated to ERP outcomes. However, total years of cannabis use correlated negatively with P3 latency and positively with P3 amplitude, and age of first cannabis use correlated negatively with P3 amplitude. The results of this study suggest that chronic cannabis use is associated with alterations in neural activity related to the processing of motivationally-relevant stimuli (P3) and errors (Pe). PMID:23427191

  1. The Venus Neutral Atmosphere from the Radio Science Experiment VeRa on Venus Express

    NASA Astrophysics Data System (ADS)

    Tellmann, S.; Haeusler, B.; Paetzold, M.; Bird, M. K.; Tyler, G. L.

    2008-12-01

    The Venus Express Radio Science Experiment VeRa is sounding the Venus neutral atmosphere and ionosphere using the spacecraft radio subsystem in the oneway radio link mode at X-band (8.4 GHz) and S- band (2.3 GHz). An Ultrastable Oscillator (USO) provides a high quality onboard frequency reference source for the derivation of electron density profiles in the ionosphere and profiles of pressure, temperature and neutral number density of the neutral atmosphere. Radial profiles of neutral number density derived from the occultations cover the altitude range 40 to 90 km, which are converted to vertical profiles of temperature and pressure. The polar orbit of Venus Express provides the opportunity to study the atmosphere at all planetocentric latitudes under varying illumination conditions. Five occultation seasons could be covered so far during the Venus Express mission resulting in a data set of more than 150 profiles of the neutral atmosphere. The thermal structure is investigated with regard to the latitudinal and temporal variability. A distinct cold collar region could be observed on both hemispheres. The tropopause altitude increases in this latitude region while the tropopause temperature shows a strong decrease. Profiles of static stability are found to be latitude-dependent and nearly adiabatic in the middle cloud region.

  2. Beyond naïve cue combination: salience and social cues in early word learning.

    PubMed

    Yurovsky, Daniel; Frank, Michael C

    2017-03-01

    Children learn their earliest words through social interaction, but it is unknown how much they rely on social information. Some theories argue that word learning is fundamentally social from its outset, with even the youngest infants understanding intentions and using them to infer a social partner's target of reference. In contrast, other theories argue that early word learning is largely a perceptual process in which young children map words onto salient objects. One way of unifying these accounts is to model word learning as weighted cue combination, in which children attend to many potential cues to reference, but only gradually learn the correct weight to assign each cue. We tested four predictions of this kind of naïve cue combination account, using an eye-tracking paradigm that combines social word teaching and two-alternative forced-choice testing. None of the predictions were supported. We thus propose an alternative unifying account: children are sensitive to social information early, but their ability to gather and deploy this information is constrained by domain-general cognitive processes. Developmental changes in children's use of social cues emerge not from learning the predictive power of social cues, but from the gradual development of attention, memory, and speed of information processing.

  3. Clozapine--a dangerous drug in a clozapine-naïve subject.

    PubMed

    Stanworth, D; Hunt, N C A; Flanagan, R J

    2012-01-10

    Clozapine is a uniquely effective antipsychotic, but is very toxic in clozapine-naïve subjects. A 34-year-old male patient in a mental health facility, who was not prescribed clozapine, took 350 mg clozapine obtained from another patient at night. He was found dead the next morning. The presence of cardiomegaly related to obesity may have increased the risk of suffering an acute cardiac event after ingestion of clozapine. The medication prescribed to the patient was not thought to have contributed to the fatal outcome. Post mortem femoral blood clozapine and norclozapine concentrations were 0.48 and 0.20mg/L, respectively. By way of comparison, audit of 104,127 plasma samples (26,796 patients) assayed for therapeutic drug monitoring purposes 1993-2007, showed plasma clozapine 0.35 mg/L or more in 57.5% samples (8.4% 1mg/L or more). Those involved in the investigation of clozapine-associated deaths need to be aware that that death in an adult may occur after a single 'therapeutic' dose. A diagnosis of fatal clozapine poisoning cannot be made solely on the basis of a post mortem blood clozapine measurement.

  4. Meta-analysis of cognitive performance in drug-naïve patients with schizophrenia.

    PubMed

    Fatouros-Bergman, Helena; Cervenka, Simon; Flyckt, Lena; Edman, Gunnar; Farde, Lars

    2014-09-01

    Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority of the clinical studies have been conducted in antipsychotic drug treated patients. Thus, it remains unclear if significant cognitive impairments exist in the absence of medication. This is the first meta-analysis of cognitive findings in drug-naïve patients with schizophrenia. Cognitive data from 23 studies encompassing 1106 patients and 1385 controls published from 1992 to 2013 were included. Tests were to a large extent ordered in cognitive domains according to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Analysis was performed with STATA using the random-effects model and heterogeneity as well as Egger's publication bias was assessed. Overall the results show that patients performed worse than healthy controls in all cognitive domains with medium to large effect sizes. Verbal memory, speed of processing and working memory were three of the domains with the greatest impairments. The pattern of results is in line with previous meta-analytic findings in antipsychotic treated patients. The present meta-analysis confirms the existence of significant cognitive impairments at the early stage of the illness in the absence of antipsychotic medication.

  5. Metabolomics study of fatigue in patients with rheumatoid arthritis naïve to biological treatment.

    PubMed

    Surowiec, Izabella; Gjesdal, Clara Gram; Jonsson, Grete; Norheim, Katrine Brække; Lundstedt, Torbjörn; Trygg, Johan; Omdal, Roald

    2016-05-01

    Fatigue occurs in all chronic inflammatory diseases, in cancer, and in some neurological conditions. Patients often regard fatigue as one of their most debilitating problems, but currently there is no established treatment and the mechanisms that lead to and regulate fatigue are incompletely understood. Our objective was to more completely understand the physiology of this phenomenon. Twenty-four patients with rheumatoid arthritis (RA) naïve to treatment with biological drugs were enrolled for the study. Fatigue was measured with a fatigue visual analogue scale (fVAS). Ethylenediaminetetraacetic acid (EDTA) plasma samples were subjected to gas chromatography-time-of-flight mass spectrometry (GC/MS-TOF)-based metabolite profiling. Obtained metabolite data were evaluated by multivariate data analysis with orthogonal projections to latent structures (OPLS) method to pinpoint metabolic changes related to fatigue severity. A significant multivariate OPLS model was obtained between the fVAS scores and the measured metabolic levels. Increasing fatigue scores were associated with a metabolic pattern characterized by down-regulation of metabolites from the urea cycle, fatty acids, tocopherols, aromatic amino acids, and hypoxanthine. Uric acid levels were increased. Apart from fatigue, we found no other disease-related variables that might be responsible for these changes. Our MS-based metabolomic approach demonstrated strong associations between fatigue and several biochemical patterns related to oxidative stress.

  6. CD45-mediated control of TCR tuning in naïve and memory CD8(+) T cells.

    PubMed

    Cho, Jae-Ho; Kim, Hee-Ok; Ju, Young-Jun; Kye, Yoon-Chul; Lee, Gil-Woo; Lee, Sung-Woo; Yun, Cheol-Heui; Bottini, Nunzio; Webster, Kylie; Goodnow, Christopher C; Surh, Charles D; King, Cecile; Sprent, Jonathan

    2016-11-14

    Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8(+)T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8(+) T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8(+) T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens.

  7. Overcoming the barrier of narrative adherence in conflicts through awareness of the psychological bias of naïve realism.

    PubMed

    Nasie, Meytal; Bar-Tal, Daniel; Pliskin, Ruthie; Nahhas, Eman; Halperin, Eran

    2014-11-01

    One significant socio-psychological barrier for peaceful resolution of conflicts is each party's adherence to its own collective narrative. We hypothesized that raising awareness to the psychological bias of naïve realism and its identification in oneself would provide a path to overcoming this barrier, thus increasing openness to the adversary's narrative. We conducted three experimental studies in the context of the Israeli-Palestinian conflict. Studies 1 and 2, conducted among Jewish Israelis and Palestinian Israelis, respectively, revealed that participants with hawkish political ideology reported greater openness to the adversary's narrative when they were made aware of naïve realism bias. Study 3 revealed that hawkish participants at the baseline adhered to the ingroup narrative and resisted the adversary's narrative more than dovish participants. They were also more able to identify the bias in themselves upon learning about it. This identification may explain why the manipulation led to bias correction only among hawkish participants.

  8. CD45-mediated control of TCR tuning in naïve and memory CD8+ T cells

    PubMed Central

    Cho, Jae-Ho; Kim, Hee-Ok; Ju, Young-Jun; Kye, Yoon-Chul; Lee, Gil-Woo; Lee, Sung-Woo; Yun, Cheol-Heui; Bottini, Nunzio; Webster, Kylie; Goodnow, Christopher C.; Surh, Charles D.; King, Cecile; Sprent, Jonathan

    2016-01-01

    Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8+T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8+ T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8+ T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens. PMID:27841348

  9. Effect of inhaled corticosteroids on blood eosinophil count in steroid-naïve patients with COPD

    PubMed Central

    Kreindler, James L; Watkins, Michael L; Lettis, Sally; Tal-Singer, Ruth; Locantore, Nicholas

    2016-01-01

    Introduction Sputum and blood eosinophil counts have attracted attention as potential biomarkers in chronic obstructive pulmonary disease (COPD). One question regarding the use of blood eosinophils as a biomarker in COPD is whether their levels are affected by the use of inhaled corticosteroids (ICS), which are commonly prescribed for COPD. Methods We performed a retrospective analysis of peripheral blood leucocytes from a previously completed clinical trial that examined effects of ICS in steroid-naïve patients with COPD. Results and conclusion The data show that the ICS-containing treatment arms (containing fluticasone propionate) had a small effect on peripheral blood eosinophils in steroid-naïve patients with COPD. Trial registration number NCT00358358; Post-results. PMID:27651909

  10. Distribution of HIV-1 Infection in Different T Lymphocyte Subsets: Antiretroviral Therapy-Naïve vs. Experienced Patients

    PubMed Central

    Perez, Raul; Gibson, Sonia; Lopez, Pablo; Koenig, Ellen; De Castro, Marisol

    2011-01-01

    Abstract Memory CD4 T cells are the primary targets of HIV-1 infection, which then subsequently spreads to other T lymphocyte subsets. Antiretroviral therapy (ART) alters the pattern of HIV-1 distribution. Blood samples were collected from ART-naïve or -experienced HIV-1 patients, and the memory and naïve subsets of CD4+ and CD8+ T lymphocytes, respectively, were isolated by cell sorting. DNA was extracted and the HIV-1 env C2/V3 region PCR amplified. Amplicons were cloned and sequenced, and genetic relatedness among different HIV-1 compartments was determined by the phylogenetic analysis of clonal sequences. The viral V3 sequence of HIV-1 in each compartment was analyzed by using webPSSM to determine CCR5 or CXCR4 coreceptor binding property of the virus. The direction of viral migration among involved compartments was determined by using the MacClade program. In ART-naïve patients, HIV-1 was generally confined to the memory CD4 T (mT4) cell compartment, even though in a few cases, naïve CD4 T (nT4) cells were also infected. When this occurred, the HIV-1 gene migrated from nT4 to mT4. In contrast, HIV-1 was detected in nT4 and mT4 as well as in the memory CD8 T (mT8) compartments of ART-experienced patients. However, no clear pattern of directional HIV-1 gene flow among the compartments could be determined because of the small sample size. All HIV-1–infected T cell compartments housed the virus that used either CCR5 or CXCR4 as the coreceptor. PMID:21054214

  11. Full-Scale Wind-Tunnel Tests of a Series of Metal Propellers on a VE-7 Airplane

    NASA Technical Reports Server (NTRS)

    Weick, Fred E

    1929-01-01

    An adjustable blade metal propeller was tested at five different angle settings, forming a series varying in pitch. The propeller was mounted on a VE-7 airplane in the twenty-foot propeller research tunnel of the National Advisory Committee for Aeronautics. The efficiencies were found to be from 4 to 7 per cent higher than those of standard wood propellers operating under the same conditions. The results are given in convenient form for use in selecting propellers for aircraft.

  12. Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model.

    PubMed

    Mika, J; Jurga, A M; Starnowska, J; Wasylewski, M; Rojewska, E; Makuch, W; Kwiatkowski, K; Malek, N; Przewlocka, B

    2015-05-21

    Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of neuropathic pain, such as tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs, doxepin and amitriptyline, in naïve animals and in a model of neuropathic pain and to determine the role of cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI), doxepin and amitriptyline attenuated the symptoms of neuropathic pain and diminished the CCI-induced increase in the levels of spinal interleukin (IL)-6 and -1β mRNA, but not the protein levels of these cytokines, measured on day 12. Unexpectedly, chronic administration of doxepin or amitriptyline for 12 days produced allodynia and hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and IL-6 mRNA, however, the protein levels of these pronociceptive factors were increased. The administration of ondansetron (5-HT3 receptor antagonist) significantly weakened the allodynia and hyperalgesia induced by both antidepressants in naïve mice; in contrast, yohimbine (α2-adrenergic receptors antagonist) did not influence these effects. Allodynia and hyperalgesia induced in naïve animals by amitriptyline and doxepin may be associated with an increase in the levels of pronociceptive cytokines resulting from 5-HT3-induced hypersensitivity. Our results provide new and important information about the possible side effects of antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for therapy.

  13. Decreased Functional Connectivity of Insular Cortex in Drug Naïve First Episode Schizophrenia: In Relation to Symptom Severity

    PubMed Central

    Pang, Lijuan; Kennedy, David; Wei, Qinling; Lv, Luxian; Gao, Jinsong; Li, Hong; Quan, Meina; Li, Xue; Yang, Yongfeng; Fan, Xiaoduo; Song, Xueqin

    2017-01-01

    Background This study was to examine the insular cortical functional connectivity in drug naïve patients with first episode schizophrenia and to explore the relationship between the connectivity and the severity of clinical symptoms. Methods Thirty-seven drug naïve patients with schizophrenia and 25 healthy controls were enrolled in this study. A seed-based approach was used to analyze the resting-state functional imaging data. Insular cortical connectivity maps were bilaterally extracted for group comparison and validated by voxel-based morphometry (VBM) analysis. Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Results There were significant reductions in the right insular cortical connectivity with the Heschl’s gyrus, anterior cingulate cortex (ACC), and caudate (p’s<0.001) in the patient group compared with the healthy control (HC) group. Reduced right insular cortical connectivity with the Heschl’s gyrus was further confirmed in the VBM analysis (FDR corrected p<0.05). Within the patient group, there was a significant positive relationship between the right insula-Heschl’s connectivity and PANSS general psychopathology scores (r = 0.384, p = 0.019). Conclusion Reduced insula-Heschl’s functional connectivity is present in drug naïve patients with first episode schizophrenia, which might be related to the manifestation of clinical symptoms. PMID:28107346

  14. Characterization and genetic manipulation of primed stem cells into a functional naïve state with ESRRB

    PubMed Central

    Rossello, Ricardo Antonio; Pfenning, Andreas; Howard, Jason T; Hochgeschwender, Ute

    2016-01-01

    AIM To identify differences between primed mouse embryonic stem cells (ESCs) and fully functional naive ESCs; to manipulate primed cells into a naive state. METHODS We have cultured 3 lines of cells from different mouse strains that have been shown to be naive or primed as determined by generating germline-transmitting chimeras. Cells were put through a battery of tests to measure the different features. RNA from cells was analyzed using microarrays, to determine a priority list of the differentially expressed genes. These were later validated by quantificational real-time polymerase chain reaction. Viral cassettes were created to induce expression of differentially expressed genes in the primed cells through lentiviral transduction. Primed reprogrammed cells were subjected to in-vivo incorporation studies. RESULTS Most results show that both primed and naive cells have similar features (morphology, proliferation rates, stem cell genes expressed). However, there were some genes that were differentially expressed in the naïve cells relative to the primed cells. Key upregulated genes in naïve cells include ESRRB, ERAS, ATRX, RNF17, KLF-5, and MYC. After over-expressing some of these genes the primed cells were able to incorporate into embryos in-vivo, re-acquiring a feature previously absent in these cells. CONCLUSION Although there are no notable phenotypic differences, there are key differences in gene expression between these naïve and primed stem cells. These differences can be overcome through overexpression. PMID:27822342

  15. The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions

    PubMed Central

    Dorland, Yvonne L.; Malinova, Tsveta S.; van Stalborch, Anne-Marieke D.; Grieve, Adam G.; van Geemen, Daphne; Jansen, Nicolette S.; de Kreuk, Bart-Jan; Nawaz, Kalim; Kole, Jeroen; Geerts, Dirk; Musters, René J. P.; de Rooij, Johan; Hordijk, Peter L.; Huveneers, Stephan

    2016-01-01

    Vascular homoeostasis, development and disease critically depend on the regulation of endothelial cell–cell junctions. Here we uncover a new role for the F-BAR protein pacsin2 in the control of VE-cadherin-based endothelial adhesion. Pacsin2 concentrates at focal adherens junctions (FAJs) that are experiencing unbalanced actomyosin-based pulling. FAJs move in response to differences in local cytoskeletal geometry and pacsin2 is recruited consistently to the trailing end of fast-moving FAJs via a mechanism that requires an intact F-BAR domain. Photoconversion, photobleaching, immunofluorescence and super-resolution microscopy reveal polarized dynamics, and organization of junctional proteins between the front of FAJs and their trailing ends. Interestingly, pacsin2 recruitment inhibits internalization of the VE-cadherin complex from FAJ trailing ends and is important for endothelial monolayer integrity. Together, these findings reveal a novel junction protective mechanism during polarized trafficking of VE-cadherin, which supports barrier maintenance within dynamic endothelial tissue. PMID:27417273

  16. Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naïve Adults

    PubMed Central

    Makris, Nikos; Liang, Lichen; Biederman, Joseph; Valera, Eve M.; Brown, Ariel B.; Petty, Carter; Spencer, Thomas J.; Faraone, Stephen V.; Seidman, Larry J.

    2014-01-01

    Objective We assessed the neural correlates of adult ADHD in treatment-naïve participants, an approach necessary for identifying neural substrates unconfounded by medication effects. Method The sample consisted of 24 medication-naïve adults with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnosed ADHD and 24 healthy controls, comparable on age, sex, handedness, reading achievement, IQ, and psychiatric comorbidity. All participants were assessed with structured diagnostic interviews. Magnetic resonance imaging (MRI)-based regional voxel-based morphometry (r-VBM) was used to assess volumetric differences in a priori defined brain regions of interest. Results VBM analysis revealed group differences in the hypothesized cortical and subcortical areas; however, only cerebellar volume reductions in ADHD retained significance (p < .05) after corrections for multiple comparisons. Conclusion These results support the notion that medication-naïve ADHD as expressed in adulthood, manifests subtle brain volume reductions from normal in the cerebellum, and possibly in other syndrome-congruent gray-matter structures. Larger samples are required to confirm these findings. PMID:24189200

  17. LaeA and VeA are involved in growth morphology, asexual development, and mycotoxin production in Alternaria alternata.

    PubMed

    Estiarte, N; Lawrence, C B; Sanchis, V; Ramos, A J; Crespo-Sempere, A

    2016-12-05

    Alternaria alternata is a common filamentous fungus that contaminates various fruits, grains and vegetables causing important economic losses to farmers and the food industry. A. alternata is a mycotoxigenic mould, which may jeopardize human and animal health. Two of the most common A. alternata mycotoxins found in food and feed are alternariol and alternariol monomethyl ether. In this study we examined the role of LaeA and VeA, two regulatory proteins belonging to the velvet family, which have been described to be involved in several functions in many fungi including secondary metabolism. We found that deletion of laeA and veA genes, respectively, greatly reduced sporulation and strongly compromised mycotoxin production, both in vitro or during pathogenesis of tomato fruits. We have also studied how the loss of laeA and veA may affect expression of genes related to alternariol and alternariol monomethyl ether biosynthesis (pksJ and altR), and to melanin biosynthesis (cmrA, pksA).

  18. HIV co-receptor tropism prediction remains stable over time in treatment-naïve patients.

    PubMed

    Philip, Keir Ej; Macartney, Malcolm J; Conibear, Tim Cr; Smith, Colette J; Marshall, Neal; Johnson, Margaret A; Haque, Tanzina; Webster, Daniel P

    2016-06-01

    HIV co-receptor tropism determination is essential before prescribing the CCR5 antagonist maraviroc. British HIV Association guidelines suggest tropism testing may remain valid for only 90 days in antiretroviral-naïve patients. We aimed to determine the accuracy of this figure. Tropism was assessed in 26 antiretroviral-naïve patients with ongoing viral replication, sampled yearly from first clinic visit. The V3 region of HIV-1 was sequenced in triplicate, then tropism predicted using the Geno2Pheno system. Baseline tropism prediction remained valid for a median of 52 months (range 7-81). For 19/26 individuals baseline tropism remained unchanged throughout a median of 54 months follow-up; 18 R5 tropic and 1 X4 tropic. In seven patients (27%) baseline tropism switched at least once (range 1-4 switches) during follow-up; however, their baseline tropism prediction remained valid for a median of 45 months. Co-receptor tropism in treatment-naïve patients with ongoing viral replication appears highly stable over time, suggesting that baseline genotypic tropism prediction may be valid for a longer duration in patients delaying ART initiation. In this study, baseline tropism prediction remained valid for a median of 52 months, suggesting current guidelines recommending repeat testing after 90 days may be excessively conservative in their assessment of tropism stability.

  19. Deadly intentions: naïve introduced foxes show rapid attraction to odour cues of an unfamiliar native prey

    PubMed Central

    Bytheway, Jenna P.; Price, Catherine J.; Banks, Peter B.

    2016-01-01

    Introduced predators have caused declines and extinctions of native species worldwide, seemingly able to find and hunt new, unfamiliar prey from the time of their introduction. Yet, just as native species are often naïve to introduced predators, in theory, introduced predators should initially be naïve in their response to novel native prey. Here we examine the response of free-living introduced red foxes (Vulpes vulpes) to their first encounter with the odour cues of a novel native prey, the long-nosed bandicoot (Perameles nasuta). Despite no experience with bandicoots at the study site, foxes were significantly more interested in bandicoot odour compared to untreated controls and to a co-evolved prey, the black rat (Rattus rattus). So what gives introduced predators a novelty advantage over native prey? Such neophilia towards novel potential food sources carries little costs, however naïve native prey often lack analogous neophobic responses towards novel predators, possibly because predator avoidance is so costly. We propose that this nexus between the costs and benefits of responding to novel information is different for alien predators and native prey, giving alien predators a novelty advantage over native prey. This may explain why some introduced predators have rapid and devastating impacts on native fauna. PMID:27416966

  20. Different genome stability proteins underpin primed and naïve adaptation in E. coli CRISPR-Cas immunity.

    PubMed

    Ivančić-Baće, Ivana; Cass, Simon D; Wearne, Stephen J; Bolt, Edward L

    2015-12-15

    CRISPR-Cas is a prokaryotic immune system built from capture and integration of invader DNA into CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, termed 'Adaptation', which is dependent on Cas1 and Cas2 proteins. In Escherichia coli, Cascade-Cas3 degrades invader DNA to effect immunity, termed 'Interference'. Adaptation can interact with interference ('primed'), or is independent of it ('naïve'). We demonstrate that primed adaptation requires the RecG helicase and PriA protein to be present. Genetic analysis of mutant phenotypes suggests that RecG is needed to dissipate R-loops at blocked replication forks. Additionally, we identify that DNA polymerase I is important for both primed and naive adaptation, and that RecB is needed for naïve adaptation. Purified Cas1-Cas2 protein shows specificity for binding to and nicking forked DNA within single strand gaps, and collapsing forks into DNA duplexes. The data suggest that different genome stability systems interact with primed or naïve adaptation when responding to blocked or collapsed invader DNA replication. In this model, RecG and Cas3 proteins respond to invader DNA replication forks that are blocked by Cascade interference, enabling DNA capture. RecBCD targets DNA ends at collapsed forks, enabling DNA capture without interference. DNA polymerase I is proposed to fill DNA gaps during spacer integration.

  1. Nelfinavir monotherapy increases naïve T-cell numbers in HIV-negative healthy young adults.

    PubMed

    Rizza, Stacey R; Tangalos, Eric G; McClees, Mark D; Strausbauch, Michael A; Targonski, Paul V; McKean, David J; Wettstein, Peter J; Badley, Andrew D

    2008-01-01

    Although patients treated with HIV protease inhibitor (PI) containing regimens manifest increases in naïve T cell number, it is unclear whether this is due to reduction in viral replication or a direct drug effect. We questioned whether Nelfinavir monotherapy directly impacted naïve T-cell number in HIV-negative individuals. HIV-negative volunteers received Nelfinavir, 1250 mg orally, BID for 3 weeks, and T-cell receptor recombination excision circles (TREC) content in peripheral blood were assessed. Whereas TREC copies did not change over 3 weeks in untreated controls, TREC copies/copies CCR5 increased following Nelfinavir monotherapy in 8 patients (p < 0.02), and did not change in 7 patients (p = NS). Those patients who responded were younger than those who did not with a median age of 55 years for responders and 71 years for non-responders (p < 0.03). The increase in TREC was most pronounced in those patients less than 40-years old (p < 0.01). Moreover, the patients who did not increase TREC levels were more likely to have suffered a medical illness previously shown to reduce thymic function. In HIV-negative patients, monotherapy with the HIV PI Nelfinavir for 21 days increases TREC-positive naïve T cell number, particularly in individuals who are healthy and young.

  2. Frontoparietal connectivity in substance-naïve youth with and without a family history of alcoholism.

    PubMed

    Wetherill, Reagan R; Bava, Sunita; Thompson, Wesley K; Boucquey, Veronique; Pulido, Carmen; Yang, Tony T; Tapert, Susan F

    2012-01-13

    Frontoparietal connections underlie key executive cognitive functions. Abnormalities in the frontoparietal network have been observed in chronic alcoholics and associated with alcohol-related cognitive deficits. It remains unclear whether neurobiological differences in frontoparietal circuitry exist in substance-naïve youth who are at-risk for alcohol use disorders. This study used functional connectivity magnetic resonance imaging and diffusion tensor imaging to examine frontoparietal connectivity and underlying white matter microstructure in 20 substance-naïve youth with a family history of alcohol dependence and 20 well-matched controls without familial substance use disorders. Youth with a family history of alcohol dependence showed significantly less functional connectivity between posterior parietal and dorsolateral prefrontal seed regions (ps<.05), as compared to family history negative controls; however, they did not show differences in white matter architecture within tracts subserving frontoparietal circuitry (ps>.34). Substance-naïve youth with a family history of alcohol dependence show less frontoparietal functional connectivity in the absence of white matter microstructural abnormalities as compared to youth with no familial risk. This may suggest a potential neurobiological marker for the development of substance use disorders.

  3. Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning

    PubMed Central

    Girardet, Clémence; Mavrikaki, Maria M.; Stevens, Joseph R.; Miller, Courtney A.; Marks, Daniel L.; Butler, Andrew A.

    2017-01-01

    Melanocortin-3 receptors (MC3R) have a contextual role in appetite control that is amplified with hypocaloric conditioning. C57BL/6J (B6) mice subjected to hypocaloric feeding schedules (HFS) exhibit compulsive behavioral responses involving food anticipatory activity (FAA) and caloric loading following food access. These homeostatic responses to calorie-poor environs are attenuated in B6 mice in which Mc3r transcription is suppressed by a lox-stop-lox sequence in the 5’UTR (Mc3rTB/TB). Here, we report that optimization of caloric loading in B6 mice subject to HFS, characterized by increased meal size and duration, is not observed in Mc3rTB/TB mice. Analysis of hypothalamic and neuroendocrine responses to HFS throughout the light-dark cycle suggests uncoupling of hypothalamic responses involving appetite-stimulating fasting-responsive hypothalamic neurons expressing agouti-related peptide (AgRP) and neuropeptide Y (Npy). Rescuing Mc3rs expression in Nkx2.1(+ve) neurons is sufficient to restore normal hypothalamic responses to negative energy balance. In addition, Mc3rs expressed in Nkx2.1(+ve) neurons are also sufficient to restore FAA and caloric loading of B6 mice subjected to HFS. In summary, MC3Rs expressed in Nkx2.1(+ve) neurons are sufficient to coordinate hypothalamic response and expression of compulsive behavioral responses involving meal anticipation and consumption of large meals during situations of prolonged negative energy balance. PMID:28294152

  4. O-GlcNAc is required for the survival of primed pluripotent stem cells and their reversion to the naïve state.

    PubMed

    Miura, Taichi; Nishihara, Shoko

    2016-10-27

    "Naïve" mouse embryonic stem cells (ESCs) are derived from pre-implantation embryos and possess pluripotency, the ability to differentiate into any cell type of the body. "Primed" mouse epiblast stem cells (EpiSCs) are also pluripotent but are derived from post-implantation embryos. ESC-derived EpiSCs (ESD-EpiSCs) are "primed" pluripotent stem cells and can revert to naïve reverted ESCs (rESCs). O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a posttranslational modification in the cytoplasm and nucleus. O-GlcNAc is transferred to serine and threonine residues of proteins by O-GlcNAc transferase (Ogt) and removed from them by O-GlcNAcase (Oga). In naïve ESCs, O-GlcNAc contributes to maintain the undifferentiated state. In the transition from naïve state to primed state, Ogt maintains cell survival, whereas Oga has no function. However, the function of O-GlcNAc in primed ESD-EpiSCs and during the reversion from the primed state to naïve rESCs remains unclear. Here, we show that Ogt is required for the survival of primed ESD-EpiSCs. The expression of cytosolic Oga was significantly increased during induction from naïve ESCs to primed ESD-EpiSCs. Furthermore, both Ogt and Oga were required for the reversion from primed ESD-EpiSCs to naïve rESCs. These findings indicate that O-GlcNAcylation plays an important role in the survival of primed ESD-EpiSCs and in their reversion to naïve rESCs.

  5. Volatile profiling reveals intracellular metabolic changes in Aspergillus parasiticus: veA regulates branched chain amino acid and ethanol metabolism

    PubMed Central

    2010-01-01

    Background Filamentous fungi in the genus Aspergillus produce a variety of natural products, including aflatoxin, the most potent naturally occurring carcinogen known. Aflatoxin biosynthesis, one of the most highly characterized secondary metabolic pathways, offers a model system to study secondary metabolism in eukaryotes. To control or customize biosynthesis of natural products we must understand how secondary metabolism integrates into the overall cellular metabolic network. By applying a metabolomics approach we analyzed volatile compounds synthesized by Aspergillus parasiticus in an attempt to define the association of secondary metabolism with other metabolic and cellular processes. Results Volatile compounds were examined using solid phase microextraction - gas chromatography/mass spectrometry. In the wild type strain Aspergillus parasiticus SU-1, the largest group of volatiles included compounds derived from catabolism of branched chain amino acids (leucine, isoleucine, and valine); we also identified alcohols, esters, aldehydes, and lipid-derived volatiles. The number and quantity of the volatiles produced depended on media composition, time of incubation, and light-dark status. A block in aflatoxin biosynthesis or disruption of the global regulator veA affected the volatile profile. In addition to its multiple functions in secondary metabolism and development, VeA negatively regulated catabolism of branched chain amino acids and synthesis of ethanol at the transcriptional level thus playing a role in controlling carbon flow within the cell. Finally, we demonstrated that volatiles generated by a veA disruption mutant are part of the complex regulatory machinery that mediates the effects of VeA on asexual conidiation and sclerotia formation. Conclusions 1) Volatile profiling provides a rapid, effective, and powerful approach to identify changes in intracellular metabolic networks in filamentous fungi. 2) VeA coordinates the biosynthesis of secondary

  6. veA-dependent RNA-pol II transcription elongation factor like protein, RtfA, is associated with secondary metabolism and morphological development in Aspergillus nidulans

    PubMed Central

    Ramamoorthy, Vellaisamy; Shantappa, Sourabha; Dhingra, Sourabh; Calvo, Ana M.

    2012-01-01

    In Aspergillus nidulans the global regulatory gene veA is necessary for the biosynthesis of several secondary metabolites, including the mycotoxin sterigmatocystin (ST). In order to identify additional veA-dependent genetic elements involved in regulating ST production, we performed a mutagenesis on a deletion veA (ΔveA) strain to obtain revertant mutants (RM) that regained the capability to produce toxin. Genetic analysis and molecular characterization of one of the revertant mutants, RM3, revealed that a point mutation occurred at the coding region of the rtfA gene, encoding a RNA-pol II transcription elongation factor like protein, similar to Saccharomyces cerevisiae Rtf1. The A. nidulans rtfA gene product accumulates in nuclei. Deletion of rtfA gene in a ΔveA background restored mycotoxin production in a medium-dependent manner. rtfA also affects the production of other metabolites including penicillin. Biosynthesis of this antibiotic decreased in the absence of rtfA. Furthermore, rtfA is necessary for normal morphological development. Deletion of the rtfA gene in wild-type strains (veA+) resulted in a slight decrease in growth rate, drastic reduction in conidiation, and complete loss of sexual development. This is the first study of an Rtf1 like gene in filamentous fungi. We found rtfA putative orthologs extensively conserved in numerous fungal species. PMID:22783880

  7. VE-cadherin involved in the pulmonary microvascular endothelial cell barrier injury induced by angiotensin II through modulating the cellular apoptosis and skeletal rearrangement

    PubMed Central

    Wu, Zhiyong; Liu, Huagang; Ren, Wei; Dai, Feifeng; Chang, Jinxing; Li, Bowen

    2016-01-01

    Objective: Angiotensin II (AngII) involved in the pathogenesis of pulmonary injury through impairing the integrity of pulmonary microvascular endothelial barrier, but the mechanism is still not clear. We aim to determine the roles of VE-cadherin, playing crucial roles in the adhesion of the vascular endothelial barrier and the barrier function, in the pulmonary microvascular endothelial cell (PMVEC) barrier injury mediated by AngII. Methods: Mice acute lung injury (ALI) model was induced through pumping of AngII. The infiltration of macrophages and neutrophils as well as the PMVEC permeability were determined in order to determine the barrier injury in vivo and in vitro. Knockdown of VE-cadherin was established using siRNA technique, and its roles in the apoptosis and skeletal rearrangement in the PMVECs were evaluated. Results: After AngII interference, the expression of VE-cadherin in the PMVECs and pulmonary tissues in mice was down-regulated. Upon VE-cadherin knockdown through siRNA technique, AngII induced susceptibility of PMVECs to apoptosis. Knockdown of VE-cadherin contributed to the skeletal rearrangement in the endothelial cells, together with increase of permeability. Conclusions: VE-cadherin expression is closely related to the apoptosis and skeletal rearrangement of PMVECs induced by AngII. PMID:27830014

  8. TAL-1/SCL and its partners E47 and LMO2 up-regulate VE-cadherin expression in endothelial cells.

    PubMed

    Deleuze, Virginie; Chalhoub, Elias; El-Hajj, Rawan; Dohet, Christiane; Le Clech, Mikaël; Couraud, Pierre-Olivier; Huber, Philippe; Mathieu, Danièle

    2007-04-01

    The basic helix-loop-helix TAL-1/SCL essential for hematopoietic development is also required during vascular development for embryonic angiogenesis. We reported that TAL-1 acts positively on postnatal angiogenesis by stimulating endothelial morphogenesis. Here, we investigated the functional consequences of TAL-1 silencing in human primary endothelial cells. We found that TAL-1 knockdown caused the inhibition of in vitro tubulomorphogenesis, which was associated with a dramatic reduction in vascular endothelial cadherin (VE-cadherin) at intercellular junctions. Consistently, silencing of TAL-1 as well as of its cofactors E47 and LMO2 down-regulated VE-cadherin at both the mRNA and the protein level. Endogenous VE-cadherin transcription could be activated in nonendothelial HEK-293 cells by the sole concomitant ectopic expression of TAL-1, E47, and LMO2. Transient transfections in human primary endothelial cells derived from umbilical vein (HUVECs) demonstrated that VE-cadherin promoter activity was dependent on the integrity of a specialized E-box associated with a GATA motif and was maximal with the coexpression of the different components of the TAL-1 complex. Finally, chromatin immunoprecipitation assays showed that TAL-1 and its cofactors occupied the VE-cadherin promoter in HUVECs. Together, these data identify VE-cadherin as a bona fide target gene of the TAL-1 complex in the endothelial lineage, providing a first clue to TAL-1 function in angiogenesis.

  9. The cytotoxic effects of VE-3N, a novel 1,4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms.

    PubMed

    Marín-Prida, Javier; Pardo Andreu, Gilberto L; Rossignoli, Camila Pederiva; Durruthy, Michael González; Rodríguez, Estael Ochoa; Reyes, Yamila Verdecia; Acosta, Roberto Fernández; Uyemura, Sergio A; Alberici, Luciane C

    2017-03-29

    Several 1,4-dihydropyridine derivatives overcome the multidrug resistance in tumors, but their intrinsic cytotoxic mechanisms remain unclear. Here we addressed if mitochondria are involved in the cytotoxicity of the novel 1,4-dihydropyridine derivative VE-3N [ethyl 6-chloro-5-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] towards cancer cells by employing hepatic carcinoma (HepG2) cells and isolated rat liver mitochondria. In HepG2 cells, VE-3N induced mitochondrial membrane potential dissipation, ATP depletion, annexin V/propidium iodide double labeling, and Hoechst staining; events indicating apoptosis induction. In isolated rat liver mitochondria, VE-3N promoted mitochondrial uncoupling by exerting protonophoric actions and by increasing membrane fluidity. Mitochondrial uncoupling was evidenced by an increase in resting respiration, dissipation of mitochondrial membrane potential, inhibition of Ca(2+) uptake, stimulation of Ca(2+) release, decrease in ATP synthesis, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. Furthermore, uncoupling concentrations of VE-3N in the presence of Ca(2+) plus ruthenium red induced the mitochondrial permeability transition process. These results indicate that mitochondrial uncoupling is potentially involved in the VE-3N cytotoxic actions towards HepG2 cells. Considering that hepatocellular carcinoma is the most common form of liver cancer, our findings may open a new avenue for the development of VE-3N-based cancer therapies, and help to unravel the cytotoxic mechanisms of 1,4-dihydropyridines towards cancer cells.

  10. Cardiovascular-sleep interaction in drug-naïve patients with essential grade I hypertension.

    PubMed

    Grimaldi, Daniela; Provini, Federica; Calandra-Buonaura, Giovanna; Barletta, Giorgio; Cecere, Annagrazia; Pierangeli, Giulia; Cortelli, Pietro

    2013-03-01

    Lack of nighttime blood pressure (BP) reduction by 10-20% from the mean daytime values (dipping) has been described as a distinguishing feature of essential hypertension and associated, also in normotensive subjects, with increased cardiovascular (CV) risk. Mechanisms involved in the loss of the nocturnal dip are still unclear, but involvement of autonomic nervous system (ANS) activity probably plays a crucial role. Sleep is fundamental in modulating ANS activity to maintain the physiological BP circadian rhythm, and for this reason its integrity has been widely investigated in hypertension. We investigated, under controlled conditions, the autonomic control of the CV system through an autonomic reflex screen in the awake condition and by assessment of circadian rhythm-, day-night-, time-, and state-dependent changes of BP and heart rate (HR) and associated sleep parameters in patients with a recent (≤1 yr) diagnosis of essential grade I hypertension naïve of therapy. Fourteen hypertensive patients (6 males, age: 43 ± 11 yrs; body mass index [BMI]: 24 ± 3 kg/m(2)) were compared with 28 healthy controls matched for sex, age, BMI (2 controls/patient) for cardiovascular reflex and to 8 different subjects from previous controls (6 males), comparable for age and BMI, for the day-night and nighttime CV profiles during two consecutive nights. The cardiovascular reflex screen data showed increased sympathetic effect in hypertensive patients, represented by higher overshoot of BP after Valsalva maneuver. Nighttime sleep architecture during the dark period in terms of duration, representation of sleep stages, sleep fragmentation, and incidence of arousals-periodic limb movements in sleep (PLMS) and PLMS arousals-was similar in patients and controls. Hypertensive patients displayed higher 24-h BP and HR values, but their sleep-related BP decrease was significantly reduced compared with controls. The circadian rhythms of BP and HR were intact and similar in

  11. Mismatched anti-predator behavioral responses in predator-naïve larval anurans

    PubMed Central

    Vance-Chalcraft, Heather D.

    2015-01-01

    Organisms are adept at altering behaviors to balance the tradeoff between foraging and predation risk in spatially and temporally shifting predator environments. In order to optimize this tradeoff, prey need to be able to display an appropriate response based on degree of predation risk. To be most beneficial in the earliest life stages in which many prey are vulnerable to predation, innate anti-predator responses should scale to match the risk imposed by predators until learned anti-predator responses can occur. We conducted an experiment that examined whether tadpoles with no previous exposure to predators (i.e., predator-naive) exhibit innate antipredator behavioral responses (e.g., via refuge use and spatial avoidance) that match the actual risk posed by each predator. Using 7 treatments (6 free-roaming, lethal predators plus no-predator control), we determined the predation rates of each predator on Lithobates sphenocephalus tadpoles. We recorded behavioral observations on an additional 7 nonlethal treatments (6 caged predators plus no-predator control). Tadpoles exhibited innate responses to fish predators, but not non-fish predators, even though two non-fish predators (newt and crayfish) consumed the most tadpoles. Due to a mismatch between innate response and predator consumption, tadpoles may be vulnerable to greater rates of predation at the earliest life stages before learning can occur. Thus, naïve tadpoles in nature may be at a high risk to predation in the presence of a novel predator until learned anti-predator responses provide additional defenses to the surviving tadpoles. PMID:26664805

  12. Serum alkaline phosphatase negatively affects endothelium-dependent vasodilation in naïve hypertensive patients.

    PubMed

    Perticone, Francesco; Perticone, Maria; Maio, Raffaele; Sciacqua, Angela; Andreucci, Michele; Tripepi, Giovanni; Corrao, Salvatore; Mallamaci, Francesca; Sesti, Giorgio; Zoccali, Carmine

    2015-10-01

    Tissue nonspecific alkaline phosphatase, promoting arterial calcification in experimental models, is a powerful predictor of total and cardiovascular mortality in general population and in patients with renal or cardiovascular diseases. For this study, to evaluate a possible correlation between serum alkaline phosphatase levels and endothelial function, assessed by strain gauge plethysmography, we enrolled 500 naïve hypertensives divided into increasing tertiles of alkaline phosphatase. The maximal response to acetylcholine was inversely related to alkaline phosphatase (r=−0.55; P<0.001), and this association was independent (r=−0.61; P<0.001) of demographic and classical risk factors, body mass index, estimated glomerular filtration rate, serum phosphorus and calcium, C-reactive protein, and albuminuria. At multiple logistic regression analysis, the risk of endothelial dysfunction was ≈3-fold higher in patients in the third tertile than that of patients in the first tertile. We also tested the combined role of alkaline phosphatase and serum phosphorus on endothelial function. The steepness of the alkaline phosphatase/vasodilating response to acetylcholine relationship was substantially attenuated (P<0.001) in patients with serum phosphorus above the median value when compared with patients with serum phosphorus below the median (−5.0% versus −10.2% per alkaline phosphatase unit, respectively), and this interaction remained highly significant (P<0.001) after adjustment of all the previously mentioned risk factors. Our data support a strong and significant inverse relationship between alkaline phosphatase and endothelium-dependent vasodilation, which was attenuated by relatively higher serum phosphorus levels.

  13. Proceedings of the XXII A.I.VE.LA. National Meeting

    NASA Astrophysics Data System (ADS)

    Primo Tomasini, Enrico

    2015-11-01

    A.I.VE.LA. - the Italian Association of Laser Velocimetry and non-invasive diagnostics - is a non-profit cultural association whose objective is to promote and support research in the field of non-contact or minimally invasive measurement techniques, particularly electromagnetic-based techniques and optical techniques. Through its Annual Meeting, AIVELA aims to create an active and stimulating forum where current research results and technical advances can be exchanged and the development of new systems for laboratory use, field testing and industrial application can be promoted. The techniques covered include Laser Doppler Anemometry - LDA, Phase Doppler Anemometry - PDA, Image Velocimetry - PIV, Flow visualization techniques, Spectroscopic measurement techniques (LIF, Raman, etc.), Laser Doppler Vibrometry - LDV, Speckle Pattern Interferometry - ESPI, Holographic techniques, Shearography, Digital Image Correlation - DIC, Moiré techniques, Structured light techniques, Infrared imaging, Photoelasticity, Image based measurement techniques, Ultrasonic sensing, Acoustic and Aeroacoustic measurements, etc. The first Annual Meeting was held back in October 1992 and since then there has been a large consensus among the research and scientific communities that the papers presented at the event are of a high scientific interest. The XXII AIVELA Annual Meeting was held at the Faculty of Engineering of University of Rome Tor Vergata on 15-16 December 2014 and was organised in collaboration with the International Master Courses in "Protection Against CBRNe Events". This volume contains a selection of the papers presented at the event. The detailed Programme of the Meeting can be found at: http://www.aivela.org/XXII_Convegno/index.html Trusting our Association and its initiatives will meet your interest, I wish to thank you in advance for your kind attention and hope to meet you soon at one of our events.

  14. ERP Correlates of Proactive and Reactive Cognitive Control in Treatment-Naïve Adult ADHD

    PubMed Central

    Endestad, Tor; Aasen, Ida Emilia S.; Kropotov, Juri; Knight, Robert Thomas

    2016-01-01

    This study investigated whether treatment naïve adults with Attention Deficit Hyperactivity Disorder (ADHD; n = 33; 19 female) differed from healthy controls (n = 31; 17 female) in behavioral performance, event-related potential (ERP) indices of preparatory attention (CueP3 and late CNV), and reactive response control (Go P3, NoGo N2, and NoGo P3) derived from a visual cued Go/NoGo task. On several critical measures, Cue P3, late CNV, and NoGo N2, there were no significant differences between the groups. This indicated normal preparatory processes and conflict monitoring in ADHD patients. However, the patients had attenuated Go P3 and NoGoP3 amplitudes relative to controls, suggesting reduced allocation of attentional resources to processes involved in response control. The patients also had a higher rate of Go signal omission errors, but no other performance decrements compared with controls. Reduced Go P3 and NoGo P3 amplitudes were associated with poorer task performance, particularly in the ADHD group. Notably, the ERPs were not associated with self-reported mood or anxiety. The results provide electrophysiological evidence for reduced effortful engagement of attentional resources to both Go and NoGo signals when reactive response control is needed. The absence of group differences in ERP components indexing proactive control points to impairments in specific aspects of cognitive processes in an untreated adult ADHD cohort. The associations between ERPs and task performance provided additional support for the altered electrophysiological responses. PMID:27448275

  15. Disrupted brain anatomical connectivity in medication-naïve patients with first-episode schizophrenia.

    PubMed

    Zhang, Ruibin; Wei, Qinling; Kang, Zhuang; Zalesky, Andrew; Li, Meng; Xu, Yong; Li, Leijun; Wang, Junjing; Zheng, Liangrong; Wang, Bin; Zhao, Jingping; Zhang, Jinbei; Huang, Ruiwang

    2015-03-01

    Previous studies suggested that the topological properties of brain anatomical networks may be aberrant in schizophrenia (SCZ), and most of them focused on the chronic and antipsychotic-medicated SCZ patients which may introduce various confounding factors due to antipsychotic medication and duration of illness. To avoid those potential confounders, a desirable approach is to select medication-naïve, first-episode schizophrenia (FE-SCZ) patients. In this study, we acquired diffusion tensor imaging datasets from 30 FE-SCZ patients and 34 age- and gender-matched healthy controls. Taking a distinct gray matter region as a node, inter-regional connectivity as edge and the corresponding streamline counts as edge weight, we constructed whole-brain anatomical networks for both groups, calculated their topological parameters using graph theory, and compared their between-group differences using nonparametric permutation tests. In addition, network-based statistic method was utilized to identify inter-regional connections which were impaired in the FE-SCZ patients. We detected only significantly decreased inter-regional connections in the FE-SCZ patients compared to the controls. These connections were primarily located in the frontal, parietal, occipital, and subcortical regions. Although small-worldness was conserved in the FE-SCZ patients, we found that the network strength and global efficiency as well as the degree were significantly decreased, and shortest path length was significantly increased in the FE-SCZ patients compared to the controls. Most of the regions that showed significantly decreased nodal parameters belonged to the top-down control, sensorimotor, basal ganglia, and limbic-visual system systems. Correlation analysis indicated that the nodal efficiency in the sensorimotor system was negatively correlated with the severity of psychosis symptoms in the FE-SCZ patients. Our results suggest that the network organization is changed in the early stages of the

  16. Hamiltonian Map to Conformal Modification of Spacetime Metric: Kaluza-Klein and TeVeS

    NASA Astrophysics Data System (ADS)

    Horwitz, Lawrence; Gershon, Avi; Schiffer, Marcelo

    2011-01-01

    It has been shown that the orbits of motion for a wide class of non-relativistic Hamiltonian systems can be described as geodesic flows on a manifold and an associated dual by means of a conformal map. This method can be applied to a four dimensional manifold of orbits in spacetime associated with a relativistic system. We show that a relativistic Hamiltonian which generates Einstein geodesics, with the addition of a world scalar field, can be put into correspondence in this way with another Hamiltonian with conformally modified metric. Such a construction could account for part of the requirements of Bekenstein for achieving the MOND theory of Milgrom in the post-Newtonian limit. The constraints on the MOND theory imposed by the galactic rotation curves, through this correspondence, would then imply constraints on the structure of the world scalar field. We then use the fact that a Hamiltonian with vector gauge fields results, through such a conformal map, in a Kaluza-Klein type theory, and indicate how the TeVeS structure of Bekenstein and Saunders can be put into this framework. We exhibit a class of infinitesimal gauge transformations on the gauge fields {mathcal{U}}_{μ}(x) which preserve the Bekenstein-Sanders condition {mathcal{U}}_{μ}{mathcal{U}}^{μ}=-1. The underlying quantum structure giving rise to these gauge fields is a Hilbert bundle, and the gauge transformations induce a non-commutative behavior to the fields, i.e. they become of Yang-Mills type. Working in the infinitesimal gauge neighborhood of the initial Abelian theory we show that in the Abelian limit the Yang-Mills field equations provide residual nonlinear terms which may avoid the caustic singularity found by Contaldi et al.

  17. Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9

    PubMed Central

    Yang, Yuanyuan; Zhang, Xiaobai; Yi, Li; Hou, Zhenzhen; Chen, Jiayu; Kou, Xiaochen; Zhao, Yanhong; Wang, Hong; Sun, Xiao-Fang; Jiang, Cizhong

    2016-01-01

    Conventional primed human embryonic stem cells and induced pluripotent stem cells (iPSCs) exhibit molecular and biological characteristics distinct from pluripotent stem cells in the naïve state. Although naïve pluripotent stem cells show much higher levels of self-renewal ability and multidifferentiation capacity, it is unknown whether naïve iPSCs can be generated directly from patient somatic cells and will be superior to primed iPSCs. In the present study, we used an established 5i/L/FA system to directly reprogram fibroblasts of a patient with β-thalassemia into transgene-free naïve iPSCs with molecular signatures of ground-state pluripotency. Furthermore, these naïve iPSCs can efficiently produce cross-species chimeras. Importantly, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 nuclease genome editing system, these naïve iPSCs exhibit significantly improved gene-correction efficiencies compared with the corresponding primed iPSCs. Furthermore, human naïve iPSCs could be directly generated from noninvasively collected urinary cells, which are easily acquired and thus represent an excellent cell resource for further clinical trials. Therefore, our findings demonstrate the feasibility and superiority of using patient-specific iPSCs in the naïve state for disease modeling, gene editing, and future clinical therapy. Significance In the present study, transgene-free naïve induced pluripotent stem cells (iPSCs) directly converted from the fibroblasts of a patient with β-thalassemia in a defined culture system were generated. These naïve iPSCs, which show ground-state pluripotency, exhibited significantly improved single-cell cloning ability, recovery capacity, and gene-targeting efficiency compared with conventional primed iPSCs. These results provide an improved strategy for personalized treatment of genetic diseases such as β-thalassemia. PMID:26676643

  18. EEG Spectral Changes in Treatment Naïve Active Alcoholics

    PubMed Central

    Fein, G.; Allen, J.

    2007-01-01

    Background The present study examines the EEG spectra of actively drinking treatment naïve alcoholics (TxNA). Methods EEGs were gathered on 51 TxNA’s and age and sex-matched controls during eyes-closed conditions. Participants were excluded for lifetime diagnoses of psychiatric or substance abuse disorders. Power for the theta to high beta bands was examined across midline electrodes. Results The TxNA sample exhibited a nexus of disinhibited traits associated with the vulnerability to alcoholism, and had developed alcohol dependence, but no other diagnosable psychiatric or substance abuse disorders. The TxNA subjects evidenced higher power for all EEG bands compared to controls. The magnitude and anterior-posterior extent of the group differences varied across bands. Within the TxNA group, EEG power was negatively correlated with average and peak alcohol drinking duration and average and peak alcohol dose. Conclusions Increased EEG power across the theta to high beta bands distinguishes TxNAs without comorbid diagnoses from controls. These effects varied across bands in their magnitude and spatial extent, suggesting that there are different effects for the different EEG spectral generators. We hypothesize the increased power in these individuals is a trait difference associated with the inherited nexus of disinhibited traits and its manifestation in alcoholism. Based on the strong negative correlations with alcohol use variables, we speculate that decreases in EEG power are a morbid effect of long-term alcohol abuse. We acknowledge that this hypothesized effect of alcohol abuse on EEG power is opposite to the increased EEG power we hypothesize is associated with alcoholism and its inherited nexus of disinhibited traits. An implication of this model is that with continuing alcohol abuse, the increased EEG power in TxNAs will eventually be overpowered by the effects of long-term severe alcohol abuse. This model predicts that in very long-term alcoholics EEG power

  19. Comparison of Serum Lipid Profile in HIV Positive Patients on ART with ART Naïve Patients

    PubMed Central

    V, Vijay; Shekhanawar, M.S.; Rajeshwari; M, Amareshwaras; D, Shantala

    2014-01-01

    Introduction: The widespread use of effective highly active antiretroviral therapy (HAART) in HIV patients has coincided with increasing reports of complications like HIV-associated lipodystrophy syndrome and the metabolic alterations, affecting the lipid and glucose metabolism. Evidences in support of lipodystrophy and dyslipidaemia associated with First- line HAART in our area is scarce. The aim of the present study was 1) to study and compare Lipid profile in HIV positive patients on ART with that of freshly diagnosed HIV positive patients who were yet to be started on ART. 2) To assess lipodystrophy syndrome in patients on ART. Materials and Methods: Hundred newly diagnosed HIV positive patients who were yet to be started on ART were taken as controls (ART-Naïve).Hundred randomly selected HIV+ patients who were already on First-line ART regimen (Stavudine/Zudovudine + Lamivudine + Nevirapine) for more than 12 months were taken as cases (ART). This study was conducted for a period of 12 months at the VIMS ART centre, Bellary, Karnataka, India. Results: There was a significant increase (p<0.001) in serum Total Cholesterol, LDL-C, TG, VLDL, Non-HDL -C & TC/HDL-C ratio in ART patients compared to ART-naïve patients. Of the 100 ART patients 23 had lipodystrophy syndrome (buffalo hump, abnormal fat deposition around neck & back, buccal fat resorption, increase in abdominal fat). Conclusion: To conclude, it is evident from our study that there is increase in lipid profile (except HDL) in ART patients compared to ART Naïve group and 23 ART patients showed lipodystrophy syndrome. Hence it appears reasonable to measure fasting lipid levels before and 3-6 months after antiretroviral therapy is initiated or when ART regimen is changed. PMID:25478335

  20. Porcine induced pluripotent stem cells analogous to naïve and primed embryonic stem cells of the mouse.

    PubMed

    Telugu, Bhanu Prakash V L; Ezashi, Toshihiko; Roberts, R Michael

    2010-01-01

    Authentic or naïve embryonic stem cells (ESC) have probably never been derived from the inner cell mass (ICM) of pig blastocysts, despite over 25 years of effort. Recently, several groups, including ours, have reported induced pluripotent stem cells (iPSC) from swine by reprogramming somatic cells with a combination of four factors, OCT4 (POU5F1)/SOX2/KLF4/c-MYC delivered by retroviral transduction. The porcine (p) iPSC resembled human (h) ESC and the mouse "Epiblast stem cells" (EpiSC) in their colony morphology and expression of pluripotent genes, and are likely dependent on FGF2/ACTIVIN/NODAL signaling, therefore representing a primed ESC state. These cells are likely to advance swine as a model in biomedical research, since grafts could potentially be matched to the animal that donated the cells for re-programming. The objective of the present work has been to develop naïve piPSC. Employing a combination of seven reprogramming factors assembled on episomal vectors, we successfully reprogrammed porcine embryonic fibroblasts on a modified LIF-medium supplemented with two kinase inhibitors; CHIR99021, which inhibits GSK-3beta, and PD0325901, a MEK inhibitor. The derived piPSC bear a striking resemblance to naïve mESC in colony morphology, are dependent on LIF to maintain an undifferentiated phenotype, and express markers consistent with pluripotency. They exhibit high telomerase activity, a short cell cycle interval, and a normal karyotype, and are able to generate teratomas. Currently, the competence of these lines for contributing to germ-line chimeras is being tested.

  1. Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells.

    PubMed

    Deuse, Tobias; Seifert, Martina; Phillips, Neil; Fire, Andrew; Tyan, Dolly; Kay, Mark; Tsao, Philip S; Hua, Xiaoqin; Velden, Joachim; Eiermann, Thomas; Volk, Hans-Dieter; Reichenspurner, Hermann; Robbins, Robert C; Schrepfer, Sonja

    2011-09-01

    Human embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESC(KD)). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESC(KD) was 88%-99% reduced. T cell activation after hESC(KD) transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESC(KD) was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESC(KD) was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.

  2. Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth.

    PubMed

    Ivanov, Iliyan; Liu, Xun; Shulz, Kurt; Fan, Jin; London, Edythe; Friston, Karl; Halperin, Jeffrey M; Newcorn, Jeffrey H

    2012-02-28

    It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-naïve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-naïve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-naïve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction.

  3. Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir.

    PubMed

    Ridruejo, E; Marciano, S; Galdame, O; Reggiardo, M V; Muñoz, A E; Adrover, R; Cocozzella, D; Fernandez, N; Estepo, C; Mendizábal, M; Romero, G A; Levi, D; Schroder, T; Paz, S; Fainboim, H; Mandó, O G; Gadano, A C; Silva, M O

    2014-08-01

    Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.

  4. Demonstration of sustained drug-resistant human immunodeficiency virus type 1 lineages circulating among treatment-naïve individuals.

    PubMed

    Hué, Stéphane; Gifford, Robert J; Dunn, David; Fernhill, Esther; Pillay, Deenan

    2009-03-01

    Transmission of human immunodeficiency virus (HIV) drug resistance is well-recognized and compromises response to first-line therapy. However, the population dynamics of transmitted resistance remains unclear, although previous models have assumed that such transmission reflects direct infection from treated individuals. We investigated whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in untreated individuals. Through the phylogenetic analysis of 14,061 HIV type 1 (HIV-1) pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals, we identified five treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages represent sustainable reservoirs of resistance among new HIV infections, independent of treatment. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo inference indicated that these reservoirs originated between 1997 and 2003 and have persisted in the HIV-infected population for up to 8 years. Since our cohort does not represent all infected individuals within the United Kingdom, our results are likely to underestimate the number and size of the resistant reservoirs circulating among drug-naïve patients. The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of antiretroviral therapy and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals, a greater proportion of resistance is likely to come from drug-naïve lineages. These findings provide new insights for the planning and management of treatment programs in resource-rich and developing countries.

  5. The transition from naïve to primed nociceptive state: A novel wind-up protocol in mice.

    PubMed

    Ziv, Nadav Y; Tal, Michael; Shavit, Yehuda

    2016-01-01

    Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naïve mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10 min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of-windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naïve animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naïve' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization.

  6. Antiretroviral drug resistance among antiretroviral-naïve and treatment experienced patients infected with HIV in Iran.

    PubMed

    Baesi, Kazem; Ravanshad, Mehrdad; Ghanbarisafari, Maryam; Saberfar, Esmaeil; Seyedalinaghi, Seyedahmad; Volk, Jonathan E

    2014-07-01

    Resistance to antiretroviral therapy (ART) threatens the success of programs to reduce HIV morbidity and mortality, particularly in countries with few treatment options. In the present study, genotype and phenotype data from ART-naïve and experienced hospitalized patients infected with HIV in Tehran, Iran were used to assess the prevalence and types of transmitted (TDR) and acquired drug resistance (ADR) mutations. All 30 participants naïve to ART and 62 of 70 (88.6%) participants receiving ART had detectable viral loads. Among participants receiving ART with sequencing data available (n = 62), 36 (58.1%) had at least one drug resistance mutation; the most common mutations were K103N (21.0%), M184V (19.4%), and the thymidine analogue mutations. Seven (11.3%), 27 (43.5%), and two (3.2%) of these participants had resistance to one, two, and three drug classes, respectively. High-level resistance to efavirenz (EFV) was more common among participants on EFV-based regimens than high-level lopinavir/ritonivar (LPV/r) resistance among those on LPV/r-based regimens (55.3% vs. 6.7%, P < 0.0001). Two (6.7%) antiretroviral-naïve participants had K103N mutations. These findings document an alarmingly high frequency of multiple HIV drug class resistance in Iran, confirm the presence of TDR, and highlight the need for systematic viral load monitoring and drug resistance testing, including at diagnosis. Expanded access to new antiretroviral medications from additional drug classes is needed.

  7. Oh What FUN We've Had! Reflections on the Past and a Look to the Future.

    PubMed

    Dickinson, Shelly D

    2012-01-01

    In 2011 FUN celebrated 20 years of training tomorrow's neuroscientists today. Over the past two decades we've become an international organization of members dedicated to excellence in teaching and research at the undergraduate level. FUN has enacted its mission through our flagship journal JUNE, student travel awards, faculty awards, education workshops, and regional conferences. More recent initiatives include the equipment loan program, department/program consulting service, the honor society Nu Rho Psi, and neuroscience study abroad opportunities. FUN is poised to continue enhancing undergraduate neuroscience education and research over the next 20 years.

  8. Olodaterol attenuates citric acid-induced cough in naïve and ovalbumin-sensitized and challenged guinea pigs.

    PubMed

    Wex, Eva; Bouyssou, Thierry

    2015-01-01

    Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p < 0.01). Formoterol and salmeterol showed a trend towards reducing cough. On the contrary, indacaterol demonstrated pro-tussive properties as it significantly increased the number of coughs, both in naïve and ovalbumin-sensitized animals (p < 0.001). In conclusion, olodaterol, at doses eliciting bronchodilation, showed antitussive properties in a model of citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the

  9. Oh What FUN We’ve Had! Reflections on the Past and a Look to the Future

    PubMed Central

    Dickinson, Shelly D.

    2012-01-01

    In 2011 FUN celebrated 20 years of training tomorrow’s neuroscientists today. Over the past two decades we’ve become an international organization of members dedicated to excellence in teaching and research at the undergraduate level. FUN has enacted its mission through our flagship journal JUNE, student travel awards, faculty awards, education workshops, and regional conferences. More recent initiatives include the equipment loan program, department/program consulting service, the honor society Nu Rho Psi, and neuroscience study abroad opportunities. FUN is poised to continue enhancing undergraduate neuroscience education and research over the next 20 years. PMID:23493526

  10. FIJI Macro 3D ART VeSElecT: 3D Automated Reconstruction Tool for Vesicle Structures of Electron Tomograms

    PubMed Central

    Kaltdorf, Kristin Verena; Schulze, Katja; Helmprobst, Frederik; Kollmannsberger, Philip; Stigloher, Christian

    2017-01-01

    Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation

  11. Water-resources reconnaissance of Île de la Gonâve, Haiti

    NASA Astrophysics Data System (ADS)

    Troester, Joseph W.; Turvey, Michael D.

    Île de la Gonâve is a 750-km2 island off the coast of Haiti. The depth to the water table ranges from less than 30 m in the Eocene and Upper Miocene limestones to over 60 m in the 300-m-thick Quaternary limestone. Annual precipitation ranges from 800-1,400 mm. Most precipitation is lost through evapotranspiration and there is virtually no surface water. Roughly estimated from chloride mass balance, about 4% of the precipitation recharges the karst aquifer. Cave pools and springs are a common source for water. Hand-dug wells provide water in coastal areas. Few productive wells have been drilled deeper than 60 m. Reconnaissance field analyses indicate that groundwater in the interior is a calcium-bicarbonate type, whereas water at the coast is a sodium-chloride type that exceeds World Health Organization recommended values for sodium and chloride. Tests for the presence of hydrogen sulfide-producing bacteria were negative in most drilled wells, but positive in cave pools, hand-dug wells, and most springs, indicating bacterial contamination of most water sources. Because of the difficulties in obtaining freshwater, the 110,000 inhabitants use an average of only 7 L per person per day. L'Île de la Gonâve est une île de 750 km2 au large de la côte d'Haïti. La profondeur de la nappe varie entre moins de 30 m dans les calcaires de l'Éocène et du Miocène supérieur à plus de 60 m dans les calcaires quaternaires épais de 300 m. Les précipitations annuelles sont comprises entre 800-1.400 mm. La plus grande partie des précipitations est perdue par évapotranspiration et il n'y a pratiquement pas d'eau de surface. Le bilan de masse des chlorures permet d'estimer à 4% des précipitations le montant de la recharge de l'aquifère karstique. Des bassins dans les grottes et des sources sont la source d'eau courante. Des puits creusés à la main fournissent de l'eau dans les zones côtières. Quelques puits productifs ont été forés dépassant 60 m de profondeur. L

  12. Activation of human naïve Th cells increases surface expression of GD3 and induces neoexpression of GD2 that colocalize with TCR clusters.

    PubMed

    Villanueva-Cabello, Tania M; Mollicone, Rosella; Cruz-Muñoz, Mario E; López-Guerrero, Delia V; Martínez-Duncker, Iván

    2015-12-01

    CD4+ T helper lymphocytes (Th) orchestrate the immune response after their activation by antigen-presenting cells. Activation of naïve Th cells is reported to generate the reduction in surface epitopes of sialic acid (Sia) in α2,3 and α2,6 linkages. In this work, we report that in spite of this glycophenotype, anti-CD3/anti-CD28-activated purified human naïve Th cells show a significant increase in surface Sia, as assessed by metabolic labeling, compared with resting naïve Th cells, suggesting an increased flux of Sia toward Siaα2,8 glycoconjugates. To understand this increase as a result of ganglioside up-regulation, we observed that very early after activation, human naïve Th cells show an increased expression in surface GD3 and neoexpression of surface GD2 gangliosides, the latter clustering with the T cell receptor (TCR). Also, we report that in contrast to GM2/GD2 synthase null mice, lentiviral vector-mediated silencing of the GM2/GD2 synthase in activated human naïve Th cells reduced efficient TCR clustering and downstream signaling, as assessed by proliferation assays and IL-2 and IL-2R expression, pointing to an important role of this enzyme in activation of human naive Th cells.

  13. Antigen-Experienced T cells Limit the Priming of Naïve T cells During Infection with Leishmania major1

    PubMed Central

    Gray, Peter M.; Reiner, Steven L.; Smith, Deborah F.; Kaye, Paul M.; Scott, Phillip

    2009-01-01

    One mechanism to control immune responses following infection is to rapidly down regulate antigen presentation, which has been observed in acute viral and bacterial infections. Here we describe experiments designed to address whether antigen presentation is decreased after an initial response to Leishmania major. Naïve α-β-Leishmania-specific (ABLE) T cell receptor transgenic T cells were adoptively transferred into mice at various times after L. major infection to determine the duration of presentation of parasite-derived antigens. ABLE T cells responded vigorously at the initiation of infection, but the ability to prime these cells quickly diminished, independent of IL-10, regulatory T cells or antigen load. However, antigen-experienced clonal and polyclonal T cell populations could respond, indicating that the diminution in naïve ABLE cell responses was not due to lack of antigen presentation. Since naïve T cell priming could be restored by removal of the endogenous T cell population, or adoptive transfer of antigen pulsed dendritic cells, it appears that T cells that have previously encountered antigen during infection compete with naïve antigen-specific T cells. These results suggest that during L. major infection antigen-experienced T cells, rather than naïve T cells, may be primarily responsible for sustaining the immune response. PMID:16818747

  14. Green tea catechins inhibit VEGF-induced angiogenesis in vitro through suppression of VE-cadherin phosphorylation and inactivation of Akt molecule.

    PubMed

    Tang, Feng-Yao; Nguyen, Nhan; Meydani, Mohsen

    2003-10-10

    Studies have indicated that the consumption of green tea is associated with a reduced risk of developing certain forms of cancer and angiogenesis. The mechanism of inhibition of angiogenesis by green tea or its catechins, however, has not been well-established. Vascular endothelial (VE)-cadherin, an adhesive molecule located at the site of intercellular contact, is involved in cell-cell recognition during vascular morphogenesis. The extracellular domain of VE-cadherin mediates initial cell adhesion, whereas the cytosolic tail binding with beta-catenin is required for interaction with the cytoskeleton and junctional strength. Therefore, the cadherin-catenin adhesion system is implicated in cell recognition, differentiation, growth and migration of capillary endothelium. Using tube formation of human microvascular endothelial cells (HMVEC) in culture as an in vitro model of angiogenesis, we reported that vascular endothelial growth factor (VEGF)-induced tube formation is inhibited by anti-VE-cadherin antibody and dose-dependently by green tea catechins. We also demonstrated here that inhibition of tube formation by epigallocatechin gallate (EGCG), one of the green tea catechins, is in part mediated through suppression of VE-cadherin tyrosine phosphorylation and inhibition of Akt activation during VEGF-induced tube formation. These findings indicate that VE-cadherin and Akt, known downstream proteins in VEGFR-2-mediated cascade, are the new-targeted proteins by which green tea catechins inhibit angiogenesis.

  15. Case report of prenatal diagnosis of Stüve-Wiedemann Syndrome in a woman with another child affected too

    PubMed Central

    Catavorello, Anita; Vitale, Salvatore Giovanni; Rossetti, Diego; Caldaci, Lisa; Panella, Marco Marzio

    2013-01-01

    Summary Objective Stüve-Wiedemann Syndrome (SWS; MIM 601 559) is an autosomal-recessive syndrome characterized by myotonia with mask-like face, skeletal dysplasia and intrauterine growth restriction. Other clinical findings are pursed mouth, hypoplastic midface, congenital contractures and muscular hypotonia. We discuss about the importance of prenatal diagnosis in SWS and the possibility of survival after the first year of life in patients suffering from this disease. Methods we report a case of Stüve-Wiedemann Syndrome detected by morphological examination in our Operative Unit. Prenatal presumptive diagnosis was given with two-dimensional and 3-D probe, during the second trimester of pregnancy. Caesarean section was performed at 38th week of gestation. Then diagnosis was genetically performed. Results at birth, clinical examination was concordant with the ultrasound findings. Genetic analysis also confirmed the presumptive diagnosis. Episodes of respiratory distress and hyperthermia decreased until it disappeared altogether at 1 year of age. Conclusion we underline the usefulness of ultrasound study of fetal skeleton in the prenatal diagnosis. It allowed us to do an early detection of birth defects and their appropriate management. PMID:24175015

  16. Isolation of an ES-Derived Cardiovascular Multipotent Cell Population Based on VE-Cadherin Promoter Activity

    PubMed Central

    Maltabe, Violetta A.; Barka, Eleonora; Kontonika, Marianthi; Florou, Dimitra; Kouvara-Pritsouli, Maria; Roumpi, Maria; Agathopoulos, Simeon; Kolettis, Theofilos M.

    2016-01-01

    Embryonic Stem (ES) or induced Pluripotent Stem (iPS) cells are important sources for cardiomyocyte generation, targeted for regenerative therapies. Several in vitro protocols are currently utilized for their differentiation, but the value of cell-based approaches remains unclear. Here, we characterized a cardiovascular progenitor population derived during ES differentiation, after selection based on VE-cadherin promoter (Pvec) activity. ESCs were genetically modified with an episomal vector, allowing the expression of puromycin resistance gene, under Pvec activity. Puromycin-surviving cells displayed cardiac and endothelial progenitor cells characteristics. Expansion and self-renewal of this cardiac and endothelial dual-progenitor population (CEDP) were achieved by Wnt/β-catenin pathway activation. CEDPs express early cardiac developmental stage-specific markers but not markers of differentiated cardiomyocytes. Similarly, CEDPs express endothelial markers. However, CEDPs can undergo differentiation predominantly to cTnT+ (~47%) and VE-cadherin+ (~28%) cells. Transplantation of CEDPs in the left heart ventricle of adult rats showed that CEDPs-derived cells survive and differentiate in vivo for at least 14 days after transplantation. A novel, dual-progenitor population was isolated during ESCs differentiation, based on Pvec activity. This lineage can self-renew, permitting its maintenance as a source of cardiovascular progenitor cells and constitutes a useful source for regenerative approaches. PMID:28101109

  17. Prediction of drug-induced eosinophilia adverse effect by using SVM and naïve Bayesian approaches.

    PubMed

    Zhang, Hui; Yu, Peng; Xiang, Ming-Li; Li, Xi-Bo; Kong, Wei-Bao; Ma, Jun-Yi; Wang, Jun-Long; Zhang, Jin-Ping; Zhang, Ji

    2016-03-01

    Drug-induced eosinophilia is a potentially life-threatening adverse effect; clinical manifestations, eosinophilia-myalgia syndrome, mainly include severe skin eruption, fever, hematologic abnormalities, and organ system dysfunction. Using experimental methods to evaluate drug-induced eosinophilia is very complicated, time-consuming, and costly in the early stage of drug development. Thus, in this investigation, we established computational prediction models of drug-induced eosinophilia using SVM and naïve Bayesian approaches. For the SVM modeling, the overall prediction accuracy for the training set by means of fivefold cross-validation is 91.6 and for the external test set is 82.9 %. For the naïve Bayesian modeling, the overall prediction accuracy for the training set is 92.5 and for the external test set is 85.4 %. Moreover, some molecular descriptors and substructures considered as important for drug-induced eosinophilia were identified. Thus, we hope the prediction models of drug-induced eosinophilia built in this work should be applied to filter early-stage molecules for potential eosinophilia adverse effect, and the selected molecular descriptors and substructures of toxic compounds should be taken into consideration in the design of new candidate drugs to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe.

  18. Behavioural responses to photographs by pictorially naïve baboons (Papio anubis), gorillas (Gorilla gorilla) and chimpanzees (Pan troglodytes).

    PubMed

    Parron, Carole; Call, Josep; Fagot, Joël

    2008-07-01

    This study assessed how pictorially naïve nonhuman primates understand pictures. Fifty-five baboons with no prior exposure to pictures were trained to grasp a slice of banana presented against a pebble in a two alternative forced choice task. Post-training testing involved three stimulus pairs: (1) real banana slice vs. its picture, (2) the banana picture vs. a real pebble and (3) banana picture vs. a pebble picture which were presented twice. Preliminary data were also collected on naïve gorillas (n=4) and chimpanzees (n=7) using the same procedure. Baboons revealed a preference for the food picture in (2) and (3) and often ate this stimulus, but the food item and its picture were accurately discriminated in (1). These results suggest that baboons mistook the pictorial stimulus and its referent, but processed the banana pictures as poor exemplars of the real banana category. Among apes, only gorillas ate the banana pictures, suggesting that picture-object confusion may also occur in this species. Findings are discussed as pertaining to the general issue of representational abilities in nonhuman primates, and its evolution.

  19. Different genome stability proteins underpin primed and naïve adaptation in E. coli CRISPR-Cas immunity

    PubMed Central

    Ivančić-Baće, Ivana; Cass, Simon D; Wearne, Stephen J; Bolt, Edward L

    2015-01-01

    CRISPR-Cas is a prokaryotic immune system built from capture and integration of invader DNA into CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, termed ‘Adaptation’, which is dependent on Cas1 and Cas2 proteins. In Escherichia coli, Cascade-Cas3 degrades invader DNA to effect immunity, termed ‘Interference’. Adaptation can interact with interference (‘primed’), or is independent of it (‘naïve’). We demonstrate that primed adaptation requires the RecG helicase and PriA protein to be present. Genetic analysis of mutant phenotypes suggests that RecG is needed to dissipate R-loops at blocked replication forks. Additionally, we identify that DNA polymerase I is important for both primed and naive adaptation, and that RecB is needed for naïve adaptation. Purified Cas1-Cas2 protein shows specificity for binding to and nicking forked DNA within single strand gaps, and collapsing forks into DNA duplexes. The data suggest that different genome stability systems interact with primed or naïve adaptation when responding to blocked or collapsed invader DNA replication. In this model, RecG and Cas3 proteins respond to invader DNA replication forks that are blocked by Cascade interference, enabling DNA capture. RecBCD targets DNA ends at collapsed forks, enabling DNA capture without interference. DNA polymerase I is proposed to fill DNA gaps during spacer integration. PMID:26578567

  20. eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases

    PubMed Central

    Di Lorenzo, Annarita; Lin, Michelle I.; Murata, Takahisa; Landskroner-Eiger, Shira; Schleicher, Michael; Kothiya, Milankumar; Iwakiri, Yasuko; Yu, Jun; Huang, Paul L.; Sessa, William C.

    2013-01-01

    Summary Transient disruption of endothelial adherens junctions and cytoskeletal remodeling are responsible for increases in vascular permeability induced by inflammatory stimuli and vascular endothelial growth factor (VEGF). Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is crucial for VEGF-induced changes in permeability in vivo; however, the molecular mechanism by which endogenous NO modulates endothelial permeability is not clear. Here, we show that the lack of eNOS reduces VEGF-induced permeability, an effect mediated by enhanced activation of the Rac GTPase and stabilization of cortical actin. The loss of NO increased the recruitment of the Rac guanine-nucleotide-exchange factor (GEF) TIAM1 to adherens junctions and VE-cadherin (also known as cadherin 5), and reduced Rho activation and stress fiber formation. In addition, NO deficiency reduced VEGF-induced VE-cadherin phosphorylation and impaired the localization, but not the activation, of c-Src to cell junctions. The physiological role of eNOS activation is clear given that VEGF-, histamine- and inflammation-induced vascular permeability is reduced in mice bearing a non-phosphorylatable knock-in mutation of the key eNOS phosphorylation site S1176. Thus, NO is crucial for Rho GTPase-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability. PMID:24046447

  1. Characterizing the V1 layer in the Venus ionosphere using VeRa observations from Venus Express

    NASA Astrophysics Data System (ADS)

    Girazian, Z.; Withers, P.; Fallows, K.; Tarrh, A.; Paetzold, M.; Tellmann, S.; Haesler, B.

    2013-12-01

    The Venus Radio Science Experiment (VeRa) on the Venus Express spacecraft sounds the Venus atmosphere during Earth occultations to obtain vertical profiles of electron density in the ionosphere. The resultant profiles reveal the vertical structure of the Venus ionosphere from the topside down to below the lower layers (< 115 km). On the dayside, the dominant plasma layer is the V2 layer at ~142 km, which is produced primarily by photoionization of CO2. Embedded on the bottomside of the V2 layer is the less prominent, and much less studied, V1 layer at ~127 km. The V1 layer is also produced by photoionization of CO2, but secondary ionization due to energetic photoelectrons is much more important. Here we investigate properties of the V1 layer using VeRa profiles from 2006 to 2012 during which the Sun went from the deep solar minimum of Solar Cycle 23 to the rising solar activity levels of Solar Cycle 24. We investigate how the peak electron density and peak altitude of the V1 layer depend on solar zenith angle. We also characterize the shapes of the V1 layer and show how they are related to the solar activity level. Solar spectra from the Solar EUV Experiment (SEE) on the Thermosphere Ionosphere Mesosphere Energetics and Dynamics (TIMED) spacecraft are used to characterize the shapes of the V1 layer with solar activity.

  2. Elevated levels of Insulin-like Growth Factor-1 (IGF-1) in drug-naïve patients with psychosis.

    PubMed

    Petrikis, Petros; Boumba, Vassiliki A; Tzallas, Alexandros T; Voulgari, Paraskevi V; Archimandriti, Dimitra T; Skapinakis, Petros; Mavreas, Venetsanos

    2016-12-30

    Insulin-like growth factor 1 (IGF-1) plays an important role in neurogenesis and synaptogenesis and may be implicated in schizophrenia, although data so far have been inconclusive. The aim of our study was to compare levels of IGF-1 in drug-naïve patients with a first episode of schizophrenia and related disorders with matched healthy controls. Forty drug naïve first-episode patients with schizophrenia and related disorders and forty healthy subjects matched for age, gender, body mass index (BMI) and smoking status were enrolled in the study. Serum levels of IGF-1 for each sample were measured in duplicate by the enzyme-linked immunosorbent assay (ELISA) method using human IGF-1. The median IGF-1 levels were significantly higher in drug-naive patients with psychosis compared to healthy controls (109.66ng/ml vs. 86.96ng/ml, respectively p=0.039). Multiple regression analysis revealed that differences in serum IGF-1 values were independent of glucose metabolism (fasting glucose, fasting insulin, insulin resistance) and cortisol. These results show that IGF-1 may be implicated in the pathophysiology of psychosis but confirmation is needed from other studies.

  3. Mental models or methodological artefacts? Adults' 'naïve' responses to a test of children's conceptions of the earth.

    PubMed

    Nobes, Gavin; Panagiotaki, Georgia

    2009-05-01

    Vosniadou and Brewer (1992) claim that children's drawings and answers to questions show that they have naive, theory-like 'mental models' of the earth; for example, they believe it to be flat, or hollow with people inside. However, recent studies that have used different methods have found little or no evidence of these misconceptions. The contrasting accounts, and possible reasons for the inconsistent findings, were tested by giving adults (N = 484) either the original task (designed for 5-year olds) or a new version in which the same drawing instructions and questions were rephrased and clarified. Many adults' responses to the original version were identical to children's 'naïve' drawings and answers. The new version elicited substantially fewer non-scientific responses. These findings indicate that even adults find the original instructions and questions ambiguous and confusing, and that this is the principal reason for their non-scientific drawings and answers. Since children must find the task even more confusing than adults, this explanation very probably applies to many of their non-scientific responses, too, and therefore accounts for the discrepant findings of previous research. 'Naïve' responses result largely from misinterpretation of Vosniadou and Brewer's apparently simple task, rather than from mental models of the earth.

  4. Phylogenetic analysis of HIV-1 subtypes and drug resistance profile among treatment-naïve people in Kuwait.

    PubMed

    Chehadeh, Wassim; Albaksami, Osama; Altawalah, Haya; Ahmad, Suhail; Madi, Nada; John, Sonia E; Abraham, Priya S; Al-Nakib, Widad

    2015-09-01

    Mutations associated with resistance to antiretroviral therapy are a major cause of failure to treatment, and surveillance for the emergence of HIV resistance became a component of all antiretroviral treatment programs. As transmission of resistant viruses to newly infected persons is possible, we aimed to determine the prevalence of primary mutations associated with antiretroviral resistance among treatment-naïve patients, with respect to HIV subtype. Viral RNA was extracted from plasma samples of 43 treatment-naïve patients. Protease (PR) and reverse transcriptase (RT) regions were amplified and sequenced using the TRUGENE HIV-1 Genotyping Assay. A phylogenetic analysis was performed for HIV subtype assignment. Complete sequence information could be obtained for 35 patients. A total of ten different HIV-1 subtypes and recombinant forms were found in Kuwait with predominance of subtypes B, C, and CRF01_AE. A62V and A98G were non-polymorphic resistance-associated mutations (RAMs) detected in the RT region of two and three patients, respectively. Non-polymorphic mutations associated with resistance to protease inhibitors were not detected. Our results support continuous surveillance of RAMs in newly infected individuals to assess the effectiveness of first-line antiretroviral regimen available in Kuwait.

  5. Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

    PubMed Central

    von Meyenn, Ferdinand; Ravichandran, Mirunalini; Ficz, Gabriella; Oxley, David; Santos, Fátima; Balasubramanian, Shankar; Jurkowski, Tomasz P.; Reik, Wolf

    2016-01-01

    Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe2+ recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome. PMID:27729528

  6. Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms.

    PubMed

    Hore, Timothy Alexander; von Meyenn, Ferdinand; Ravichandran, Mirunalini; Bachman, Martin; Ficz, Gabriella; Oxley, David; Santos, Fátima; Balasubramanian, Shankar; Jurkowski, Tomasz P; Reik, Wolf

    2016-10-25

    Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe(2+) recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome.

  7. Motor deficits and schizophrenia: the evidence from neuroleptic-naïve patients and populations at risk.

    PubMed Central

    Wolff, A L; O'Driscoll, G A

    1999-01-01

    Patients with schizophrenia and high-risk populations have elevated rates of eye movement abnormalities. However, it is not known whether these abnormalities are specific to eye movements or whether they are also found in more traditional domains of motor control. Most studies examining the motor function of patients with schizophrenia have involved patients treated with medication; abnormalities in motor function could be a result of treatment rather than the disease itself. If motor abnormalities are related to schizophrenia, they should also be found in neuroleptic-naïve patients and possibly in high-risk populations in whom eye movement abnormalities are also observed. We reviewed relevant empirical papers published in the last 35 years. Results suggest that approximately one-fifth of neuroleptic-naïve patients with schizophrenia have increased rates of parkinsonism and neurological soft signs. In high-risk populations, replicated findings include delayed motor development in preschizophrenia subjects, and poor motor skills in the offspring of patients with schizophrenia. In first-degree relatives, increased rates of neurological soft signs were reported. These findings suggest that motor abnormalities are not limited to eye movements and may constitute markers of vulnerability. The literature has several weaknesses that should be addressed in future studies. PMID:10516797

  8. Design and construction of a new human naïve single-chain fragment variable antibody library, IORISS1.

    PubMed

    Pasello, Michela; Zamboni, Silvia; Mallano, Alessandra; Flego, Michela; Picci, Piero; Cianfriglia, Maurizio; Scotlandi, Katia

    2016-04-20

    Human monoclonal antibodies are a powerful tool with increasingly successful exploitations and the single chain fragment variable format can be considered the building block for the implementation of more complex and effective antibody-based constructs. Phage display is one of the best and most efficient methods to isolate human antibodies selected from an efficient and variable phage display library. We report a method for the construction of a human naïve single-chain variable fragment library, termed IORISS1. Many different sets of oligonucleotide primers as well as optimized electroporation and ligation reactions were used to generate this library of 1.2×10(9) individual clones. The key difference is the diversity of variable gene templates, which was derived from only 15 non-immunized human donors. The method described here, was used to make a new human naïve single-chain fragment variable phage display library that represents a valuable source of diverse antibodies that can be used as research reagents or as a starting point for the development of therapeutics. Using biopanning, we determined the ability of IORISS1 to yield antibodies. The results we obtained suggest that, by using an optimized protocol, an efficient phage antibody library can be generated.

  9. Altered fronto-cerebellar connectivity in alcohol-naïve youth with a family history of alcoholism.

    PubMed

    Herting, Megan M; Fair, Damien; Nagel, Bonnie J

    2011-02-14

    Fronto-cerebellar connections are thought to be involved in higher-order cognitive functioning. It is suspected that damage to this network may contribute to cognitive deficits in chronic alcoholics. However, it remains to be elucidated if fronto-cerebellar circuitry is altered in high-risk individuals even prior to alcohol use onset. The current study used functional connectivity MRI (fcMRI) to examine fronto-cerebellar circuitry in 13 alcohol-naïve, at-risk youth with a family history of alcoholism (FH+) and 14 age-matched controls. In addition, we examined how white matter microstructure, as evidenced by fractional anisotropy (FA), related to fcMRI. FH+youth showed significantly reduced functional connectivity between bilateral anterior prefrontal cortices and contralateral cerebellar seed regions compared to controls. We found that this reduction in connectivity significantly correlated with reduced FA in the anterior limb of the internal capsule and the superior longitudinal fasciculus. Taken together, our findings reflect associated aberrant functional and structural connectivity in substance-naïve FH+adolescents, perhaps suggesting an identifiable neurophenotypic precursor to substance use. Given the role of frontal and cerebellar brain regions in subserving executive functioning, the presence of premorbid abnormalities in fronto-cerebellar circuitry may heighten the risk for developing an alcohol use disorder in FH+youth through atypical control processing.

  10. VE-Cadherin Disassembly and Cell Contractility in the Endothelium are Necessary for Barrier Disruption Induced by Tumor Cells

    PubMed Central

    Aragon-Sanabria, Virginia; Pohler, Steven E.; Eswar, Vikram J.; Bierowski, Matthew; Gomez, Esther W.; Dong, Cheng

    2017-01-01

    During metastasis, breakdown of the endothelial barrier is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. However, a complete mechanism governing tumor cell transendothelial migration remains unclear. Here, we investigate the roles of tumor-associated signals in regulating endothelial cell contractility and adherens junction disassembly leading to endothelial barrier breakdown. We show that Src mediates VE-cadherin disassembly in response to metastatic melanoma cells. Through the use of pharmacological inhibitors of cytoskeletal contractility we find that endothelial cell contractility is responsive to interactions with metastatic cancer cells and that reducing endothelial cell contractility abrogates migration of melanoma cells across endothelial monolayers. Furthermore, we find that a combination of tumor secreted soluble factors and receptor-ligand interactions mediate activation of Src within endothelial cells that is necessary for phosphorylation of VE-cadherin and for breakdown of the endothelial barrier. Together, these results provide insight into how tumor cell signals act in concert to modulate cytoskeletal contractility and adherens junctions disassembly during extravasation and may aid in identification of therapeutic targets to block metastasis. PMID:28393886

  11. İhtimaller Hesabına Dayalı İstanbul ve Çevresindeki Deprem Tehlikesi (Seismic hazard assessment of Istanbul and its surroundings)

    USGS Publications Warehouse

    Gulkan, Polat; Kalkan, E.

    2010-01-01

    Bu yazının amacı, İstanbul ve yakın çevresinin maruz olduğu deprem tehlikesine dair 1999 depremlerinden bu yana devam eden tartışmalara bilimsel verilere ve hesaplara dayanan ve mümkün olduğu ölçüde kolay anlaşılır bir açıklama getirmektir. Depremlerin bir bölgede yaratabileceği tehlike, yani yerin sarsılması yüzünden yapılar üzerinde doğacak deprem etkileri, bölgenin deprem riskine, yani o bölgede olabilecek en yüksek deprem büyüklüğüne ve bölgenin zemin durumuna bağlıdır. Bu çalışmada, deprem oluşturma potansiyeline sahip aktif faylar ve son 500 yılda meydana gelmiş depremler ihtimal hesapları kullanılarak ilişkilendirilmiş ve Marmara Bölgesi’nde deprem sonucu doğacak yer hareketi şiddetinin dağılımı haritalanmıştır. Sunulan yeni deprem tehlike haritaları önceki bölgesel tehlike haritaları ile karşılaştırıldığında, Marmara Bölgesi’nde hissedilebilecek yer hareketi şiddetinde, benzer çalışmalara oranla % 10 ila % 15 arası artış görülmektedir.

  12. Estimation of rate constant for VE excitation of the С2(D1Σ) state in Не-СО-О2 discharge plasma

    NASA Astrophysics Data System (ADS)

    Grigorian, G.; Cenian, Adam

    2013-01-01

    The paper discusses the experimental results pointing to the efficient channel of the CO vibrational to the C2 electronic energy-transfer. The radiation spectra D1Σu - X1Σg , known as Mulliken bands, are investigated and the relation of their kinetics to a vibrational excitation of CO molecules in the He-CO-O2 plasma is discussed. The rate constant for VE process ( CO(v >= 25) + C2 → CO(v - 25) + C2(D1Σu) ) is estimated, kVE ~ 10-14 см3/с.

  13. The Ve-mediated resistance response of the tomato to Verticillium dahliae involves H2O2, peroxidase and lignins and drives PAL gene expression

    PubMed Central

    2010-01-01

    Background Verticillium dahliae is a fungal pathogen that infects a wide range of hosts. The only known genes for resistance to Verticillium in the Solanaceae are found in the tomato (Solanum lycopersicum) Ve locus, formed by two linked genes, Ve1 and Ve2. To characterize the resistance response mediated by the tomato Ve gene, we inoculated two nearly isogenic tomato lines, LA3030 (ve/ve) and LA3038 (Ve/Ve), with V. dahliae. Results We found induction of H2O2 production in roots of inoculated plants, followed by an increase in peroxidase activity only in roots of inoculated resistant plants. Phenylalanine-ammonia lyase (PAL) activity was also increased in resistant roots 2 hours after inoculation, while induction of PAL activity in susceptible roots was not seen until 48 hours after inoculation. Phenylpropanoid metabolism was also affected, with increases in ferulic acid, p-coumaric acid, vanillin and p-hydroxybenzaldehyde contents in resistant roots after inoculation. Six tomato PAL cDNA sequences (PAL1 - PAL6) were found in the SolGenes tomato EST database. RT-PCR analysis showed that these genes were expressed in all organs of the plant, albeit at different levels. Real-time RT-PCR indicated distinct patterns of expression of the different PAL genes in V. dahliae-inoculated roots. Phylogenetic analysis of 48 partial PAL cDNAs corresponding to 19 plant species grouped angiosperm PAL sequences into four clusters, suggesting functional differences among the six tomato genes, with PAL2 and PAL6 presumably involved in lignification, and the remaining PAL genes implicated in other biological processes. An increase in the synthesis of lignins was found 16 and 28 days after inoculation in both lines; this increase was greater and faster to develop in the resistant line. In both resistant and susceptible inoculated plants, an increase in the ratio of guaiacyl/syringyl units was detected 16 days after inoculation, resulting from the lowered amount of syringyl units in the

  14. Temporary Threshold Shifts in Naïve and Experienced Belugas: Can Dampening of the Effects of Fatiguing Sounds Be Learned?

    PubMed

    Popov, Vladimir; Supin, Alexander; Nechaev, Dmitry; Sysueva, Evgenia; Rozhnov, Viatcheslav

    2016-01-01

    In belugas (Delphinapterus leucas), substantial (10-15 dB) differences in temporary threshold shifts (TTSs) were observed between the first and subsequent experimental sessions in the same subjects. In the first session (naïve subject state), the TTSs produced by exposure to fatiguing noises were larger than the TTSs produced in subsequent sessions (experienced subject state). After one to two sessions, the TTSs stabilized. The baseline hearing thresholds did not differ between the naïve and experienced states. One possible explanation for this effect is that the animals learned to dampen their hearing during exposure to fatiguing noises and thus mitigate the impact of those noises.

  15. Relationship between Interleukin-6 Gene Polymorphism and Hippocampal Volume in Antipsychotic-Naïve Schizophrenia: Evidence for Differential Susceptibility?

    PubMed Central

    Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan; Shivakumar, Venkataram; Gautham, S.; Subramaniam, Aditi; Jose, Dania Alphonse; Maitra, Arindam; Ravi, Vasanthapuram; Gangadhar, Bangalore N.

    2014-01-01

    Background Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. Methodology We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla – MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Results Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Conclusion Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal

  16. Sleep disturbances in drug naïve Parkinson's disease (PD) patients and effect of levodopa on sleep

    PubMed Central

    Ferreira, Teresa; Prabhakar, Sudesh; Kharbanda, Parampreet S.

    2014-01-01

    Context: Parkinson's disease (PD) is associated with sleep disturbances, attributed to the neurodegenerative process and therapeutic drugs. Studies have found levodopa to increase wakefulness in some patients while increasing sleepiness in others. Aims: To confirm sleep disturbances in drug naïve PD patients and understand the impact of levodopa on their sleep. Materials and Methods: Twenty-three drug naïve PD patients and 31 age-gender matched controls were compared using the Parkinson's Disease Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS). A polysomnogram objectively compared sleep quality. Of the 23 patients, the 12 initiated on levodopa were reassessed subjectively and through polysomnography after 2 months of therapy. Statistical Analysis: Data was expressed as mean ± standard deviation, median, and range. Continuous variables were analyzed by Student's T test for normally distributed data and Mann–Whitney U test for skewed data. Discrete variables were compared by Chi Square tests (Pearson Chi square Test or Fisher's Exact Test). Wilcoxon signed ranks test was applied in the analysis of paired data pre- and post-levodopa. A P value < 0.05 was considered as statistically significant. Statistical analysis of the data was done using the Statistical Package for the Social Sciences (SPSS) version 12. Results: Drug naïve PD patients had lower PDSS scores than controls. The sleep architecture changes observed on polysomnogram were reduced NREM Stage III and REM sleep and increased sleep latency and wake after sleep onset time. Following levodopa, improved sleep efficiency with reduced sleep latency and wake after sleep onset time was noted, coupled with improved PDSS scores. However, NREM Stage III and REM sleep duration did not increase. Discussion: PD patients take longer to fall asleep and have difficulty in sleep maintenance. Sleep maintenance is affected by nocturia, REM behavioral disorder, nocturnal cramps, akinesia, and tremors, as observed in

  17. Spontaneous preference for visual cues of animacy in naïve domestic chicks: The case of speed changes.

    PubMed

    Rosa-Salva, O; Grassi, M; Lorenzi, E; Regolin, L; Vallortigara, G

    2016-12-01

    Animacy perception arises in human adults from motion cues implying an internal energy source to the moving object. The internal energy of the object is often represented by a change in speed. The same features cause preferential attention in infants. We investigated whether speed changes affecting adults' animacy ratings elicit spontaneous social preferences in visually-naïve chicks. Human observers evaluated the similarity between the movement of a red blob stimulus and that of a living creature. The stimulus entered the screen and moved along the azimuth; halfway through its trajectory it could either continue to move at a constant speed or linearly increase in speed. The average speed, the distance covered and the overall motion duration were kept constant. Animacy ratings of humans were higher for accelerating stimuli (Exp. 1). Naïve chicks were then tested for their spontaneous preference for approaching the stimulus moving at a constant speed and trajectory or an identical stimulus, which suddenly accelerated and then decelerated again to the original speed. Chicks showed a significant preference for the 'speed-change stimulus' (Exp. 2). Two additional controls (Exp. 3 and 4) showed that matching the variability of the control 'speed-constant' stimulus to that of the 'speed-change stimulus' did not alter chicks' preference for the latter. Chicks' preference was suppressed by adding two occluders on both displays, positioned along the stimulus trajectory in such a way to occlude the moment of the speed change (Exp. 5). This confirms that, for chicks to show a preference, the moments of speed change need to be visible. Finally, chicks' preference extended to stimuli displaying a direction change, another motion cue eliciting animacy perception in human observers, if the speed- and direction-profile were consistent with each other and resembled what expected for biological entities that invert their motion direction (Exp. 6). Overall, this is the first

  18. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.

    PubMed

    Théry, Clotilde; Duban, Livine; Segura, Elodie; Véron, Philippe; Lantz, Olivier; Amigorena, Sebastian

    2002-12-01

    Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that bear major histocompatibility complex (MHC) and T cell costimulatory molecules. Here, we found that injection of antigen- or peptide-bearing exosomes induced antigen-specific naïve CD4+ T cell activation in vivo. In vitro, exosomes did not induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also present in the cultures. These mature DCs could be MHC class II-negative, but had to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes promote the exchange of functional peptide-MHC complexes between DCs. Such a mechanism may increase the number of DCs bearing a particular peptide, thus amplifying the initiation of primary adaptive immune responses.

  19. Human memory T cells with a naïve phenotype accumulate with aging and respond to persistent viruses

    PubMed Central

    Pulko, Vesna; Davies, John S.; Martinez, Carmine; Lanteri, Marion C.; Busch, Michael P.; Diamond, Michael S.; Knox, Kenneth; Busch, Erin S.; Sims, Peter A.; Sinari, Shripad; Billheimer, Dean; Haddad, Elias K.; Murray, Kristy O.; Wertheimer, Anne M.; Nikolich-Žugich, Janko

    2016-01-01

    The numbers of naive T cells decrease, and the susceptibility to new microbial infections increases with age. Here, we describe a new subset of phenotypically naive human CD8+T cells that rapidly secrete multiple cytokines in response to persistent viral antigens but differ transcriptionally from memory and effector T cells. The frequency of these CD8+T cells, named T memory cells with naïve phenotype (TMNP) increased with age and following severe acute infection and inversely correlated with the residual immune capacity to respond to new infections with age. CD8+TMNP cells represent a new potential target for immunotherapy of persistent infections, and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens. PMID:27270402

  20. Modelling Miscible Fluid Displacements in Porous Media Using Karhunen-Loéve Decomposition and Artificial Neural Networks

    NASA Astrophysics Data System (ADS)

    Smaoui, Nejib; Gharbi, Ridha

    2000-11-01

    An approach to model fluid displacements in porous media that combines two powerful techniques, namely Karhunen-Loéve (KL) decomposition and artificial neural networks (ANNs) is descibed. KL decomposition known, for data compression and feature identification, is used to extract coherent structures or eigenfunctions using fluid concentration maps obtained from fine-mesh numerical simulations of miscible fluid displacements of oil by solvent in a two-dimensional vertical cross-section. Twenty KL eigenfunctions that capture 98.8% of the total energy are extracted. Corresponding data coefficients are constructed by projecting the fluid concentration maps of the numerical simulations onto the KL eigenfunctions. Processing these data coefficients through an ANN is found to be a powerful tool in predicting the fluid displacements of the fine-mesh numerical simulations without actually performing these simulations.

  1. Sudden Oak Death: Interactions of the Exotic Oomycete Phytophthora ramorum with Naïve North American Hosts

    PubMed Central

    Hayden, Katherine J.

    2012-01-01

    Ten years after a threatening and previously unknown disease of oaks and tanoaks appeared in coastal California, a significant amount of progress has been made toward the understanding of its causal agent Phytophthora ramorum and of the novel pathosystems associated with this exotic organism. However, a complete understanding of the ecology and epidemiology of this species still eludes us. In part, our inability to fully understand this organism is due to its phylogenetic, phylogeographic, phenotypic, and epidemiological complexities, all reviewed in this paper. Most lines of evidence suggest that the high degree of disease severity reported in California is not simply due to a generalized lack of resistance or tolerance in naïve hosts but also to an innate ability of the pathogen to survive in unfavorable climatic conditions and to reproduce rapidly when conditions become once again favorable. PMID:23002108

  2. Delusion of pregnancy in a drug-naïve young woman showing hyperprolactinemia and hypothyroidism: a case report.

    PubMed

    Penta, Elena; Lasalvia, Antonio

    2013-01-01

    The present article reports the case of a delusional pregnancy that developed in a drug-naïve young woman affected by paranoid schizophrenia and Hashimoto-related hyperprolactinemia. The literature in this field has addressed the phenomenon of distorted thoughts of pregnancy being elicited by physical changes due to drug-induced hyperprolactinemia. The present report gives account of a case of delusional pregnancy that developed in a schizophrenic patient with concurrent hyperprolactinemia induced by a primary endocrine disease. In this instance, however, amelioration of delusional beliefs did not ensue from hyperprolactinemia normalization, but was mostly due to cognitive restructuring of distorted thinking (together with the antipsychotic treatment). This finding confirms the importance of considering the key role of the interaction of biological, cognitive and psychological mechanisms in the construction of inaccurate beliefs and feelings about pregnancy.

  3. Prediction of cancer rescue p53 mutants in silico using Naïve Bayes learning methodology.

    PubMed

    Ramani, R Geetha; Jacob, Shomona Gracia

    2013-11-01

    This research is focussed on predicting through Naïve Bayes learning, the possible p53 rescue mutants from amino-acid substitutions at the second, third and fourth site recombination that could reinstate normal p53 activity. The Naïve Bayes probability values of the amino-acid substitutions at the respective site-wise recombination were utilized to formulate the proposed Genetic Mutant Marker Extraction (GMME) technique that could unearth the hot spot cancer, strong rescue and weak rescue mutants. The p53 mutation records depicting the amino-acid substitutions obtained by yeast assays comprising of nearly 16,700 records, available at the University of California, Machine Learning Repository, were utilized as the training dataset for the GMME technique. The proposed GMME technique revealed the hot spot cancer mutants, strong rescue and weak rescue mutants leading to the detection of probable genetic markers for Cancer prediction from the surface regions 96-289 constituting the second, third and fourth site recombinations. Thus far, computational approaches have been able to predict rescue markers at region-specific mutations (96-105, 114-123, 130-156 and 223- 232) with respect to the second site recombination for three hot spot cancer mutants only viz, P152L, R158L and G245S. The GMME technique aimed at predicting possible rescue markers for p53 mutants at the second, third and fourth site recombinations revealing novel rescue markers for fourteen hot spot cancer mutants. Moreover, the GMME technique can be extended effectively to increasing number of recombinant sites that can be efficiently utilized to predict novel rescue markers.

  4. A Highly Diverse and Functional Naïve Ubiquitin Variant Library for Generation of Intracellular Affinity Reagents.

    PubMed

    Leung, Isabel; Jarvik, Nick; Sidhu, Sachdev S

    2017-01-06

    We report the design, construction, and validation of a highly diverse phage-displayed naïve ubiquitin variant (Ubv) library. We first conducted a mutation tolerance scan of 27 residues and confirmed that 24 of these could be substituted by chemically diverse amino acids without compromising the display of Ubvs on phage. Subsequently, we constructed a library containing 6.8×10(10) unique members, in which these 24 positions were diversified with a degenerate codon that encodes for 6 aa that are prevalent in protein interaction sites. To ensure the optimal structural stability of the Ubvs, we constructed the library in a two-step process, whereby 12 positions were randomized first, and following the selection for displayed Ubvs, the resulting pool was further diversified at the other 12 positions. The resulting library was validated by conducting binding selections against a panel of 40 diverse protein antigens and was found to be as functional as a highly validated synthetic antibody library, yielding binders against 30 of the antigens. Detailed characterization of an Ubv that bound to the cell-surface receptor human epidermal growth factor receptor 3 revealed tight binding in the single-digit nanomolar range. Moreover, Ubvs that bound to two distinct sites on the intracellular adapter Grb2 could be combined to generate a potent inhibitor that functioned in cells. These results validate ubiquitin as a robust scaffold for the construction of naïve libraries that can be used to generate Ubvs that target signaling networks both outside and inside the cells.

  5. The differential effects of chronic imipramine or citalopram administration on physiological and behavioral outcomes in naïve mice.

    PubMed

    Strekalova, Tatyana; Anthony, Daniel C; Dolgov, Oleg; Anokhin, Konstantin; Kubatiev, Aslan; Steinbusch, Harry M W; Schroeter, Careen

    2013-05-15

    Tricyclics and selective serotonin reuptake inhibitors (SSRIs) are probably the most widely employed reference antidepressants in animal studies on depression. Using imipramine and citalopram, we sought to assess which drug would be more appropriate as pharmacological reference in paradigms of depression in C57BL6N mice by measuring their effect on liquid consumption, home cage activity, body weight and long-term memory in naïve animals treated with each compound at generally used dose of 15 mg/kg/day. Continuous logging of home cage movement, weekly monitoring of vertical activity in a novel cage, and body weight was recorded during four-week treatment period and for four weeks after discontinuation of the antidepressant; sucrose preference was evaluated at weekly intervals during drug administration. A novel object recognition memory test was performed in mice treated the antidepressants for two weeks. Compared to control, imipramine-treated mice displayed increased sucrose and water intake, as well as enhanced home-cage and novelty exploration activities, and reduced body weight. Imipramine also impaired learning in the object recognition task, but citalopram diminished object exploration sufficiently to invalidate the test. Citalopram-treated animals demonstrated no changes in a sucrose test and had elevated body mass. Thus basic physiological and behavioral outcomes in naïve mice were significantly altered by the chronic administration of imipramine and, to a lesser extent, citalopram. As altered variables are crucial for the evaluation of antidepressant-like effects in mice, our data suggest that, at commonly used doses, both drugs must be applied in mouse models of depression with caution.

  6. Polymorphisms of HIV RT Gene Among the ART Naïve Native Drug Exposed Rural PLHA

    PubMed Central

    Krishnan, K Mohana; Amsavathani, SK

    2012-01-01

    Background: The number of people living with human immunodeficiency virus (HIV) is increasing day by day in India. The disease has now spread from urban areas to rural areas. The proof reading of the reverse transcriptase enzyme is poor, which may lead to genetic diversity within the HIV strains, which in turn leads to problems like failure or resistance in antiretroviral treatment. This study is designed to find out the polymorphisms of the reverse transcriptase gene of HIV, after the native drug pressure among antiretroviral therapy (ART) naïve rural people living with HIV/AIDS (RPLHA). Materials and Methods: A total of 207 HIV-Reactive patients were allowed to take native drugs from the local area and were advised to attend the center for HIV after six months for a follow-up. At the time of the follow-up visit, a second blood sample was taken from 20 reactive native-drug exposed ART-naïve patients. The plasma was separated and transported at 20°C to the YRG Care Center for genotyping. Results: Among the 20 HIV-reactive samples processed for gene sequencing analysis to detect the genotypic variations, only one sample (5%) showed high-level mutational resistance variations and the predominant polymorphisms detected were V35T (100%), K122E (94.44%), and V60I (88.88%). Conclusions: The presence of drug-resistance mutations, although minimal, was important, as the drug-resistant strains could spread among the RPLHA and to their sexual partners. There was a definite need to generate a drug resistance database and the polymorphic pattern of Indian strains concern to the future clinical management of the disease, and a vaccine design to contain the disease. PMID:22754246

  7. In vitro maintenance of Schistosoma japonicum and surgical transfer from donor to naïve recipient pigs.

    PubMed

    Schou, T W; Bøgh, H O; Willingham, A L; Brück, I; Nielsen, C G; Sørensen, E; Eriksen, L; Andreassen, J

    1997-12-15

    An objective of this study was to find a culture medium and a temperature range suitable for in vitro maintenance of adult Schistosoma japonicum during surgical transplantation experiments. Adult S. japonicum were cultivated in four different media (NCTC 135, NCTC 109, RPMI 1640 and 0.85% physiological saline) supplemented with 10% heat-inactivated normal pig serum (hiNPS) at either 4 degrees C, 22-25 degrees C (room temperature) or 37 degrees C. Based on survival and morphologic evaluation, NCTC 135 at room temperature was found to be the best medium/temperature combination for maintenance of worms. An additional objective was to develop a method for transplanting adult S. japonicum from experimentally infected donor pigs to naïve recipient pigs. Six Landrace/Yorkshire crossbred pigs were used as donors to supply worms for two recipient pigs. Worms for transplantation were obtained by perfusion of the mesenteric veins of the donor pigs and maintained for a maximum of 3 h in NCTC 135 + 10% hiNPS at room temperature. A total of 148 and 132 worms were surgically transferred by way of an infusion tube into caecal veins of the two recipients. Six weeks after transplantation, 14% and 36% of the transferred worms were recovered by perfusion and subsequent manual inspection of the mesenteric veins of the two recipient pigs, respectively. The successful results suggest that surgical transfer of S. japonicum worms from donor to naïve recipient pigs may be useful for future studies on population genetics, dynamics and regulation in the pig/S. japonicum model.

  8. Selection of cholera toxin specific IgNAR single-domain antibodies from a naïve shark library.

    PubMed

    Liu, Jinny L; Anderson, George P; Delehanty, James B; Baumann, Richard; Hayhurst, Andrew; Goldman, Ellen R

    2007-03-01

    Shark immunoglobulin new antigen receptor (IgNAR, also referred to as NAR) variable domains (Vs) are single-domain antibody (sdAb) fragments containing only two hypervariable loop structures forming 3D topologies for a wide range of antigen recognition and binding. Their small size ( approximately 12kDa) and high solubility, thermostability and binding specificity make IgNARs an exceptional alternative source of engineered antibodies for sensor applications. Here, two new shark NAR V display libraries containing >10(7) unique clones from non-immunized (naïve) adult spiny dogfish (Squalus acanthias) and smooth dogfish (Mustelus canis) sharks were constructed. The most conserved consensus sequences derived from random clone sequence were compared with published nurse shark (Ginglymostoma cirratum) sequences. Cholera toxin (CT) was chosen for panning one of the naïve display libraries due to its severe pathogenicity and commercial availability. Three very similar CT binders were selected and purified soluble monomeric anti-CT sdAbs were characterized using Luminex(100) and traditional ELISA assays. These novel anti-CT sdAbs selected from our newly constructed shark NAR V sdAb library specifically bound to soluble antigen, without cross reacting with other irrelevant antigens. They also showed superior heat stability, exhibiting slow loss of activity over the course of one hour at high temperature (95 degrees C), while conventional antibodies lost all activity in the first 5-10min. The successful isolation of target specific sdAbs from one of our non-biased NAR libraries, demonstrate their ability to provide binders against an unacquainted antigen of interest.

  9. Neurocognitive Function in Acromegaly after Surgical Resection of GH-Secreting Adenoma versus Naïve Acromegaly

    PubMed Central

    Martín-Rodríguez, Juan Francisco; Madrazo-Atutxa, Ainara; Venegas-Moreno, Eva; Benito-López, Pedro; Gálvez, María Ángeles; Cano, David A.; Tinahones, Francisco J.; Torres-Vela, Elena; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso

    2013-01-01

    Patients with active untreated acromegaly show mild to moderate neurocognitive disorders that are associated to chronic exposure to growth hormone (GH) and insulin-like growth factor (IGF-I) hypersecretion. However, it is unknown whether these disorders improve after controlling GH/IGF-I hypersecretion. The aim of this study was to compare neurocognitive functions of patients who successfully underwent GH-secreting adenoma transsphenoidal surgery (cured patients) with patients with naive acromegaly. In addition, we wanted to determine the impact of different clinical and biochemical variables on neurocognitive status in patients with active disease and after long-term cure. A battery of six standardized neuropsychological tests assessed attention, memory and executive functioning. In addition, a quantitative electroencephalography with Low-Resolution Electromagnetic Tomography (LORETA) solution was performed to obtain information about the neurophysiological state of the patients. Neurocognitive data was compared to that of a healthy control group. Multiple linear regression analysis was also conducted using clinical and hormonal parameters to obtain a set of independent predictors of neurocognitive state before and after cure. Both groups of patients scored significantly poorer than the healthy controls on memory tests, especially those assessing visual and verbal recall. Patients with cured acromegaly did not obtain better cognitive measures than naïve patients. Furthermore memory deficits were associated with decreased beta activity in left medial temporal cortex in both groups of patients. Regression analysis showed longer duration of untreated acromegaly was associated with more severe neurocognitive complications, regardless of the diagnostic group, whereas GH levels at the time of assessment was related to neurocognitive outcome only in naïve patients. Longer duration of post-operative biochemical remission of acromegaly was associated with better

  10. Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China

    PubMed Central

    Li, Xu; Xu, Hongqin; Gao, Yang; Pan, Meng; Wang, Le; Gao, Pujun

    2017-01-01

    Abstract We investigated the link between diabetes mellitus (DM) and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) risk in treatment-naïve chronic hepatitis C (CHC) patients in China. To examine the association between DM and HCC, we conducted a case–control study of 300 Chinese CHC patients with HCC, compared to an age- and sex-matched control group of 517 CHC patients not diagnosed with HCC. We found that DM was more prevalent in the HCC patient group (18.7%) than in the CHC-only patient group (10.8%). We conducted logistic regression analyses adjusting for demographics features and other HCC risk factors and found that DM increased the risk of HCC development nearly 2-fold [adjusted odds ratio (AOR), 95% confidence interval (95% CI), 1.80 (1.17–2.75)]. Meanwhile, the proportion of HCC patients and CHC-only patients with liver cirrhosis were 79.3% and 46.2%, respectively, yielding an AOR of 4.62 (95% CI, 3.31–6.46). Multivariate analyses comparing the risk of HCV-related HCC development in DM patients with and without liver cirrhosis revealed that the estimated AOR (95% CI) for those with liver cirrhosis was 5.60 (2.25–13.96). However, the HCC risk decreased significantly with a later age of diabetes onset (AOR [95% CI], 0.94 [0.89–0.99]). DM was associated with an increased risk for HCC development in treatment-naïve CHC patients in China. Furthermore, liver cirrhosis and an early DM diagnoses further increased the risks of HCC development in patients diagnosed with both CHC and DM. PMID:28353605

  11. Normalization with Corresponding Naïve Tissue Minimizes Bias Caused by Commercial Reverse Transcription Kits on Quantitative Real-Time PCR Results

    PubMed Central

    Garcia-Bardon, Andreas

    2016-01-01

    Real-time reverse transcription polymerase chain reaction (PCR) is the gold standard for expression analysis. Designed to improve reproducibility and sensitivity, commercial kits are commonly used for the critical step of cDNA synthesis. The present study was designed to determine the impact of these kits. mRNA from mouse brains were pooled to create serial dilutions ranging from 0.0625 μg to 2 μg, which were transcribed into cDNA using four different commercial reverse-transcription kits. Next, we transcribed mRNA from brain tissue after acute brain injury and naïve mice into cDNA for qPCR. Depending on tested genes, some kits failed to show linear results in dilution series and revealed strong variations in cDNA yield. Absolute expression data in naïve and trauma settings varied substantially between these kits. Normalization with a housekeeping gene failed to reduce kit-dependent variations, whereas normalization eliminated differences when naïve samples from the same region were used. The study shows strong evidence that choice of commercial cDNA synthesis kit has a major impact on PCR results and, consequently, on comparability between studies. Additionally, it provides a solution to overcome this limitation by normalization with data from naïve samples. This simple step helps to compare mRNA expression data between different studies and groups. PMID:27898720

  12. Endothelial tyrosine kinase receptor B prevents VE-cadherin cleavage and protects against atherosclerotic lesion development in ApoE−/− mice

    PubMed Central

    Jiang, Hong; Huang, Shuhong; Li, Xinyun; Li, Xian; Huang, Shanying; Zhang, Yun; Chen, Zhe-Yu

    2015-01-01

    Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF). In addition to its nervous system functions, TrkB is also expressed in the aortic endothelium. However, the effects of endothelial TrkB signaling on atherosclerosis remained unknown. Immunofluorescence analysis revealed that TrkB expression is downregulated in the endothelium of atherosclerotic lesions from ApoE−/− mice compared with the atheroma-free aorta of WT mice. Endothelial TrkB knockdown led to increased lesion size, lipid deposition and inflammatory responses in the atherosclerotic lesions of the ApoE−/− mice compared with the control mice. Mechanistic studies showed that TrkB activation prevented VE-cadherin shedding by enhancing the interaction between vascular endothelial protein tyrosine phosphatase and VE-cadherin, maintaining VE-cadherin in a dephosphorylated state. Our data demonstrate that TrkB is an endothelial injury-response molecule in atherogenesis. Endothelial BDNF/TrkB signaling reduces VE-cadherin shedding and protects against atherosclerotic lesion development in ApoE−/− mice. PMID:26431274

  13. Transcriptome analysis of Aspergillus flavus reveals veA-dependent regulation of secondary metabolite gene clusters, including the novel aflavarin cluster

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The global regulatory veA gene governs development and secondary metabolism in numerous fungal species, including Aspergillus flavus. This is especially relevant since A. flavus infects crops of agricultural importance worldwide, contaminating them with potent mycotoxins. The most well-known are afl...

  14. Factors associated with acute-phase response of bisphosphonate-naïve or pretreated women with osteoporosis receiving an intravenous first dose of zoledronate or ibandronate.

    PubMed

    Popp, A W; Senn, R; Curkovic, I; Senn, C; Buffat, H; Popp, P F; Lippuner, K

    2017-03-15

    A first intravenous dose of bisphosphonates may be associated with an acute-phase response (APR). In bisphosphonate-naïve women with postmenopausal osteoporosis, the characteristics and frequency of APR may differ by compound. Prior bisphosphonate exposure was predictive of APR risk and severity.

  15. Interferon-α-induced CD100 on naïve CD8(+) T cells enhances antiviral responses to hepatitis C infection through CD72 signal transduction.

    PubMed

    Li, Bing Jie; He, Yu; Zhang, Ying; Guo, Yong Hong; Zhou, Yun; Zhang, Pei Xin; Wang, Wei; Zhao, Jie Ru; Li, Jin Ge; Zuo, Wei Ze; Fan, Chao; Jia, Zhan Sheng

    2017-02-01

    Objectives We investigated the effects of CD100 on naïve CD8(+) T cells during hepatitis C virus (HCV) infection after interferon-α (IFN-α) therapy to clarify the mechanism underlying the effect of IFN-α in enhancing the antiviral response. Methods The CD100 molecules on subsets of CD8(+) T cells were analysed with flow cytometry. The effects of CD100-overexpressing naïve CD8(+) T cells were determined with ELISAs and an MTT cytotoxicity assay. The role of CD100-CD72 signal transduction was analysed with a neutralization and transwell assays. Results HCV infection reduced CD100 expression on CD8(+) T cells, whereas IFN-α treatment significantly increased CD100 expression on naïve CD8(+) T cells. The increased CD100 interacted with the CD72 receptor and enhanced PBMC cytokine secretion (IFN-γ and tumour necrosis factor-α) and cytotoxicity. Conclusions IFN-α-induced CD100 on naïve CD8(+) T cells promotes PBMC cytokine secretion and cytotoxicity through CD100-CD72 signalling during HCV infection.

  16. Having Students Create Short Video Clips to Help Transition from Naïve Conceptions about Mechanics to True Newtonian Physics

    ERIC Educational Resources Information Center

    Corten-Gualtieri, Pascale; Ritter, Christian; Plumat, Jim; Keunings, Roland; Lebrun, Marcel; Raucent, Benoit

    2016-01-01

    Most students enter their first university physics course with a system of beliefs and intuitions which are often inconsistent with the Newtonian frame of reference. This article presents an experiment of collaborative learning aiming at helping first-year students in an engineering programme to transition from their naïve intuition about dynamics…

  17. Mutations in the Reverse Transcriptase and Protease Genes of Human Immunodeficiency Virus-1 from Antiretroviral Naïve and Treated Pediatric Patients

    PubMed Central

    Bure, Dinesh; Makhdoomi, Muzamil A.; Lodha, Rakesh; Prakash, Somi Sankaran; Kumar, Rajesh; Parray, Hilal A.; Singh, Ravinder; Kabra, Sushil K.; Luthra, Kalpana

    2015-01-01

    The success of highly active antiretroviral therapy (HAART) is challenged by the emergence of resistance-associated mutations in human immunodeficiency virus-1 (HIV-1). In this study, resistance associated mutations in the reverse transcriptase (RT) and protease (PR) genes in antiretroviral therapy (ART) naïve and treated HIV-1 infected pediatric patients from North India were evaluated. Genotyping was successfully performed in 46 patients (30 ART naive and 16 treated) for the RT gene and in 53 patients (27 ART naive and 26 treated) for PR gene and mutations were identified using Stanford HIV Drug Resistance Database. A major drug resistant mutation in RT gene, L74I (NRTI), and two such mutations, K101E and G190A (NNRTI), were observed in two ART naïve patients, while M184V was detected in two ART treated patients. Overall, major resistance associated mutations in RT gene were observed in nine (30%) and seven (36%) of ART naïve and treated children respectively. Minor mutations were identified in PR gene in five children. Few non-clade C viral strains (≈30%) were detected, although subtype C was most predominant. The screening of ART naïve children for mutations in HIV-1 RT and protease genes, before and after initiation of ART is desirable for drug efficacy and good prognosis. PMID:25674767

  18. Mutations in the reverse transcriptase and protease genes of human immunodeficiency virus-1 from antiretroviral naïve and treated pediatric patients.

    PubMed

    Bure, Dinesh; Makhdoomi, Muzamil A; Lodha, Rakesh; Prakash, Somi Sankaran; Kumar, Rajesh; Parray, Hilal A; Singh, Ravinder; Kabra, Sushil K; Luthra, Kalpana

    2015-02-10

    The success of highly active antiretroviral therapy (HAART) is challenged by the emergence of resistance-associated mutations in human immunodeficiency virus-1 (HIV-1). In this study, resistance associated mutations in the reverse transcriptase (RT) and protease (PR) genes in antiretroviral therapy (ART) naïve and treated HIV-1 infected pediatric patients from North India were evaluated. Genotyping was successfully performed in 46 patients (30 ART naive and 16 treated) for the RT gene and in 53 patients (27 ART naive and 26 treated) for PR gene and mutations were identified using Stanford HIV Drug Resistance Database. A major drug resistant mutation in RT gene, L74I (NRTI), and two such mutations, K101E and G190A (NNRTI), were observed in two ART naïve patients, while M184V was detected in two ART treated patients. Overall, major resistance associated mutations in RT gene were observed in nine (30%) and seven (36%) of ART naïve and treated children respectively. Minor mutations were identified in PR gene in five children. Few non-clade C viral strains (≈30%) were detected, although subtype C was most predominant. The screening of ART naïve children for mutations in HIV-1 RT and protease genes, before and after initiation of ART is desirable for drug efficacy and good prognosis.

  19. A Study of the Education Professions Development Act Training Programs for Higher Education Personnel, Volume III: The EPDA V-E Training Programs. Final Report.

    ERIC Educational Resources Information Center

    Boyle, E.; Carlson, K.

    Volume III of a study of the Education Professions Development Act (EPDA) training programs for higher education personnel presents the second of a three-faceted approach to assess current needs. This document reviews the task of profiling EPDA V-E training programs to produce a small-scale information system. Section one reviews the profiling…

  20. Gene profiling approach to establish the molecular bases for partial versus full activation of naïve CD8 T lymphocytes.

    PubMed

    Verdeil, Gréory; Puthier, Denis; Nguyen, Catherine; Schmitt-Verhulst, Anne-Marie; Auphan-Anezin, Nathalie

    2002-12-01

    When initial antigen encounter involves optimal antigenic and costimulatory stimuli, naïve CD8 T cells undergo a developmental program that leads to their activation, expansion and acquisition of effector functions (including production of IL-2, IFNgamma and expression of cytolytic effector molecules). A subset of the activated CD8 T cells thrives as long-lived memory cells. Encounter of tissue-associated, and in particular tumor-associated antigen, may often be suboptimal in terms of antigenicity and costimulation, however. We previously developed a model of naïve CD8 T cells from transgenic mice expressing an alloreactive TCR for which a mutant alloantigen behaved as a partial agonist, inducing only some of the effector functions induced by the native alloantigen. To ascertain the molecular bases for the establishment of divergent fates within the same naïve CD8 T cells, we have used cDNA microarrays to monitor sequential gene expression patterns in conditions of full or partial response of these naïve CD8 T cells. Of the 5000 different genes monitored on the array, 18% showed changes in expression in activated versus naïve CD8 T cells, independent of whether stimulation was with full or partial agonist. These included antigen-induced upregulated as well as downregulated genes. Clusters of genes that were differentially expressed were also identified, being either (i) weakly versus strongly, or (ii) transiently versus stably expressed in response to partial and full agonist, respectively. They included (i) genes encoding costimulatory molecules and (ii) genes controlling cytolytic function, cytokine production, and chemokines. Therefore, the cDNA microarray approach was a sensitive tool to provide an exhaustive picture of T cell activation as it could discriminate quantitative, qualitative and dynamic differences in mRNA expression profiles between fully or partially activated T cells.

  1. Tenofovir has inferior efficacy in adefovir-experienced chronic hepatitis B patients compared to nucleos(t)ide-naïve patients

    PubMed Central

    Chung, Goh Eun; Cho, Eun Ju; Lee, Jeong-Hoon; Yoo, Jeong-ju; Lee, Minjong; Cho, Yuri; Lee, Dong Hyeon; Kim, Hwi Young; Yu, Su Jong; Kim, Yoon Jun; Yoon, Jung-Hwan; Zoulim, Fabien

    2017-01-01

    Background/Aims A recent study reported that entecavir had inferior efficacy in nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients compared to NA-naïve patients. We sought to compare the efficacy of tenofovir disoproxil fumarate (TDF) in NA-experienced and NA-naïve CHB patients. Methods We retrospectively enrolled 252 consecutive patients who had a serum hepatitis B virus (HBV) DNA level greater than 2,000 IU/mL at the initiation of TDF treatment and who received TDF for at least 6 months. Complete virologic suppression (CVS) was defined as undetectable serum HBV DNA. We generated a multivariate Cox proportional-hazard model to examine predictive factors that were independently associated with time to CVS. Results The mean age of patients was 48.2 years, and the cohort included 181 NA-naïve patients and 71 NA-experienced patients. The median duration of TDF treatment was 14.4 (interquartile range, 9.5-17.8) months. A total of 167 (92.3%) of 181 NA-naïve patients achieved CVS, and 60 (84.5%) of 71 NA-exposed patients achieved CVS. Forty-nine (89.1%) of 55 patients who previously took an NA aside from adefovir and 11 (68.8%) of 16 adefovir-experienced patients achieved CVS. In multivariable analysis, previous adefovir exposure significantly influenced time to CVS (hazard ratio, 0.37; 95% confidence interval, 0.19-0.72; P=0.003), after adjusting for HBeAg positivity, baseline HBV DNA level and cirrhosis. Conclusions Tenofovir had inferior efficacy in adefovir-experienced CHB patients compared to NA-naïve patients. The response of patients with previous adefovir exposure to TDF monotherapy should be monitored closely. PMID:28190329

  2. Naïve subset develops the most important alloreactive response among human CD4+ T lymphocytes in human leukocyte antigen-identical related setting.

    PubMed

    Chérel, Mathilde; Choufi, Bachra; Trauet, Jacques; Cracco, Pascale; Dessaint, Jean-Paul; Yakoub-Agha, Ibrahim; Labalette, Myriam

    2014-06-01

    In longitudinal clinical studies, receiving a high percentage of allogeneic donor-derived CD4(+) CCR7(+) T cells, which include naïve and central memory subsets have been correlated with increased incidence and severity of acute GVHD. Whether naïve and central memory CD4(+) T-cell subsets contribute more or equally to alloimmune responses are still unclear in human. The aim of this study was to investigate in vitro the alloreactive response of purified naïve, central memory, and effector memory CD4(+) T-cell subsets in HLA identical setting. By coculturing monocyte-derived dendritic cells and purified CD4(+) T-cell subsets, from healthy HLA-identical male and female sibling pairs, we found that naïve CD4(+) CCR7(+) CD45RA(+) T cells developed the highest proliferative response upon stimulation by minor histocompatibility antigens and were progressively driven to produce high levels of interferon-γ, tumor necrosis factor, and interleukin-6. Comparatively, the central memory CD4(+) CCR7(+) CD45RA(neg) subset proliferated to a lower extent and produced very low amounts of pro-inflammatory cytokines while the CCR7(neg) effector memory CD4(+) subset was unresponsive. This study demonstrates the superior capacity of naïve CD4(+) T cells to mount a primary alloreactive response as compared to central memory T cells. Their proliferative response associated with a pro-inflammatory differentiation makes them potentially acute GVHD inducers. These in vitro results in line with what we have observed in clinical studies and may also lend support to approaches of partial selective T-cell depletion for GVHD prevention.

  3. Historical Incidence of Spontaneous Lesions in Kidneys from Naïve Swine Utilized In Interventional Renal Denervation Studies.

    PubMed

    Rouselle, Serge D; Dillon, Krista N; Rousselle-Sabiac, Theo H; Brady, Dane A; Tunev, Stefan; Tellez, Armando

    2016-08-01

    The use of preclinical animal models is integral to the safety assessment, pathogenesis research, and testing of diagnostic technologies and therapeutic interventions. With inherent similarity to human anatomy and physiology, various porcine models have been the preferred preclinical model in some research areas such as medical devices, wound healing, and skin therapies. The porcine model has been the cornerstone for interventional cardiology for the evaluation and development of this catheter-based renal denervation (RDN) therapy. The porcine model provides similar vascular access and renal neurovascular anatomy to humans. In these preclinical studies, the downstream kidneys from treated arteries are assessed for possible histopathological changes in the vessel dependent territories. In assessing renal safety following RDN, it becomes critical to distinguish treatment-related changes from pre-existing background pathologies. The incidence of background pathological changes in porcine kidneys has not been previously established in normal clinically healthy. Samples from the cranial, middle, and caudal portion of 331 naïve kidneys from 181 swine were processed histologically to slides and evaluated microscopically. The most commonly encountered spontaneous changes were chronic pyelonephritis found in nearly half of the evaluated naïve kidneys (∼40 %; score 1 = 91 %, score 2 = 8.4 %, score 3 = 0.76 %) followed by chronic interstitial inflammation in 9.7 % of the kidneys (score 1 = 90.6 %, score 2 = 9.4 %). Interestingly, there were a few rare spontaneous vascular changes that could potentially affect data interpretation in interventional and toxicology studies: arteritis and arteriolar dissection. The presence of pelvic cysts was a common occurrence (6.3 %) in the kidney. The domestic swine is a widely used preclinical species in interventional research, namely in the emerging field of transcatheter renal denervation. This

  4. Transmitted Drug Resistance Mutations in Antiretroviral-Naïve Injection Drug Users with Chronic HIV-1 Infection in Iran

    PubMed Central

    Memarnejadian, Arash; Menbari, Shahoo; Vahabpour, Rouhollah; Aghasadeghi, Mohammad Reza; Mostafavi, Ehsan; Abdi, Mohammad

    2015-01-01

    The growing incidence and transmission of drug resistant HIV-1 strains due to widespread use of antiretroviral therapy (ART) can jeopardize the success of first-line ART. While there is a known moderate prevalence of transmitted drug resistance (TDR) among newly infected Iranians, no data exist about the rate of these primary resistance mutations among the ART-naïve, chronically infected individuals who are, in fact, the main candidates for ART initiation. To address this issue, we collected blood samples from 40 ART-naïve injection drug-users (IDUs) with chronic HIV-1 infection (seroconversion time ranging from 2 to 9 years) living in Sanandaj, Iran, followed by sequencing of the protease and reverse-transcriptase regions from their HIV-1 genome. Phylogenetic analyses of the sequenced regions revealed that all samples were CRF35_AD. Transmitted resistance mutations were interpreted as surveillance drug-resistant mutations (SDRMs) based on the world health organization (WHO) algorithm. The frequency of SDRMs to any class of antiretroviral drugs was 15%, which included mutations to nucleoside reverse transcriptase inhibitors (NRTIs, 10%), with M41L and M184V as the most common (5%), and non-nucleoside reverse transcriptase inhibitors (NNRTIs, 5%), with K103N as the only detected mutation (5%). Although not in the WHO SDRMs list, several minor protease inhibitor resistant mutations listed in the International Antiviral Society-USA panel were identified, of which M36I, H69K, L89M/V/I (each one 100%) and K20R/T (92.5%) can be considered as polymorphic signatures for CRF35_AD.The relatively high rate of TDR mutations in our study raises concerns about the risk of treatment failure in chronically infected IDUs of Sanandaj city. These results suggest that routine resistance testing should be considered before the therapy initiation in this area. Additional surveillance studies are required to generalize this deduction to other cities of Iran. PMID:25962088

  5. Efficacy of a preservative-free formulation of fixed-combination bimatoprost and timolol (Ganfort PF) in treatment-naïve patients vs previously treated patients

    PubMed Central

    Cordeiro, M Francesca; Goldberg, Ivan; Schiffman, Rhett; Bernstein, Paula; Bejanian, Marina

    2015-01-01

    Purpose To evaluate, using subgroup analysis, the effect of treatment status on the intraocular pressure (IOP)-lowering efficacy of a preservative-free formulation of fixed-combination bimatoprost 0.03%/timolol 0.5% (FCBT PF). Methods A primary, multicenter, randomized, double-masked, 12-week study compared the efficacy and safety of FCBT PF with preserved FCBT (Ganfort®) in 561 patients diagnosed with glaucoma or ocular hypertension. For this analysis, eligible patients were treatment-naïve or had inadequate IOP lowering and underwent a washout of previous treatment. IOP (8 am, 10 am, and 4 pm) was measured at baseline and weeks 2, 6, and 12. Subgroup analysis of the FCBT PF arm assessed changes in average eye IOP from baseline in treatment-naïve vs previously treated patients. To evaluate the effect of treatment status at baseline (treatment-naïve vs previously treated) on IOP reduction in the FCBT PF treatment group, an analysis of covariance model was used with treatment status and investigator as fixed effects, and baseline average eye IOP, age, glaucoma diagnosis, and baseline average eye corneal thickness as covariates. P-values and the 95% confidence intervals were determined using the model. Results In the FCBT PF arm, IOP mean changes from baseline ranged from −8.7 mmHg to −9.8 mmHg in treatment-naïve patients (N=50), compared with −7.3 mmHg to −8.5 mmHg in previously treated patients (N=228). Baseline IOP, age, glaucoma diagnosis, and corneal thickness significantly affected IOP reduction in the FCBT PF group. Adjusting for these covariates, FCBT PF had a greater IOP-lowering effect (0.8–1.7 mmHg) in treatment-naïve patients than previously treated patients, which was statistically significant (P≤0.05) at seven of nine time points. Conclusion In this subgroup analysis, FCBT PF reduced IOP more effectively in treatment-naïve than in previously treated patients possibly due, in part, to altered responsiveness or tachyphylaxis that has

  6. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors.

    PubMed

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras.

  7. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors

    PubMed Central

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras. PMID:26287611

  8. Multiple signal propagation at the tropopause of the Venusian atmosphere: new insights from the Radio Science Experiment (VeRa) onboard Venus Express

    NASA Astrophysics Data System (ADS)

    Herrmann, Maren; Oschlisniok, Janusz; Remus, Stefan; Tellmann, Silvia; Häusler, Bernd; Pätzold, Martin

    2016-10-01

    The rapid change of the refractive index over a short altitude range in a planetary atmosphere can lead to multi-path effects when sounding the atmosphere with radio waves. The Radio Science Experiment (VeRa) [1,2] onboard Venus Express sounded the Venusian atmosphere from 90 km downward to 40 km altitude[3,4]. More than 800 profiles of temperature, pressure and neutral number density could be retrieved which cover almost all local times and latitudes. A specially developed analysis method based on the VeRa open loop receiving technique deciphers the multi-path effect and identifies an inversion layer near the tropopause at an altitude of about 60km. This layer is of particular interest - it separates the stratified troposphere from the highly variable mesosphere and can be a likely location for the formation of gravity waves [5]. The new retrieval method shows an inversion layer up to 15 K colder than commonly thought. Local time and latitude dependence including the influence of the spacecraft trajectory on this effect will be discussed. These results will contribute to a consistent picture of the Venus' thermal atmosphere structure and therefore help to improve atmospheric models.[1] Häusler, B. et al: 'Radio science investigations by VeRa onboard the Venus Express spacecraft' Planetary and Space Science 54, 2006[2] Häusler, B. et al, 'Venus Atmospheric, Ionospheric, Surface and Interplanetery Radio-Wave Propagation Studies with the VeRa Radio Science experiment' Eur. Space Agencys, Spec. Publ., ESA SP 1295, 2007[3] Pätzold, M. et al: 'The structure of Venus' middle atmosphere and ionosphere', Nature 450, 2007[4] Tellmann, S. et al : 'Structure of the Venus neutral atmosphere as observed by the Radio Science experiment VeRa on Venus Express', Journal of Geophysical Research 114, 2009[5] Tellmann, S. et al: 'Small-scale temperature fluctuations seen by the VeRa Radio Science Experiment on Venus Express' Icarus 221, 2012.

  9. DoD Value Engineering Conference Report. Value Engineering (VE) - A Tool that Benefits Line Management Held at Leesburg, Virginia on 1-2 November 1984. Part 2. Plenary Session,

    DTIC Science & Technology

    1985-06-01

    3734 AYERS, Chesley X A Professional Engineer DCASMA Detroit DCRO-GTCS 477 Michigan Avenue Detroit, MI 48226 (313)226-5199/AV 346-5199 BANASH , Robert C...Angeles, CA 90009 AV 833-0734 MALLARD, Jack X B VE Analyst HQ AFCMD/EPL Kirtland AFB, NM 87117 AV 244-4834 or 9627 MARK , Melvin X E VE Officer U.S Army...ELSEN, Mark A. No A VE Program Manager Mmear Hill Air Force Base -. Mmear Hill AFB, UT 84056 (801)777-7481/AV 458-7481 11-228

  10. Using symbolic knowledge in the UMLS to disambiguate words in small datasets with a naïve Bayes classifier.

    PubMed

    Leroy, Gondy; Rindflesch, Thomas C

    2004-01-01

    Current approaches to word sense disambiguation use and combine various machine-learning techniques. Most refer to characteristics of the ambiguous word and surrounding words and are based on hundreds of examples. Unfortunately, developing large training sets is time-consuming. We investigate the use of symbolic knowledge to augment machine-learning techniques for small datasets. UMLS semantic types assigned to concepts found in the sentence and relationships between these semantic types form the knowledge base. A naïve Bayes classifier was trained for 15 words with 100 examples for each. The most frequent sense of a word served as the baseline. The effect of increasingly accurate symbolic knowledge was evaluated in eight experimental conditions. Performance was measured by accuracy based on 10-fold cross-validation. The best condition used only the semantic types of the words in the sentence. Accuracy was then on average 10% higher than the baseline; however, it varied from 8% deterioration to 29% improvement. In a follow-up evaluation, we noted a trend that the best disambiguation was found for words that were the least troublesome to the human evaluators.

  11. Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene.

    PubMed

    Oxford, Alexandra E; Jorcyk, Cheryl L; Oxford, Julia Thom

    2016-01-01

    Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare disease that results in dysfunction of the autonomic nervous system, which controls involuntary processes such as breathing rate and body temperature. In infants, this can result in respiratory distress, feeding and swallowing difficulties, and hyperthermic episodes. Individuals may sweat excessively when body temperature is not elevated. Additionally, individuals have reduced ability to feel pain and may lose reflexes such as the corneal reflex that normally causes one to blink, and the patellar reflex resulting in the knee-jerk. STWS usually results in infant mortality, yet some STWS patients survive into early adulthood. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomal-recessive pattern. Most LIFR mutations resulting in STWS cause instability of the mRNA due to frameshift mutations leading to premature stop codons, which prevent the formation of LIFR protein. STWS is managed on a symptomatic basis as no treatment is currently available.

  12. Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses.

    PubMed

    Adam, Jacqueline; Wuillemin, Natascha; Watkins, Stephan; Jamin, Heidi; Eriksson, Klara K; Villiger, Peter; Fontana, Stefano; Pichler, Werner J; Yerly, Daniel

    2014-01-01

    Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele ('altered self-allele') and create the potential for robust T cell responses.

  13. Assessing sandy beach macrofaunal patterns along large-scale environmental gradients: A Fuzzy Naïve Bayes approach

    NASA Astrophysics Data System (ADS)

    Bozzeda, Fabio; Zangrilli, Maria Paola; Defeo, Omar

    2016-06-01

    A Fuzzy Naïve Bayes (FNB) classifier was developed to assess large-scale variations in abundance, species richness and diversity of the macrofauna inhabiting fifteen Uruguayan sandy beaches affected by the effects of beach morphodynamics and the estuarine gradient generated by Rio de la Plata. Information from six beaches was used to estimate FNB parameters, while abiotic data of the remaining nine beaches were used to forecast abundance, species richness and diversity. FNB simulations reproduced the general increasing trend of target variables from inner estuarine reflective beaches to marine dissipative ones. The FNB model also identified a threshold value of salinity range beyond which diversity markedly increased towards marine beaches. Salinity range is suggested as an ecological master factor governing distributional patterns in sandy beach macrofauna. However, the model: 1) underestimated abundance and species richness at the innermost estuarine beach, with the lowest salinity, and 2) overestimated species richness in marine beaches with a reflective morphodynamic state, which is strongly linked to low abundance, species richness and diversity. Therefore, future modeling efforts should be refined by giving a dissimilar weigh to the gradients defined by estuarine (estuarine beaches) and morphodynamic (marine beaches) variables, which could improve predictions of target variables. Our modeling approach could be applied to a wide spectrum of issues, ranging from basic ecology to social-ecological systems. This approach seems relevant, given the current challenge to develop predictive methodologies to assess the simultaneous and nonlinear effects of anthropogenic and natural impacts in coastal ecosystems.

  14. Karhunen-Loève treatment to remove noise and facilitate data analysis in sensing, spectroscopy and other applications.

    PubMed

    Zaharov, V V; Farahi, R H; Snyder, P J; Davison, B H; Passian, A

    2014-11-21

    Resolving weak spectral variations in the dynamic response of materials that are either dominated or excited by stochastic processes remains a challenge. Responses that are thermal in origin are particularly relevant examples due to the delocalized nature of heat. Despite its inherent properties in dealing with stochastic processes, the Karhunen-Loève expansion has not been fully exploited in measurement of systems that are driven solely by random forces or can exhibit large thermally driven random fluctuations. Here, we present experimental results and analysis of the archetypes (a) the resonant excitation and transient response of an atomic force microscope probe by the ambient random fluctuations and nanoscale photothermal sample response, and (b) the photothermally scattered photons in pump-probe spectroscopy. In each case, the dynamic process is represented as an infinite series with random coefficients to obtain pertinent frequency shifts and spectral peaks and demonstrate spectral enhancement for a set of compounds including the spectrally complex biomass. The considered cases find important applications in nanoscale material characterization, biosensing, and spectral identification of biological and chemical agents.

  15. Utilizing computerized entertainment education in the development of decision aids for lower literate and naïve computer users.

    PubMed

    Jibaja-Weiss, Maria L; Volk, Robert J

    2007-01-01

    Decision aids have been developed by using various delivery methods, including interactive computer programs. Such programs, however, still rely heavily on written information, health and digital literacy, and reading ease. We describe an approach to overcome these potential barriers for low-literate, underserved populations by making design considerations for poor readers and naïve computer users and by using concepts from entertainment education to engage the user and to contextualize the content for the user. The system design goals are to make the program both didactic and entertaining and the navigation and graphical user interface as simple as possible. One entertainment education strategy, the soap opera, is linked seamlessly to interactive learning modules to enhance the content of the soap opera episodes. The edutainment decision aid model (EDAM) guides developers through the design process. Although designing patient decision aids that are educational, entertaining, and targeted toward poor readers and those with limited computer skills is a complex task, it is a promising strategy for aiding this population. Entertainment education may be a highly effective approach to promoting informed decision making for patients with low health literacy.

  16. Persisting primitive reflexes in medication-naïve girls with attention-deficit and hyperactivity disorder

    PubMed Central

    Konicarova, Jana; Bob, Petr; Raboch, Jiri

    2013-01-01

    Background and objectives Recent and historical findings suggest that later-developed functions during brain ontogenesis related to higher levels of cognitive and motor integration tend to replace the older, more primitive, ones, and the persistence of the older functions may be linked to specific neuropsychiatric disorders. Currently, there is growing evidence to suggest that persisting primitive reflexes may be related to developmental and neurodegenerative disorders. Preliminary data also suggest that persisting primitive reflexes may be specifically linked to attention-deficit and hyperactivity disorder (ADHD). Methods In the study reported here, we tested to what extent the persisting primitive asymmetric tonic neck reflex and symmetric tonic neck reflex are related to ADHD symptoms measured by Conners’ Parent Questionnaire in 35 medication-naïve girls of school age (8–11 years) with ADHD. The results were compared with those of a control group of 30 girls of the same age. Results This study showed that persisting primitive reflexes are closely linked to ADHD symptoms. Conclusion The data suggest that ADHD symptoms may be linked to more primitive neural mechanisms interfering with higher brain functions due to insufficiently developed cognitive and motor integration. PMID:24092983

  17. Insulin-like growth factor-1 and progression of motor symptoms in early, drug-naïve Parkinson's disease.

    PubMed

    Picillo, Marina; Erro, Roberto; Santangelo, Gabriella; Pivonello, Rosario; Longo, Katia; Pivonello, Claudia; Vitale, Carmine; Amboni, Marianna; Moccia, Marcello; Colao, Annamaria; Barone, Paolo; Pellecchia, Maria Teresa

    2013-07-01

    Much pre-clinical evidence show that insulin-like growth factor 1 (IGF-1) provides protection against loss of dopaminergic neurons. Recently, IGF-1 has been proposed as a possible biomarker for early diagnosis of Parkinson's disease (PD). We aimed to assess the relationship between serum IGF-1 levels and progression of motor symptoms in a cohort of drug-naïve PD patients. Serum IGF-1 was measured at baseline in 37 early, drug-naive PD patients; subsequently, patients were evaluated "on drug" by means of UPDRS-III, UPDRS dopa-resistant score and dopaminergic score at 12, 18 and 24 month follow-up. Repeated measures ANOVA was used both to evaluate progression of motor scores within time and differences between serum IGF-1 quartiles, age at onset and motor phenotype. Patients at the highest IGF-1 quartile were found to have significantly higher UPDRS-III (p < 0.001) and dopaminergic score (p < 0.001), as compared to patients at other quartiles. Mean serum IGF-1 level was moderately increased in PD as compared to healthy controls (p < 0.011). IGF-1 levels are related to those symptoms predominantly responsive to dopaminergic treatment. This is the first study to demonstrate a relationship between serum IGF-1 and progression of motor symptoms in the early stage of disease.

  18. Integrating Entropy-Based Naïve Bayes and GIS for Spatial Evaluation of Flood Hazard.

    PubMed

    Liu, Rui; Chen, Yun; Wu, Jianping; Gao, Lei; Barrett, Damian; Xu, Tingbao; Li, Xiaojuan; Li, Linyi; Huang, Chang; Yu, Jia

    2016-09-24

    Regional flood risk caused by intensive rainfall under extreme climate conditions has increasingly attracted global attention. Mapping and evaluation of flood hazard are vital parts in flood risk assessment. This study develops an integrated framework for estimating spatial likelihood of flood hazard by coupling weighted naïve Bayes (WNB), geographic information system, and remote sensing. The north part of Fitzroy River Basin in Queensland, Australia, was selected as a case study site. The environmental indices, including extreme rainfall, evapotranspiration, net-water index, soil water retention, elevation, slope, drainage proximity, and density, were generated from spatial data representing climate, soil, vegetation, hydrology, and topography. These indices were weighted using the statistics-based entropy method. The weighted indices were input into the WNB-based model to delineate a regional flood risk map that indicates the likelihood of flood occurrence. The resultant map was validated by the maximum inundation extent extracted from moderate resolution imaging spectroradiometer (MODIS) imagery. The evaluation results, including mapping and evaluation of the distribution of flood hazard, are helpful in guiding flood inundation disaster responses for the region. The novel approach presented consists of weighted grid data, image-based sampling and validation, cell-by-cell probability inferring and spatial mapping. It is superior to an existing spatial naive Bayes (NB) method for regional flood hazard assessment. It can also be extended to other likelihood-related environmental hazard studies.

  19. A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation

    PubMed Central

    Fogar, Paola; Padoan, Andrea; Nante, Giovanni; Pelloso, Michela; Moz, Stefania; Frigo, Anna Chiara; Groppa, Francesca; Bozzato, Dania; Tiso, Enrico; Gnatta, Elisa; Denas, Gentian; Padayattil Jose, Seena; Padrini, Roberto; Basso, Daniela; Plebani, Mario

    2015-01-01

    Genotype-guided warfarin dosing have been proposed to improve patient’s management. This study is aimed to determine whether a CYP2C9- VKORC1- CYP4F2-based pharmacogenetic algorithm is superior to a standard, clinically adopted, pharmacodynamic method. Two-hundred naïve patients with non-valvular atrial fibrillation were randomized to trial arms and 180 completed the study. No significant differences were found in the number of out-of-range INRs (INR<2.0 or >3.0) (p = 0.79) and in the mean percentage of time spent in the therapeutic range (TTR) after 19 days in the pharmacogenetic (51.9%) and in the control arm (53.2%, p = 0.71). The percentage of time spent at INR>4.0 was significantly lower in the pharmacogenetic (0.7%) than in the control arm (1.8%) (p = 0.02). Genotype-guided warfarin dosing is not superior in overall anticoagulation control when compared to accurate clinical standard of care. Trial Registration ClinicalTrials.gov NCT01178034 PMID:26710337

  20. Pressure Distribution over a Wing and Tail Rib of a VE-7 and of a TS Airplane in Flight

    NASA Technical Reports Server (NTRS)

    Crowley, J W , Jr

    1928-01-01

    This investigation was made to determine the pressure distribution over a rib of the wing and over a rib of the horizontal tail surface of an airplane in flight and to obtain information as to the time correlation of the loads occurring on these ribs. Two airplanes, VE-7 and TS, were selected in order to obtain the information for a thin and a thick wing section. In each case the pressure distribution was recorded for the full range of angle of attack in level flight and throughout violent maneuvers. The results show: (a) that the present rib load specifications in use by the Army Air Corps and the Bureau of Aeronautics, Navy Department, are in fair agreement with the loads actually occurring in flight, but could be slightly improved; (b) that there appears to be no definite sequence in which wing and tail surface ribs reach their respective maximum loads in different maneuvers; (c) that in accelerated flight, at air speeds less than or equal to 60 per cent of the maximum speed, the accelerations measured agree very closely with the theoretically possible maximum accelerations. In maneuvers at higher air speeds the observed accelerations were smaller than those theoretically possible. (author)

  1. An Automatic Multidocument Text Summarization Approach Based on Naïve Bayesian Classifier Using Timestamp Strategy

    PubMed Central

    Ramanujam, Nedunchelian; Kaliappan, Manivannan

    2016-01-01

    Nowadays, automatic multidocument text summarization systems can successfully retrieve the summary sentences from the input documents. But, it has many limitations such as inaccurate extraction to essential sentences, low coverage, poor coherence among the sentences, and redundancy. This paper introduces a new concept of timestamp approach with Naïve Bayesian Classification approach for multidocument text summarization. The timestamp provides the summary an ordered look, which achieves the coherent looking summary. It extracts the more relevant information from the multiple documents. Here, scoring strategy is also used to calculate the score for the words to obtain the word frequency. The higher linguistic quality is estimated in terms of readability and comprehensibility. In order to show the efficiency of the proposed method, this paper presents the comparison between the proposed methods with the existing MEAD algorithm. The timestamp procedure is also applied on the MEAD algorithm and the results are examined with the proposed method. The results show that the proposed method results in lesser time than the existing MEAD algorithm to execute the summarization process. Moreover, the proposed method results in better precision, recall, and F-score than the existing clustering with lexical chaining approach. PMID:27034971

  2. Successful sulfonylurea treatment of an insulin-naïve neonate with diabetes mellitus due to a KCNJ11 mutation.

    PubMed

    Wambach, Jennifer A; Marshall, Bess A; Koster, Joseph C; White, Neil H; Nichols, Colin G

    2010-06-01

    Activating mutations in the K(ATP)-channel cause neonatal diabetes mellitus (NDM), and patients have been safely transitioned from insulin to sulfonylureas. We report a male infant with permanent NDM (PNDM), born to a PNDM mother. Blood glucose began to rise on day of life (DOL) 2, and sulfonylurea (glyburide) therapy was initiated on DOL 5. Glucose was subsequently well controlled and normal at 3 months. A K(ATP) mutation (R201H; KCNJ11) was detected in the infant, the mother, and 6-yr-old sister with PNDM; both were also subsequently transitioned off insulin onto glyburide. To our knowledge, this is the youngest NDM patient to receive oral glyburide and, importantly, the only one deliberately initiated on sulfonylureas. Strikingly, the current dose (0.017 mg/kg/d) is below the reported therapeutic range and approximately 75-fold lower than doses required by the affected sister and mother. Pancreatic insulin disappears in an animal model of K(ATP)-induced NDM, unless glycemia is well controlled, thus, a dramatically lower glyburide requirement in the infant may reflect preserved insulin content because of early sulfonylurea intervention. Safe and effective initiation of glyburide in an insulin-naïve neonatal patient with K(ATP)-dependent PNDM argues for early detection and sulfonylurea intervention.

  3. Regulation of naïve fetal T-cell migration by the chemokines Exodus-2 and Exodus-3.

    PubMed

    Christopherson, K; Brahmi, Z; Hromas, R

    1999-08-03

    We and other workers have recently isolated three novel CC chemokines termed Exodus-1/LARC/Mip-3alpha, Exodus-2/6Ckine/SLC/TCA4, and Exodus-3/Mip-3beta/CKbeta11/ELC. These chemokines share an amino terminal Asp-Cys-Cys-Leu sequence, unique among all chemokines. They also selectively regulate migration of adult T cells. Indeed, there is evidence that Exodus-2 and -3 are critical for adult T-cell adhesion to high endothelial venules in lymph nodes, a rate-limiting step for T-cell trafficking through nodal tissue. Less is known of the factors controlling migration of naïve human fetal T cells. We tested whether these chemokines could regulate chemotaxis in cord blood T-cell populations, and compared that efficacy with normal peripheral blood adult T cells. The findings indicated that naive CD45RA+ cord blood T-cell migration is stimulated by Exodus-2 and -3, and CD4+ cord blood T cells are attracted preferentially by Exodus-2 or -3 as compared with CD8+. Exodus-2 and -3 are likely to be critical in regulating the flux of naive CD4 + fetal T-cell population of secondary lymphoid tissue.

  4. Recommendations for patient engagement in guideline development panels: A qualitative focus group study of guideline-naïve patients

    PubMed Central

    Mullins, C. Daniel; Gronseth, Gary S.; Gagliardi, Anna R.

    2017-01-01

    Background Patient and consumer engagement in clinical practice guideline development is internationally advocated, but limited research explores mechanisms for successful engagement. Objective To investigate the perspectives of potential patient/consumer guideline representatives on topics pertaining to engagement including guideline development group composition and barriers to and facilitators of engagement. Setting and participants Participants were guideline-naïve volunteers for programs designed to link community members to academic research with diverse ages, gender, race, and degrees of experience interacting with health care professionals. Methods Three focus groups and one key informant interview were conducted and analyzed using a qualitative descriptive approach. Results Participants recommended small, diverse guideline development groups engaging multiple patient/consumer stakeholders with no prior relationships with each other or professional panel members. No consensus was achieved on the ideal balance of patient/consumer and professional stakeholders. Pre-meeting reading/training and an identified contact person were described as keys to successful early engagement; skilled facilitators, understandable speech and language, and established mechanisms for soliciting patient opinions were suggested to enhance engagement at meetings. Conclusions Most suggestions for effective patient/consumer engagement in guidelines require forethought and planning but little additional expense, making these strategies easily accessible to guideline developers desiring to achieve more meaningful patient and consumer engagement. PMID:28319201

  5. The Structure of the Venus Neutral Atmosphere from the Radio Science Experiment VeRa on Venus Express

    NASA Astrophysics Data System (ADS)

    Tellmann, S. A.; Häusler, B.; Pätzold, M.; Bird, M. K.; Tyler, G. L.

    2007-12-01

    The Venus Express Radio Science Experiment VeRa is sounding the Venus neutral atmosphere and ionosphere using the spacecraft radio subsystem in the oneway radio link mode. An Ultrastable Oscillator (USO) provides a high quality onboard frequency reference source for the derivation of electron density profiles in the ionosphere and profiles of pressure, temperature and neutral number density of the neutral atmosphere. The measurement configuration allows an altitude resolution of only a few hundred metres from the cloud deck at about 40 km to approximately 100 km. Three occultation seasons could be covered in the first two years of the Venus Express mission resulting in a data set of about 140 profiles of the neutral atmosphere. The polar orbit of Venus Express provides the opportunity to study the atmosphere at all planetocentric latitudes under varying illumination conditions. Special attention will be given to day-night variations of the thermal structure and the temperature distribution at high polar latitudes on both hemispheres ("cold collar region") and signal absorption effects caused by the H2SO4 vapour.

  6. Neural correlates of mindful self-awareness in mindfulness meditators and meditation-naïve subjects revisited.

    PubMed

    Lutz, J; Brühl, A B; Scheerer, H; Jäncke, L; Herwig, U

    2016-09-01

    Mindful self-awareness is central to mindfulness meditation and plays a key role in its salutary effects. It has been related to decreased activation in cortical midline structures (CMS) and amygdala, and increased activation in somatosensory regions. However, findings in untrained individuals are contradictory, and scarce in experienced meditators. Using fMRI, we investigated experienced mindfulness meditators (LTM, n=21, average 4652 practice-hours) and matched meditation-naïve participants (MNP, n=19) during short periods of mindful self-awareness (FEEL) and self-referential thinking (THINK). We report somatosensory activations and decreases in CMS during FEEL for both groups, but significantly stronger decreases in prefrontal CMS in LTM. LTM further showed decreases in language-related and amygdala regions, but the latter was not significantly different between groups. Overall, higher activations in amygdala and mid-line regions during FEEL were related to levels of depressiveness. Neural patterns of mindful self-awareness emerge already in MNP but more pronounced in LTM. Specifically, meditation training might reduce self-reference and verbalization during mindful awareness. We further corroborate the suggested link between mindfulness and healthy self-related functions on the neural level. Longitudinal studies need to corroborate these findings.

  7. Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

    PubMed

    Suzuki, Seiichiro; Karayama, Masato; Inui, Naoki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Kuroishi, Shigeki; Matsuda, Hiroyuki; Yokomura, Koshi; Koshimizu, Naoki; Toyoshima, Mikio; Imokawa, Shiro; Asada, Kazuhiro; Masuda, Masafumi; Yamada, Takashi; Watanabe, Hiroshi; Suda, Takafumi

    2016-08-01

    Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer.

  8. When the expectations from a message will not be realized: Naïve theories can eliminate expectation–congruent judgments via correction

    PubMed Central

    Handley, Ian M.; Albarracín, Dolores; Brown, Rick D.; Li, Hong; Kumkale, Ece C.; Kumkale, G. Tarcan

    2013-01-01

    Research typically reveals that individuals like an object more when a persuasive message convinces them that this object is pleasant. In this paper, two experiments were conducted to understand the influence of such message-induced affective-expectations on judgments of experienced affect following direct encounter with an alcohol type of drink. As predicted, before trying the drink, recipients of the positive-expectation message had more positive expectations than recipients of the negative-expectation message. After drinking, participants judged the beverage to elicit affect congruent with message-induced expectations to the extent they did not endorse a naïve theory that their affective expectations congruently influence their experienced affect. In contrast, after drinking, the effect of the message disappeared when participants did endorse this naïve theory. Moderation of these effects, as well as theoretical and practical implications, are addressed. PMID:24619304

  9. When the expectations from a message will not be realized: Naïve theories can eliminate expectation-congruent judgments via correction.

    PubMed

    Handley, Ian M; Albarracín, Dolores; Brown, Rick D; Li, Hong; Kumkale, Ece C; Kumkale, G Tarcan

    2009-07-01

    Research typically reveals that individuals like an object more when a persuasive message convinces them that this object is pleasant. In this paper, two experiments were conducted to understand the influence of such message-induced affective-expectations on judgments of experienced affect following direct encounter with an alcohol type of drink. As predicted, before trying the drink, recipients of the positive-expectation message had more positive expectations than recipients of the negative-expectation message. After drinking, participants judged the beverage to elicit affect congruent with message-induced expectations to the extent they did not endorse a naïve theory that their affective expectations congruently influence their experienced affect. In contrast, after drinking, the effect of the message disappeared when participants did endorse this naïve theory. Moderation of these effects, as well as theoretical and practical implications, are addressed.

  10. Maraviroc Clinical Test (MCT) as an alternative tool to decide CCR5-antagonists prescription in naïve HIV-infected patients.

    PubMed

    Genebat, Miguel; de Pablo-Bernal, Rebeca S; Pulido, Ildefonso; Jiménez-Mejías, Manuel E; Martínez, Onofre; Pacheco, Yolanda M; Raffi-El-Idrissi Benhia, Mohammed; Abad, María Antonia; Ruiz-Mateos, Ezequiel; Leal, Manuel

    2015-09-01

    Our aim was to analyze the virological response to a combined antiretroviral therapy started after Maraviroc Clinical Test (MCT) in naïve HIV-infected patients. Forty-one patients were exposed to MCT, based on an 8-day MVC monotherapy. If undetectability or a viral load reduction >1 log10 HIV-RNA copies/ml was achieved, a MVC-containing cART was prescribed. Forty patients showed a positive MCT; undetectability after 48weeks on cART was achieved in 34/41 (82.9%) patients. The result of MCT was compared with a genotypic tropism method and with Trofile®, showing 10.7% and 18.75% discordance rates, respectively. MCT is a reliable tool to decide CCR5-antagonists prescription, also in the naïve scenario where most patients show a virological response to MVC independently the tropism result reported by genotypic or phenotypic methods.

  11. Performance analysis of junctionless double gate VeSFET considering the effects of thermal variation - An explicit 2D analytical model

    NASA Astrophysics Data System (ADS)

    Chaudhary, Tarun; Khanna, Gargi

    2017-03-01

    The purpose of this paper is to explore junctionless double gate vertical slit field effect transistor (JLDG VeSFET) with reduced short channel effects and to develop an analytical threshold voltage model for the device considering the impact of thermal variations for the very first time. The model has been derived by solving 2D Poisson's equation and the effects of variation in temperature on various electrical parameters of the device such as Rout, drain current, mobility, subthreshold slope and DIBL has been studied and described in the paper. The model provides a deep physical insight of the device behavior and is also very helpful in contributing to the design space exploration for JLDG VeSFET. The proposed model is verified with simulative analysis at different radii of the device and it has been observed that there is a good agreement between the analytical model and simulation results.

  12. Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase.

    PubMed

    Zimran, Ari; Gonzalez-Rodriguez, Derlis Emilio; Abrahamov, Aya; Cooper, Peter A; Varughese, Sheeba; Giraldo, Pilar; Petakov, Milan; Tan, Ee Shien; Chertkoff, Raul

    2016-10-20

    Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n=10) or switched from imiglucerase (n=5). Patients received taliglucerase alfa 30 or 60U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60U/kg, respectively, reduced mean spleen volume (-18.6 multiples of normal [MN] and -26.0MN), liver volume (-0.8MN and -0.9MN), and chitotriosidase activity (-72.7% and -84.4%), and increased mean Hb concentration (+2.0g/dL and +2.3g/dL) and mean platelet count (+38,200/mm(3) and +138,250/mm(3)) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.

  13. Sevoflurane prevents lipopolysaccharide-induced barrier dysfunction in human lung microvascular endothelial cells: Rho-mediated alterations of VE-cadherin.

    PubMed

    Huang, Yiran; Tan, Qindong; Chen, Rui; Cao, Biao; Li, Wenhong

    Acute lung injury (ALI) mainly occurs as increased permeability of lung tissue and pleural effusion. Inhaled anesthetic sevoflurane has been demonstrated to alleviate lung permeability by upregulating junction proteins after ischemia-reperfusion. However, the exact mechanisms of its protective effect on reperfusion injury remain elusive. The aim of this study was to assess possible preconditioning with sevoflurane in an in vitro model of lipopolysaccharide (LPS)-induced barrier dysfunction in human lung microvascular endothelial cells (HMVEC-Ls). In this study, HMVEC-Ls were exposed to minimum alveolar concentration of sevoflurane for 2 h. LPS significantly increased the permeability of HMVEC-L. Moreover, the distribution of junction protein, vascular endothelial (VE)-cadherin, in cell-cell junction area and the total expression in HMVEC-Ls were significantly decreased by LPS treatment. However, the abnormal distribution and decreased expression of VE-cadherin and hyperpermeability of HMVEC-Ls were significantly reversed by pretreatment with sevoflurane. Furthermore, LPS-induced activation of the RhoA/ROCK signaling pathway was significantly inhibited with sevoflurane. Such activation, abnormal distribution and decreased expression of VE-cadherin and hyperpermeability of HMVEC-Ls were significantly inhibited with sevoflurane pretreatment or knockdown of RhoA or ROCK-2. In conclusion, sevoflurane prevented LPS-induced rupture of HMVEC-L monolayers by suppressing the RhoA/ROCK-mediated VE-cadherin signaling pathway. Our results may explain, at least in part, some beneficial effects of sevoflurane on pulmonary dysfunction such as ischemia-reperfusion injury.

  14. Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8+ T cells in aged mice

    PubMed Central

    Quinn, Kylie M.; Zaloumis, Sophie G.; Cukalac, Tania; Kan, Wan-Ting; Sng, Xavier Y. X.; Mirams, Michiko; Watson, Katherine A.; Doherty, Peter C.; Thomas, Paul G.; Handel, Andreas; La Gruta, Nicole L.

    2016-01-01

    In advanced age, decreased CD8+ cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8+ T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8+ T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8+ T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8+ T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8+ T cells expressing markers of heightened self-recognition are selectively retained, but not clonally expanded, during aging. PMID:26787864

  15. Prevalence of Hypertension and Its Associated Risk Factors among 34,111 HAART Naïve HIV-Infected Adults in Dar es Salaam, Tanzania

    PubMed Central

    Aveika, Akum; Spiegelman, Donna; Hawkins, Claudia; Armstrong, Catharina; Liu, Enju; Okuma, James; Chalamila, Guerino; Kaaya, Sylvia; Mugusi, Ferdinand; Fawzi, Wafaie

    2016-01-01

    Background. Elevated blood pressure has been reported among treatment naïve HIV-infected patients. We investigated prevalence of hypertension and its associated risk factors in a HAART naïve HIV-infected population in Dar es Salaam, Tanzania. Methods. A cross-sectional analysis was conducted among HAART naïve HIV-infected patients. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg. Overweight and obesity were defined as body mass index (BMI) between 25.0–29.9 kg/m2 and ≥30 kg/m2, respectively. We used relative risks to examine factors associated with hypertension. Results. Prevalence of hypertension was found to be 12.5%. After adjusting for possible confounders, risk of hypertension was 10% more in male than female patients. Patients aged ≥50 years had more than 2-fold increased risk for hypertension compared to 30–39-years-old patients. Overweight and obesity were associated with 51% and 94% increased risk for hypertension compared to normal weight patients. Low CD4+ T-cell count, advanced WHO clinical disease stage, and history of TB were associated with 10%, 42%, and 14% decreased risk for hypertension. Conclusions. Older age, male gender, and overweight/obesity were associated with hypertension. Immune suppression and history of TB were associated with lower risk for hypertension. HIV treatment programs should screen and manage hypertension even in HAART naïve individuals. PMID:27872756

  16. Long-lasting stem cell-like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination.

    PubMed

    Fuertes Marraco, Silvia A; Soneson, Charlotte; Cagnon, Laurène; Gannon, Philippe O; Allard, Mathilde; Abed Maillard, Samia; Montandon, Nicole; Rufer, Nathalie; Waldvogel, Sophie; Delorenzi, Mauro; Speiser, Daniel E

    2015-04-08

    Efficient and persisting immune memory is essential for long-term protection from infectious and malignant diseases. The yellow fever (YF) vaccine is a live attenuated virus that mediates lifelong protection, with recent studies showing that the CD8(+) T cell response is particularly robust. Yet, limited data exist regarding the long-term CD8(+) T cell response, with no studies beyond 5 years after vaccination. We investigated 41 vaccinees, spanning 0.27 to 35 years after vaccination. YF-specific CD8(+) T cells were readily detected in almost all donors (38 of 41), with frequencies decreasing with time. As previously described, effector cells dominated the response early after vaccination. We detected a population of naïve-like YF-specific CD8(+) T cells that was stably maintained for more than 25 years and was capable of self-renewal ex vivo. In-depth analyses of markers and genome-wide mRNA profiling showed that naïve-like YF-specific CD8(+) T cells in vaccinees (i) were distinct from genuine naïve cells in unvaccinated donors, (ii) resembled the recently described stem cell-like memory subset (Tscm), and (iii) among all differentiated subsets, had profiles closest to naïve cells. Our findings reveal that CD8(+) Tscm are efficiently induced by a vaccine in humans, persist for decades, and preserve a naïveness-like profile. These data support YF vaccination as an optimal mechanistic model for the study of long-lasting memory CD8(+) T cells in humans.

  17. Distinct Kinetics of Effector CD8+ Cytotoxic T Cells after Infection with Trypanosoma cruzi in Naïve or Vaccinated Mice

    PubMed Central

    Tzelepis, Fanny; de Alencar, Bruna C. G.; Penido, Marcus L. O.; Gazzinelli, Ricardo T.; Persechini, Pedro M.; Rodrigues, Mauricio M.

    2006-01-01

    The kinetics of effector CD8+-T-cell responses to specific Trypanosoma cruzi epitopes was investigated after challenge. Our results suggest that the delayed kinetics differs from that observed in other microbial infections and facilitates the establishment of the disease in naïve mice. In contrast, in vaccinated mice, the swift CD8+-T-cell response helps host survival after challenge. PMID:16552083

  18. Changes in endothelial connexin 43 expression inversely correlate with microvessel permeability and VE-cadherin expression in endotoxin-challenged lungs

    PubMed Central

    Kandasamy, Kathirvel; Escue, Rachel; Manna, Jayeeta; Adebiyi, Adebowale

    2015-01-01

    Endothelial barrier restoration reverses microvessel hyperpermeability and facilitates recovery from lung injury. Because inhibiting connexin 43 (Cx43)-dependent interendothelial communication blunts hyperpermeability in single microvessels, we determined whether endothelial Cx43 levels correlate with changes in microvessel permeability during recovery from lung injury. Toward this, bacterial endotoxin was instilled intratracheally into rat lungs, and at different durations postinstillation the lungs were isolated and blood perfused. Microvessel Cx43 expression was quantified by in situ immunofluorescence and microvessel permeability via a fluorescence method. To supplement the immunofluorescence data, protein levels were determined by immunoblots of lung tissue from endotoxin-instilled rats. Immunofluorescence and immunoblot together revealed that both Cx43 expression and microvessel permeability increased above baseline within a few hours after endotoxin instillation but declined progressively over the next few days. On day 5 postendotoxin, microvessel Cx43 declined to negligible levels, resulting in complete absence of intermicrovessel communication determined by photolytic uncaging of Ca2+. However, by day 14, both Cx43 expression and microvessel permeability returned to baseline levels. In contrast to Cx43, expression of microvessel vascular endothelial (VE)-cadherin, a critical determinant of vascular barrier integrity, exhibited an inverse trend by initially declining below baseline and then returning to baseline at a longer duration. Knockdown of vascular Cx43 by tail vein injection of Cx43 shRNA increased VE-cadherin expression, suggesting that reduction in Cx43 levels may modulate VE-cadherin levels in lung microvessels. Together, the data suggest that endotoxin challenge initiates interrelated changes in microvessel Cx43, VE-cadherin, and microvessel permeability, with changes in Cx43 temporally leading the other responses. PMID:26163513

  19. Effector, memory and naïve CD8+ T cells in peripheral blood and pleural effusion from lung adenocarcinoma patients.

    PubMed

    Prado-Garcia, Heriberto; Aguilar-Cazares, Dolores; Flores-Vergara, Hector; Mandoki, Juan Jose; Lopez-Gonzalez, Jose Sullivan

    2005-03-01

    The proportions of naïve, memory and effector CD8+ T cells in peripheral blood and pleural effusion from lung adenocarcinoma patients were studied. CD8+ T subsets were identified by using a combination of the following antibodies: anti-CD45RA, anti-CD45RO, anti-CD27 and anti-CD28, as well as antibodies to other markers. Fas-positive cells were determined in each CD8+ T subset. Also, the intracellular cytokine patterns of CD4+ and CD8+ lymphocytes from pleural effusion were analysed. In naïve, memory and effector CD8+ T subsets no significant differences were observed in peripheral blood between healthy donors and cancer patients. In contrast, a high proportion of cells with memory phenotype (CD45RA-CD45RO+CD27+CD28+) and a low proportion of cells with effector phenotype (CD45RA+CD45RO-CD27-CD28-) were found in pleural effusion with respect to peripheral blood (P<0.001). The altered proportions of CD8+ T subsets in pleural effusion were not mediated by type 2 cytokines produced by CD4+ or CD8+ lymphocytes. In the effector CD8+ T subset, from peripheral blood as well as from pleural effusion, a low percentage of perforin-expressing cells was observed compared to granzyme A-expressing cells. Additionally, a high percentage of naïve CD8+ T cells expressing Fas was found. Our data suggest that: (i) terminal-differentiation process of CD8+ T cells is blocked, and (ii) early Fas-expression in CD8+ T cells, which was reflected even in peripheral blood, may lead to apoptosis of naïve cells when they reach the effector stage. All these processes may contribute to the inadequate antitumour immune response found in lung carcinoma patients.

  20. Changes in endothelial connexin 43 expression inversely correlate with microvessel permeability and VE-cadherin expression in endotoxin-challenged lungs.

    PubMed

    Kandasamy, Kathirvel; Escue, Rachel; Manna, Jayeeta; Adebiyi, Adebowale; Parthasarathi, Kaushik

    2015-09-15

    Endothelial barrier restoration reverses microvessel hyperpermeability and facilitates recovery from lung injury. Because inhibiting connexin 43 (Cx43)-dependent interendothelial communication blunts hyperpermeability in single microvessels, we determined whether endothelial Cx43 levels correlate with changes in microvessel permeability during recovery from lung injury. Toward this, bacterial endotoxin was instilled intratracheally into rat lungs, and at different durations postinstillation the lungs were isolated and blood perfused. Microvessel Cx43 expression was quantified by in situ immunofluorescence and microvessel permeability via a fluorescence method. To supplement the immunofluorescence data, protein levels were determined by immunoblots of lung tissue from endotoxin-instilled rats. Immunofluorescence and immunoblot together revealed that both Cx43 expression and microvessel permeability increased above baseline within a few hours after endotoxin instillation but declined progressively over the next few days. On day 5 postendotoxin, microvessel Cx43 declined to negligible levels, resulting in complete absence of intermicrovessel communication determined by photolytic uncaging of Ca(2+). However, by day 14, both Cx43 expression and microvessel permeability returned to baseline levels. In contrast to Cx43, expression of microvessel vascular endothelial (VE)-cadherin, a critical determinant of vascular barrier integrity, exhibited an inverse trend by initially declining below baseline and then returning to baseline at a longer duration. Knockdown of vascular Cx43 by tail vein injection of Cx43 shRNA increased VE-cadherin expression, suggesting that reduction in Cx43 levels may modulate VE-cadherin levels in lung microvessels. Together, the data suggest that endotoxin challenge initiates interrelated changes in microvessel Cx43, VE-cadherin, and microvessel permeability, with changes in Cx43 temporally leading the other responses.

  1. Behavioural response of sexually naïve and experienced male rats to the smell of 6-methyl-5-hepten-2-one and female rat faeces.

    PubMed

    Nielsen, Birte L; Jerôme, Nathalie; Saint-Albin, Audrey; Rampin, Olivier; Maurin, Yves

    2013-08-15

    Sexually experienced male rats display penile erections when exposed to faeces from mammalian females in oestrus (Rampin et al., Behav Brain Res, 172:169, 2006), suggesting that specific odours indicate female receptiveness across species. However, it is unknown to what extent the sexual response observed results from an odorous conditioning acquired during sexual experience. We tested the behavioural response of male Brown Norway rats both when sexually naïve and experienced to four odours, including oestrous rat faeces and 6-methyl-5-hepten-2-one (methylheptenone; a molecule found in higher concentrations during oestrus in female rats, foxes and horses). Odour had a significant effect on the sexual response of the naïve rats, with oestrus faeces provoking significantly more erections than herb odour, and with methylheptenone and di-oestrus faeces being intermediate. This indicates that sexually naïve male rats have an unconditioned ability to detect oestrous mediated via odour. After gaining sexual experience, the response to methylheptenone, di- and oestrus faeces was significantly higher than that observed with herb odour. These results strongly suggest that methylheptenone is part of the odorous bouquet of oestrus and contributes to the olfactory determination of female receptiveness.

  2. Polysomnographic Assessment of Sleep Comorbidities in Drug-Naïve Narcolepsy-Spectrum Disorders--A Japanese Cross-Sectional Study.

    PubMed

    Sasai-Sakuma, Taeko; Kinoshita, Akihiko; Inoue, Yuichi

    2015-01-01

    This is a large cross-sectional study which aimed to investigate comorbidity rate, degree of sleep-related breathing disorder, polysomnigraphically diagnosible rapid eye movement sleep behavior disorder/rapid eye movement sleep without atonia and periodic limb movements during sleep in Japanese drug-naïve patients with narcolepsy-spectrum disorders. A total of 158 consecutive drug naïve patients with narcolepsy with cataplexy, 295 patients with narcolepsy without cataplexy and 395 patients with idiopathic hypersomnia without long sleep time were enrolled. From retrospectively analyzed data of nocturnal polysomnography and multiple sleep latency test, higher rates of periodic limb movements during sleep (> = 15 h(-1)) (10.2%) and polysomnographically diagnosable rapid eye movement sleep behavior disorder (1.9%) were found in patients with narcolepsy with cataplexy. They had more severe periodic limb movements during sleep especially during rapid eye movement sleep and higher percentages of rapid eye movement sleep without atonia than the other two patient groups. In the present large sample study, Japanese drug naïve patients with narcolepsy with cataplexy showed the highest comorbidity rates of periodic limb movements during sleep, polysomnographically diagnosable rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia among those with the other narcolepsy-spectrum disorders; the rates were lower than those for Western patients.

  3. Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length

    PubMed Central

    Wallace, Diana L; Bérard, Marion; Soares, Maria V D; Oldham, Janine; Cook, Joanne E; Akbar, Arne N; Tough, David F; Beverley, Peter C L

    2006-01-01

    Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL-15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up-regulation of telomerase and the maintenance of telomere length. These data show that IL-7 and IL-15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset-dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T-cell pool. PMID:17005004

  4. AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin

    PubMed Central

    Cai, Junting; Suber, Tomeka

    2017-01-01

    Maintenance of pulmonary endothelial barrier integrity is important for reducing severity of lung injury. Lysophosphatidic acid (LPA) regulates cell motility, cytoskeletal rearrangement, and cell growth. Knockdown of LPA receptor 1 (LPA1) has been shown to mitigate lung injury and pulmonary fibrosis. AM966, an LPA1 antagonist exhibiting an antifibrotic property, has been considered to be a future antifibrotic medicine. Here, we report an unexpected effect of AM966, which increases lung endothelial barrier permeability. An electric cell-substrate sensing (ECIS) system was used to measure permeability in human lung microvascular endothelial cells (HLMVECs). AM966 decreased the transendothelial electrical resistance (TEER) value immediately in a dose-dependent manner. VE-cadherin and f-actin double immunostaining reveals that AM966 increases stress fibers and gap formation between endothelial cells. AM966 induced phosphorylation of myosin light chain (MLC) through activation of RhoA/Rho kinase pathway. Unlike LPA treatment, AM966 had no effect on phosphorylation of extracellular signal-regulated kinases (Erk). Further, in LPA1 silencing cells, we observed that AM966-increased lung endothelial permeability as well as phosphorylation of VE-cadherin and focal adhesion kinase (FAK) were attenuated. This study reveals that AM966 induces lung endothelial barrier dysfunction, which is regulated by LPA1-mediated activation of RhoA/MLC and phosphorylation of VE-cadherin. PMID:28348461

  5. Peripheral Tissue Homing Receptor Control of Naïve, Effector, and Memory CD8 T Cell Localization in Lymphoid and Non-Lymphoid Tissues

    PubMed Central

    Brinkman, C. Colin; Peske, J. David; Engelhard, Victor Henry

    2013-01-01

    T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues. PMID:23966998

  6. Systemizers Are Better Code-Breakers: Self-Reported Systemizing Predicts Code-Breaking Performance in Expert Hackers and Naïve Participants.

    PubMed

    Harvey, India; Bolgan, Samuela; Mosca, Daniel; McLean, Colin; Rusconi, Elena

    2016-01-01

    Studies on hacking have typically focused on motivational aspects and general personality traits of the individuals who engage in hacking; little systematic research has been conducted on predispositions that may be associated not only with the choice to pursue a hacking career but also with performance in either naïve or expert populations. Here, we test the hypotheses that two traits that are typically enhanced in autism spectrum disorders-attention to detail and systemizing-may be positively related to both the choice of pursuing a career in information security and skilled performance in a prototypical hacking task (i.e., crypto-analysis or code-breaking). A group of naïve participants and of ethical hackers completed the Autism Spectrum Quotient, including an attention to detail scale, and the Systemizing Quotient (Baron-Cohen et al., 2001, 2003). They were also tested with behavioral tasks involving code-breaking and a control task involving security X-ray image interpretation. Hackers reported significantly higher systemizing and attention to detail than non-hackers. We found a positive relation between self-reported systemizing (but not attention to detail) and code-breaking skills in both hackers and non-hackers, whereas attention to detail (but not systemizing) was related with performance in the X-ray screening task in both groups, as previously reported with naïve participants (Rusconi et al., 2015). We discuss the theoretical and translational implications of our findings.

  7. Systemizers Are Better Code-Breakers: Self-Reported Systemizing Predicts Code-Breaking Performance in Expert Hackers and Naïve Participants

    PubMed Central

    Harvey, India; Bolgan, Samuela; Mosca, Daniel; McLean, Colin; Rusconi, Elena

    2016-01-01

    Studies on hacking have typically focused on motivational aspects and general personality traits of the individuals who engage in hacking; little systematic research has been conducted on predispositions that may be associated not only with the choice to pursue a hacking career but also with performance in either naïve or expert populations. Here, we test the hypotheses that two traits that are typically enhanced in autism spectrum disorders—attention to detail and systemizing—may be positively related to both the choice of pursuing a career in information security and skilled performance in a prototypical hacking task (i.e., crypto-analysis or code-breaking). A group of naïve participants and of ethical hackers completed the Autism Spectrum Quotient, including an attention to detail scale, and the Systemizing Quotient (Baron-Cohen et al., 2001, 2003). They were also tested with behavioral tasks involving code-breaking and a control task involving security X-ray image interpretation. Hackers reported significantly higher systemizing and attention to detail than non-hackers. We found a positive relation between self-reported systemizing (but not attention to detail) and code-breaking skills in both hackers and non-hackers, whereas attention to detail (but not systemizing) was related with performance in the X-ray screening task in both groups, as previously reported with naïve participants (Rusconi et al., 2015). We discuss the theoretical and translational implications of our findings. PMID:27242491

  8. A longitudinal event-related potential study of selective serotonin reuptake inhibitor therapy in treatment-naïve pediatric obsessive compulsive disorder patients.

    PubMed

    Yamamuro, Kazuhiko; Ota, Toyosaku; Iida, Junzo; Kishimoto, Naoko; Nakanishi, Yoko; Matsuura, Hiroki; Uratani, Mitsuhiro; Okazaki, Kosuke; Kishimoto, Toshifumi

    2016-11-30

    Obsessive-compulsive disorder (OCD) is characterized by obsessive thoughts and/or compulsive behaviors, involving specific cognition and/or information processing disorders. Event-related potentials (ERPs) are commonly used as physiological measures of cognitive function. In conscious patients, ERPs are easily and non-invasively measured. Previous ERP studies have revealed differences between OCD patients and control subjects. Whether ERPs reflect the pharmacological effects of OCD treatment, particularly in treatment-naïve pediatric patients, remains unknown. We used the Child's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) to evaluate the symptomatic severity of 12 treatment-naïve pediatric OCD patients. Comparisons were made with 12 age-, sex-, and intelligence-matched controls. The P300 and mismatch negativity (MMN) components were measured during an auditory odd-ball task at baseline in both groups and after the 3-year serotonin reuptake inhibitor (SSRI) treatment in OCD patients. Compared with controls, P300 amplitudes were smaller n the OCD group at Fz, Cz, Pz, C3, and C4. After SSRI treatment, P300 amplitudes increased partly at Fz and C4 in association with symptomatic improvements. We found a significant positive correlation between P300 amplitude in C4 and CY-BOCS scores. Our findings confirm the utility of SSRIs in pediatric OCD, and suggest the utility of ERPs for evaluating pharmacological effects in treatment-naïve pediatric OCD patients.

  9. Identification and characterization of Penicillium citrinum VeA and LaeA as global regulators for ML-236B production.

    PubMed

    Baba, Satoshi; Kinoshita, Hiroshi; Nihira, Takuya

    2012-02-01

    In filamentous fungi, production of multiple secondary metabolites is controlled by so-called global regulators. In this study, two genes encoding homologs of VeA and LaeA, representative fungal global regulators, were identified in ML-236B-producing Penicillium citrinum. Disruption of VeA and/or LaeA and complementation clearly demonstrated that both of them played critical roles in ML-236B production by controlling the expression of mlcR, the pathway-specific activator gene for ML-236B biosynthesis. Moreover, sequence analysis revealed that laeA in a mutant strain producing high levels of ML-236B (strain S-1567) possessed a single nucleotide alteration, which resulted in 15 surplus amino acids at the carboxyl terminus of LaeA compared to the LaeA in the wild-type strain (strain SANK18767). Introduction of the mutated laeA into SANK18767 proved that the extended carboxyl region plays a crucial role in the higher production of ML-236B. These results indicated that VeA and LaeA dominantly control the biosynthesis of ML-236B, and the enhanced production in the strain S-1567 is attributable to the mutation in laeA.

  10. Plasmodium vivax infection induces expansion of activated naïve/memory T cells and differentiation into a central memory profile.

    PubMed

    Silva, Ana Luiza Teixeira; Lacerda, Marcus Vinícius; Fujiwara, Ricardo Toshio; Bueno, Lilian Lacerda; Braga, Erika Martins

    2013-11-01

    Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we characterized the profile of circulating naïve and memory (including central and effector) CD4⁺ T cells responses of individuals naturally infected by Plasmodium vivax. In the current study, we demonstrated that acute P. vivax infection induces a significant increase in the absolute number of both naïve and memory cells, which were responsible for the production of anti-inflammatory (IL-10) and pro-inflammatory (IFN-γ) cytokines. Finally, we described the profile of memory cell subtypes (T(CM)-CD45RO(high)CCR7⁺ and T(EM)-CD45RO(high)CCR7⁻), as well as the pattern of cell migration based on CD62L selectin expression, demonstrating that P. vivax-infected donors presented with a predominantly central memory cell profile. Our results indicate that the expansion of both naïve and memory T cells, responsible for the production of both pro-inflammatory and regulatory cytokines, which might also contribute to the modulation of immune responses during P. vivax infection.

  11. Interaction of fibrin(ogen) with the endothelial cell receptor VE-cadherin: mapping of the receptor-binding site in the NH2-terminal portions of the fibrin beta chains.

    PubMed

    Gorlatov, Sergei; Medved, Leonid

    2002-03-26

    Interaction of fibrin with endothelial cells stimulates capillary tube formation thus promoting angiogenesis. This interaction occurs via endothelial cell receptor VE-cadherin and fibrin beta chain 15-42 regions [Bach, T. L., et al. (1998) J. Biol. Chem. 272, 30719-30728]. To clarify the mechanism of this interaction, we expressed in Escherichia coli a number of recombinant fibrin(ogen) fragments containing the beta15-42 region or the VE-cad(1-2) and VE-cad(1-4) fragments encompassing two and four extracellular NH2-terminal domains of VE-cadherin, respectively, and tested interaction between them by surface plasmon resonance and ELISA. Neither the recombinant Bbeta1-57 or Bbeta1-64 fragments, nor beta15-57 or beta15-64 prepared from the latter fragments by thrombin treatment to remove fibrinopeptides B, bound the recombinant VE-cadherin fragments. At the same time, a dimeric recombinant thrombin-treated (beta15-66)2 fragment, which had been disulfide-linked via Cys65 to mimic the dimeric arrangement of the beta chains in fibrin, bound VE-cad(1-4) well, but not VE-cad(1-2); no binding was observed with the untreated (Bbeta1-66)2 dimer. We next mutated several residues in the dimer, His16, Arg17, Pro18, and Asp20, and tested the interaction of the thrombin-treated mutants with VE-cad(1-4) by ligand blotting and surface plasmon resonance. No binding was observed with the H16A and R17Q single mutants and the H16P, P18V double mutant while the P18A and D20N single mutants bound VE-cad(1-4) with the same affinity as the thrombin-treated wild-type dimer. These results indicate that the VE-cadherin binding site in fibrin includes NH2-terminal regions of both fibrin beta-chains, that His16 and Arg17 are critical for the binding, and that the third and/or fourth extracellular domains of VE-cadherin are required for the binding to occur.

  12. Recombinant Bivalent Fusion Protein rVE Induces CD4+ and CD8+ T-Cell Mediated Memory Immune Response for Protection Against Yersinia enterocolitica Infection

    PubMed Central

    Singh, Amit K.; Kingston, Joseph J.; Gupta, Shishir K.; Batra, Harsh V.

    2015-01-01

    Studies investigating the correlates of immune protection against Yersinia infection have established that both humoral and cell mediated immune responses are required for the comprehensive protection. In our previous study, we established that the bivalent fusion protein (rVE) comprising immunologically active regions of Y. pestis LcrV (100–270 aa) and YopE (50–213 aa) proteins conferred complete passive and active protection against lethal Y. enterocolitica 8081 challenge. In the present study, cohort of BALB/c mice immunized with rVE or its component proteins rV, rE were assessed for cell mediated immune responses and memory immune protection against Y. enterocolitica 8081. rVE immunization resulted in extensive proliferation of both CD4 and CD8 T cell subsets; significantly high antibody titer with balanced IgG1: IgG2a/IgG2b isotypes (1:1 ratio) and up-regulation of both Th1 (TNF-α, IFN-γ, IL-2, and IL-12) and Th2 (IL-4) cytokines. On the other hand, rV immunization resulted in Th2 biased IgG response (11:1 ratio) and proliferation of CD4+ T-cell; rE group of mice exhibited considerably lower serum antibody titer with predominant Th1 response (1:3 ratio) and CD8+ T-cell proliferation. Comprehensive protection with superior survival (100%) was observed among rVE immunized mice when compared to the significantly lower survival rates among rE (37.5%) and rV (25%) groups when IP challenged with Y. enterocolitica 8081 after 120 days of immunization. Findings in this and our earlier studies define the bivalent fusion protein rVE as a potent candidate vaccine molecule with the capability to concurrently stimulate humoral and cell mediated immune responses and a proof of concept for developing efficient subunit vaccines against Gram negative facultative intracellular bacterial pathogens. PMID:26733956

  13. Direct Contra Naïve-Indirect Comparison of Clinical Failure Rates between High-Viscosity GIC and Conventional Amalgam Restorations: An Empirical Study

    PubMed Central

    Mickenautsch, Steffen; Yengopal, Veerasamy

    2013-01-01

    Background Naïve-indirect comparisons are comparisons between competing clinical interventions’ evidence from separate (uncontrolled) trials. Direct comparisons are comparisons within randomised control trials (RCTs). The objective of this empirical study is to test the null-hypothesis that trends and performance differences inferred from naïve-indirect comparisons and from direct comparisons/RCTs regarding the failure rates of amalgam and direct high-viscosity glass-ionomer cement (HVGIC) restorations in permanent posterior teeth have similar direction and magnitude. Methods A total of 896 citations were identified through systematic literature search. From these, ten and two uncontrolled clinical longitudinal studies for HVGIC and amalgam, respectively, were included for naïve-indirect comparison and could be matched with three out twenty RCTs. Summary effects sizes were computed as Odds ratios (OR; 95% Confidence intervals) and compared with those from RCTs. Trend directions were inferred from 95% Confidence interval overlaps and direction of point estimates; magnitudes of performance differences were inferred from the median point estimates (OR) with 25% and 75% percentile range, for both types of comparison. Mann-Whitney U test was applied to test for statistically significant differences between point estimates of both comparison types. Results Trends and performance differences inferred from naïve-indirect comparison based on evidence from uncontrolled clinical longitudinal studies and from direct comparisons based on RCT evidence are not the same. The distributions of the point estimates differed significantly for both comparison types (Mann–Whitney U  =  25, nindirect  =  26; ndirect  =  8; p  =  0.0013, two-tailed). Conclusion The null-hypothesis was rejected. Trends and performance differences inferred from either comparison between HVGIC and amalgam restorations failure rates in permanent posterior teeth are not the same. It is

  14. Efficacy of Entecavir Treatment for up to 5 Years in Nucleos(t)ide-Naïve Chronic Hepatitis B Patients in Real Life

    PubMed Central

    Luo, Jie; Li, Xiangyong; Wu, Yuankai; Lin, Guoli; Pang, Yihua; Zhang, Xiao; Ao, Yunlong; Du, Zhan; Zhao, Zhixin; Chong, Yutian

    2013-01-01

    Objective: To analyze the efficacy and safety of entecavir (ETV) treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life. Methods: We retrospectively analyzed 230 nucleos(t)ide naïve chronic hepatitis B patients who received ETV 0.5 mg/day monotherapy for at least 3 months, of whom 113 were HBeAg positive and 117 were HBeAg negative. The primary endpoints was cumulative probability of achieving a virological response (undetectable serum HBV DNA, <100IU/mL). Secondary endpoints were rates of ALT normalization (ALT < upper limit of normal), HBeAg seroconversion, resistance, and safety. Results: The median follow-up duration was 27.5 months (3-73 months) and mean age was 42 years. With 230, 214, 180, 142, 88, 42 and 11 patients followed-up for at least 3 months,6 months, 1, 2, 3, 4 and 5 years, respectively. In all, Incremental increases were observed in the rates of undetectable HBV DNA. 67.0%, 85.0%, 89.4%, 94.4%, 95.5%, 97.6%, 100% had undetectable HBV DNA at month 3, month 6, 1 year, 2 years, 3 years, 4 years and 5 years. Proportions of patients achieving normal ALT were 73.9%, 85.5%, 82.8%, 89.4%, 80.7%, 85.7%, 100%, respectively. The rate of HBeAg seroconversion reached 21.4% and 15.4% at year2, 3, respectively. One patient achieved HBsAg seroclearance after 1 year, and achieved anti-HBs seroconversion at year 3. Of 180 patients, HBV DNA was detectable (partial virological response, PVR) in 19 patients at year 1 of follow-up, twelve of 14 (85.7%) patients with PVR need more than 1 year of continuous ETV therapy to achieved VR. At baseline, no ETV-resistance was detected in 25 ETV-naïve patients. One patient developed ETV-resistance mutations due to noncompliance. No serious adverse event was reported. Conclusion: Long-term ETV treatment of nucleos(t)ide-naïve was effective and safe in real life. Adjustment of ETV monotherapy in nucleos(t)ide-naïve patients with a partial virological response at 1 year may be unnecessary

  15. Effect of Amitriptyline on Symptoms in Treatment Naïve Patients with Interstitial Cystitis/Painful Bladder Syndrome

    PubMed Central

    Foster, Harris E.; Hanno, Philip M.; Nickel, J. Curtis; Payne, Christopher K.; Mayer, Robert D.; Burks, David A.; Yang, Claire C.; Chai, Toby C.; Kreder, Karl J.; Peters, Kenneth M.; Lukacz, Emily S.; FitzGerald, Mary P.; Cen, Liyi; Landis, J. Richard; Propert, Kathleen J.; Yang, Wei; Kusek, John W.; Nyberg, Leroy M.

    2010-01-01

    Background Amitriptyline is frequently used to treat patients with IC/PBS. The evidence to support this practice is derived mainly from a small single site clinical trial and case reports. Methods We conducted a multi-center, randomized, double blind, placebo controlled clinical trial of amitriptyline in subjects with IC/PBS who were naive to therapy. Study participants in both treatment arms received a standardized education and behavioral modification program (EBMP). The drug dose was increased over a six-week period from 10 mg up to 75 mg once daily. The primary outcome was a patient-reported global response assessment (GRA) of symptom improvement evaluated after 12 weeks of treatment. Results A total of 271 subjects were randomized and 231 (85%) provided a GRA at 12 weeks of follow-up. Study participants were primarily women (83%), Caucasian (74%) with a median age of 38 years. In an intention-to-treat analysis (n=271), the rate of response of subjects reporting either moderately or markedly improved from baseline in the amitriptyline and placebo groups was 55% and 45% respectively (p=0.12). Among the subgroup of subjects (n=207) who achieved a drug dose of at least 50 mg, a significantly higher response rate was observed in the amitriptyline group (66%) compared to placebo (47%) (p=0.01). Conclusion When all randomized subjects were considered, amitriptyline in combination with an EBMP did not significantly improve symptoms in patients with IC/PBS who are treatment naïve. Amitriptyline, however, may be beneficial in persons who can achieve a daily dose of 50 mg or greater, although this subgroup comparison was not specified in advance. PMID:20303115

  16. Work productivity among treatment-naïve patients with genotype 1 chronic hepatitis C infection receiving telaprevir combination treatment.

    PubMed

    Aggarwal, J; Vera-Llonch, M; Donepudi, M; Suthoff, E; Younossi, Z; Goss, T F

    2015-01-01

    Work productivity is impacted in hepatitis C virus (HCV)-infected patients and has been linked to treatment. In two Phase 3 trials, ADVANCE and ILLUMINATE, treatment-naïve genotype 1 chronic HCV-infected patients received 12-week telaprevir (T) with 24 (T12PR24)- or 48 (T12PR48)-week peginterferon alfa-2a/ribavirin. The objective of this analysis was to examine the impact of chronic HCV infection and its treatment with combination therapy on work productivity. The 5-item, self-reported work productivity questionnaire (WPQ) was administered in Phase 3 trials to assess unemployment status, days unable to work due to HCV/treatment, reduced hours worked and impact on productivity in prior 4 weeks. Descriptive statistics and multivariate regression analyses were employed in analyses of pooled trial data. About 1147 patients were included; 22% (n = 255) were unemployed at baseline, with 8% being unemployed due to health reasons. At week 12, there were no differences by treatment regimen in the number of days unable to work. At week 48, improvements were observed earlier among patients receiving the shorter duration of T combination treatment. Mean (95% CI) change from baseline in days unable to work was -0.48 (-0.85, -0.11) days for T12PR24, 1.43 (0.63, 2.24) days for T12PR48 and 1.24 (0.18, 2.30) days for PR48 with placebo. Predictors of days unable to work were identified and include demographic characteristics, pretreatment and on-treatment levels of fatigue, as well regional variation. In post hoc analyses of the ADVANCE and ILLUMINATE trials, work productivity decreased during the initial 12 weeks regardless of treatment group.

  17. Knocking on Heaven's Door: Are Novel Invaders Necessarily Facing Naïve Native Species on Islands?

    PubMed

    Gérard, Agathe; Jourdan, Hervé; Millon, Alexandre; Vidal, Eric

    2016-01-01

    The impact of alien predator species on insular native biota has often been attributed to island prey naïveté (i.e. lack of, or inefficient, anti-predator behavior). Only rarely, however, has the concept of island prey naïveté been tested, and then only a posteriori (i.e. hundreds or thousands of years after alien species introduction). The presence of native or anciently introduced predators or competitors may be crucial for the recognition and development of adaptive behavior toward unknown predators or competitors of the same archetype (i.e. a set of species that occupy a similar ecological niche and show similar morphological and behavioral traits when interacting with other species). Here, we tested whether two squamates endemic to New Caledonia, a skink, Caledoniscincus austrocaledonicus, and a gecko, Bavayia septuiclavis, recognized and responded to the odor of two major invaders introduced into the Pacific islands, but not yet into New Caledonia. We chose one predator, the small Indian mongoose Herpestes javanicus and one competitor, the cane toad Rhinella marina, which belong respectively to the same archetype as the following two species already introduced into New Caledonia in the nineteenth century: the feral cat Felis catus and the golden bell frog Litoria aurea. Our experiment reveals that geckos are naïve with respect to the odors of both an unknown predator and an unknown competitor, as well as to the odors of a predator and a competitor they have lived with for centuries. In contrast, skinks seem to have lost some naïveté regarding the odor of a predator they have lived with for centuries and seem "predisposed" to avoid the odor of an unknown potential competitor. These results indicate that insular species living in contact with invasive alien species for centuries may be, although not systematically, predisposed toward developing adaptive behavior with respect to species belonging to the same archetype and introduced into their native

  18. Effect of caffeine as an ergogenic aid during anaerobic exercise performance in caffeine naïve collegiate football players.

    PubMed

    Woolf, Kathleen; Bidwell, Wendy K; Carlson, Amanda G

    2009-08-01

    Research suggests that caffeine may improve performance in aerobic exercise; the evidence for anaerobic performance is mixed. This study examined the effect of caffeine (5 mg/kg body weight [BW]) vs. placebo on performance-based anaerobic exercise tests used during the National Football League (NFL) Combine. Collegiate football athletes (n = 17; 20 +/- 2 yr; body mass index 29.4 +/- 3.6 kg/m) completed 2 study visits, 1 week apart. Participants were low caffeine users with a reported average intake of 16 +/- 20 mg/day. On the day of testing, participants ingested a caffeinated (5 mg/kg BW caffeine + 0.125 g/kg BW carbohydrate) or placebo (0.125 g/kg BW carbohydrate) beverage, ate a light meal, and completed 3 exercise tests (40-yard dash, 20-yard shuttle, and a bench press) 60 minutes later. Borg's rating of perceived exertion (RPE) was recorded after each exercise test. Heart rate (HR) and blood pressure (BP) were monitored (pre-exercise and postexercise). Data were analyzed using paired t-tests, Wilcoxon signed rank test, and repeated measures analysis of variance. No significant differences were found between treatments for the exercise tests (40-yard dash: 5.01 +/- 0.25 vs. 5.03 +/- 0.26 s, p = 0.43; 20-yard shuttle: 4.64 +/- 0.19 vs. 4.66 +/- 0.24 s, p = 0.51; bench press: 17 +/- 8 vs. 17 +/- 8 reps, p = 0.51; caffeine vs. placebo, respectively). However, 59% of the participants improved in performance with the caffeine during the bench press and the 40-yard dash. No differences were found between treatments for RPE, HR, and BP. Caffeine did not improve performance for anaerobic exercise tests used at the NFL Combine in caffeine naïve male football athletes.

  19. Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients

    PubMed Central

    Bergamaschi, Mateus M; Queiroz, Regina Helena Costa; Chagas, Marcos Hortes Nisihara; de Oliveira, Danielle Chaves Gomes; De Martinis, Bruno Spinosa; Kapczinski, Flávio; Quevedo, João; Roesler, Rafael; Schröder, Nadja; Nardi, Antonio E; Martín-Santos, Rocio; Hallak, Jaime Eduardo Cecílio; Zuardi, Antonio Waldo; Crippa, José Alexandre S

    2011-01-01

    Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC. PMID:21307846

  20. Stellar Activity at the End of the Main Sequence: GHRS Observations of the M8 Ve Star VB 10

    NASA Technical Reports Server (NTRS)

    Linsky, Jeffrey L.; Wood, Brian E.; Brown, Alexander; Giampapa, Mark S.; Ambruster, Carol

    1995-01-01

    We present Goddard High Resolution Spectrograph observations of the M8 Ve star VB 10 (equal to G1 752B), located very near the end of the stellar main sequence, and its dM3.5 binary companion G1 752A. These coeval stars provide a test bed for studying whether the outer atmospheres of stars respond to changes in internal structure as stars become fully convective near mass 0.3 solar mass (about spectral type M5), where the nature of the stellar magnetic dynamo presumably changes, and near the transition from red to brown dwarfs near mass 0.08 solar mass (about spectral type M9), when hydrogen burning ceases at the end of the main sequence. We obtain upper limits for the quiescent emission of VB 10 but observe a transition region spectrum during a large flare, which indicates that some type of magnetic dynamo must be present. Two indirect lines of evidence-scaling from the observed X-ray emission and scaling from a time-resolved flare on AD Leo suggest that the fraction of the stellar bolometric luminosity that heats the transition region of VB 10 outside of obvious flares is comparable to, or larger than, that for G1 752A. This suggests an increase in the magnetic heating rates, as measured by L(sub line)/L(sub bol) ratios, across the radiative/convective core boundary and as stars approach the red/brown dwarf boundary. These results provide new constraints for dynamo models and models of coronal and transition-region heating in late-type stars.

  1. Evolution of an Eurasian avian-like influenza virus in naïve and vaccinated pigs.

    PubMed

    Murcia, Pablo R; Hughes, Joseph; Battista, Patrizia; Lloyd, Lucy; Baillie, Gregory J; Ramirez-Gonzalez, Ricardo H; Ormond, Doug; Oliver, Karen; Elton, Debra; Mumford, Jennifer A; Caccamo, Mario; Kellam, Paul; Grenfell, Bryan T; Holmes, Edward C; Wood, James L N

    2012-01-01

    Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals before emerging in humans. Although segment reassortment has commonly been associated with influenza emergence, an expanded host-range is also likely to be associated with the accumulation of specific beneficial point mutations. To better understand the mechanisms that shape the genetic diversity of avian-like viruses in pigs, we studied the evolutionary dynamics of an Eurasian Avian-like swine influenza virus (EA-SIV) in naïve and vaccinated pigs linked by natural transmission. We analyzed multiple clones of the hemagglutinin 1 (HA1) gene derived from consecutive daily viral populations. Strikingly, we observed both transient and fixed changes in the consensus sequence along the transmission chain. Hence, the mutational spectrum of intra-host EA-SIV populations is highly dynamic and allele fixation can occur with extreme rapidity. In addition, mutations that could potentially alter host-range and antigenicity were transmitted between animals and mixed infections were commonplace, even in vaccinated pigs. Finally, we repeatedly detected distinct stop codons in virus samples from co-housed pigs, suggesting that they persisted within hosts and were transmitted among them. This implies that mutations that reduce viral fitness in one host, but which could lead to fitness benefits in a novel host, can circulate at low frequencies.

  2. Mismatch negativity in tobacco-naïve cannabis users and its alteration with acute nicotine administration.

    PubMed

    Impey, Danielle; El-Marj, Nicole; Parks, Andrea; Choueiry, Joelle; Fisher, Derek; Knott, Verner J

    2015-09-01

    Chronic cannabis use may interact with factors, such as age of onset of cannabis use, family history, and genetic factors, to elicit schizophrenia (SZ)-like symptoms, including sensory and cognitive deficits. However, evidence of a relationship between cannabis use and cognitive impairment is confounded by concomitant use of tobacco. The objective of this study was to compare tobacco-naïve cannabis users with individuals without a history of tobacco/cannabis use on the auditory mismatch negativity (MMN) event-related potential (ERP), a neural measure of auditory deviance detection which is diminished in SZ. An exploratory arm of the study, conducted within a randomized, double-blind, placebo controlled design, examined the acute effects of nicotine gum (6mg) on MMN in cannabis users. MMN was recorded in response to 5 deviant stimuli within an optimal MMN paradigm in 44 healthy, non-tobacco smoking volunteers aged 18-26. Cannabis users (n=21) started smoking cannabis prior to age 17, at least 1 joint per month. To examine the effects of chronicity, users were grouped into relatively heavy long-term (HLT; n=11) users and light short-term (LST; n=10) users. Impaired deviance detection was shown in cannabis users vs. nonusers as reflected by a smaller MMN to duration deviants. Chronicity of use was also associated with MMN alterations, as HLTs displayed a reduced duration and gap MMN vs. LSTs. Compared with placebo, nicotine treatment enhanced select MMN deviants in cannabis user subgroups. As deficits associated with early and persistent cannabis use are similar to those seen in SZ, these dose-dependant disturbances in early sensory processing with cannabis use may be one cognitive pathway which mediates an increased risk for SZ in vulnerable youth, and be influenced by concurrent cigarette smoking behavior.

  3. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients.

    PubMed

    Bergamaschi, Mateus M; Queiroz, Regina Helena Costa; Chagas, Marcos Hortes Nisihara; de Oliveira, Danielle Chaves Gomes; De Martinis, Bruno Spinosa; Kapczinski, Flávio; Quevedo, João; Roesler, Rafael; Schröder, Nadja; Nardi, Antonio E; Martín-Santos, Rocio; Hallak, Jaime Eduardo Cecílio; Zuardi, Antonio Waldo; Crippa, José Alexandre S

    2011-05-01

    Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.

  4. Metabolic syndrome before and after initiation of antiretroviral therapy in treatment-naïve HIV-infected individuals

    PubMed Central

    Krishnan, S; Schouten, JT; Atkinson, B; Brown, T; Wohl, D; McComsey, GA; Glesby, MJ; Shikuma, C; Haubrich, R; Tebas, P; Campbell, TB; Jacobson, DL

    2012-01-01

    Background Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease and diabetes, many of which are associated with HIV and antiretroviral therapy (ART). We examined prevalence and incidence of MetS, and risk factors for MetS in ART-naïve HIV-infected individuals starting ART. Methods MetS, defined by the Adult Treatment Panel III criteria, was assessed at and after ART initiation in HIV-infected individuals who enrolled in selected AIDS Clinical Trials Group (ACTG) trials and were followed long-term after these trials as part of the ACTG Longitudinal Linked Randomized Trials cohort. Cox proportional hazards models were used to examine risk factors of incident MetS. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) are reported. Results At ART initiation, the prevalence of MetS was 20%. After ART initiation, the incidence of MetS was 8.5 per 100 person-years. After adjusting for demographics and body mass index, the risk of MetS was decreased for CD4+ T-cell counts>50 cells/mm3 (aHR = 0.62, 95% CI=0.43 to 0.90 for CD4>500), and the risk was increased for HIV-1 RNA >400 copies/mL (aHR=1.55 (95% CI=1.25 to 1.92) and use of a protease-inhibitor (PI) based regimen (relative to no PI use, aHR=1.25 (95% CI=1.04 to 1.51) for any PI use). Conclusion In HIV-infected individuals on ART, virologic suppression and maintenance of high CD4+ T-cell counts may be potentially modifiable factors that can reduce the risk of MetS. The effect of MetS on the risk of cardiovascular disease and diabetes needs to be evaluated. PMID:22828718

  5. Evidence for Persistence of Ectromelia Virus in Inbred Mice, Recrudescence Following Immunosuppression and Transmission to Naïve Mice.

    PubMed

    Sakala, Isaac G; Chaudhri, Geeta; Scalzo, Anthony A; Eldi, Preethi; Newsome, Timothy P; Buller, Robert M; Karupiah, Gunasegaran

    2015-12-01

    Orthopoxviruses (OPV), including variola, vaccinia, monkeypox, cowpox and ectromelia viruses cause acute infections in their hosts. With the exception of variola virus (VARV), the etiological agent of smallpox, other OPV have been reported to persist in a variety of animal species following natural or experimental infection. Despite the implications and significance for the ecology and epidemiology of diseases these viruses cause, those reports have never been thoroughly investigated. We used the mouse pathogen ectromelia virus (ECTV), the agent of mousepox and a close relative of VARV to investigate virus persistence in inbred mice. We provide evidence that ECTV causes a persistent infection in some susceptible strains of mice in which low levels of virus genomes were detected in various tissues late in infection. The bone marrow (BM) and blood appeared to be key sites of persistence. Contemporaneous with virus persistence, antiviral CD8 T cell responses were demonstrable over the entire 25-week study period, with a change in the immunodominance hierarchy evident during the first 3 weeks. Some virus-encoded host response modifiers were found to modulate virus persistence whereas host genes encoded by the NKC and MHC class I reduced the potential for persistence. When susceptible strains of mice that had apparently recovered from infection were subjected to sustained immunosuppression with cyclophosphamide (CTX), animals succumbed to mousepox with high titers of infectious virus in various organs. CTX treated index mice transmitted virus to, and caused disease in, co-housed naïve mice. The most surprising but significant finding was that immunosuppression of disease-resistant C57BL/6 mice several weeks after recovery from primary infection generated high titers of virus in multiple tissues. Resistant mice showed no evidence of a persistent infection. This is the strongest evidence that ECTV can persist in inbred mice, regardless of their resistance status.

  6. Phase-1 study of abiraterone acetate in chemotherapy-naïve Japanese patients with castration-resistant prostate cancer.

    PubMed

    Matsubara, Nobuaki; Uemura, Hiroji; Fukui, Iwao; Niwakawa, Masashi; Yamaguchi, Akito; Iizuka, Koho; Akaza, Hideyuki

    2014-10-01

    Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1-7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2-3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484.

  7. Rearing environment, sex and developmental lead exposure modify gene expression in the hippocampus of behaviorally naïve animals.

    PubMed

    Anderson, D W; Mettil, W A; Schneider, J S

    2013-03-01

    Developmental lead (Pb) exposure impairs various cognitive processes and behaviors in both humans and animals. In particular, specific deficits in spatial learning and memory have been described in Pb-exposed rats. It is also known that rearing environment (i.e., non-enriched vs. enriched) can have significant influences on cognitive performance and that rearing environment and sex may modify the influence of Pb exposure on learning and memory processes. It is also known that behavioral testing can alter hippocampal gene expression and interactive effects of environment. Little is known however about the molecular correlates of developmental Pb-exposure on expression of key sets of cognition-relevant genes in the hippocampus and how sex and environmental rearing condition may modify these effects. The present study examined expression profiles of neurobiologically-relevant genes (i.e., neurotrophic factors, NMDA receptors, metabotropic glutamate receptors, synaptic function/plasticity, and transcription/gene regulation) in behaviorally naïve rats with perinatal exposure (i.e., gestation through weaning) to different levels of Pb (250, 750 and 1,500 ppm Pb acetate) in males and females raised in a non-enriched environment (standard housing without toys) or an enriched environment (large cage containing toys changed twice weekly). Unlike previous studies identifying gene changes following behavioral testing, which alters expression analysis, we identified both sex and environmental related changes in hippocampal genes following Pb exposure alone. The gene expression changes described may be associated with learning and memory and may pre-determine how cognitive profiles develop following Pb exposure.

  8. TEMEL ETİK KURAMLAR AÇISINDAN ADALET ve SAĞLIK HAKKI KAVRAMLARININ DEĞERLENDİRMESİ1,2

    PubMed Central

    Ekmekçi, Perihan Elif; Arda, Berna

    2015-01-01

    Sağlık hakkı temel bir insan hakkıdır. Ancak günümüzde sağlık hakkının hayata geçmesi, sağlık sunumunda gereksinim duyulan kaynakların kısıtlı olması nedeniyle engeller ile karşılaşmaktadır. Ayrıca tıp alanındaki hızlı teknolojik ilerlemeler, tanı ve tedavi imkânlarının her geçen gün gelişmesine yol açmaktadır. Bu durum, sağlık hizmetlerinin sunumunu dağıtıcı adaletin bir süjesi haline getirmektedir. Adalet kavramının tanımlanabilmesi için öncelikle, birey ya da toplulukların bir şeye ilişkin hak talebinde bulunmalarının koşullarını tanımlanmalı daha sonra hak edilenin kim tarafından ve nasıl verileceğinin belirlenmelidir. Etik kuramlar, etik açıdan doğru eyleyebilmek için hangi dayanak noktalarından yola çıkarak hangi değerleri önceleyerek karar vermek gerektiği konusunda kendi paradigmalarını oluşturmuşlardır. Adalet ve sağlık hakkı gibi temel kavramlar, temel etik kuramlar tarafından, o kuramın bağlamı içinde değerlendirilmekte ve anlam kazanmaktadır. Sağlık hakkı bazı etik kuramlar tarafından insan varlığının doğal bir bileşeni olarak tanımlanırken, bazı etik kuramlar tarafından bağlamsal olarak kabul edilmekte bazıları tarafından ise reddedilmekte, adalet kavramı ve bağlantılı olarak adaletin materyal ve formal ilkeleri gibi kavramların içerikleri ve taşıdıkları değerler içinden bakılan etik kuramın paradigmasına bağlı olarak farklıklar içermektedir. Etik kuramların paradigmaları sadece kavramların tanımlanmasında değil, aynı zamanda pratik uygulamalarda da farklı yaklaşımları gerektirmektedir. Bu çalışmada, erdem etiği, faydacı etik kuram, ödev etiği, liberal etik kuram ve kommuniteryan etik kuramın adalet ve sağlık hakkını nasıl kavramsallaştırdıklarını ortaya konmaktır. Bu amaçla öncelikle her bir etik kuramın genel çerçevesi tanımlanmış ve bu çerçevenin çizdiği teorik paradigma i

  9. VE-Suite

    SciTech Connect

    Bryden, Kenneth Mark

    2006-10-01

    an open source virtual engineering software toolkit that simplifies information management so users can simultaneously interact with engineering analyses and graphical models to create a virtual decision-making environment.

  10. Antibody and cellular immune responses of naïve mares to repeated vaccination with an inactivated equine herpesvirus vaccine.

    PubMed

    Wagner, B; Goodman, L B; Babasyan, S; Freer, H; Torsteinsdóttir, S; Svansson, V; Björnsdóttir, S; Perkins, G A

    2015-10-13

    Equine herpesvirus type 1 (EHV-1) continues to cause severe outbreaks of abortions or myeloencephalopathy in horses despite widely used vaccination. The aim of this work was to determine the effects of frequent vaccination with an inactivated EHV vaccine on immune development in horses. Fifteen EHV-1 naïve mares were vaccinated a total of 5 times over a period of 8 months with intervals of 20, 60, 90 and 60 days between vaccine administrations. Total antibody and antibody isotype responses were evaluated with a new sensitive EHV-1 Multiplex assay to glycoprotein C (gC) and gD for up to 14 months after initial vaccination. Antibodies peaked after the first two vaccine doses and then declined despite a third administration of the vaccine. The fourth vaccine dose was given at 6 months and the gC and gD antibody titers increased again. Mixed responses with increasing gC but decreasing gD antibody values were observed after the fifth vaccination at 8 months. IgG4/7 isotype responses mimicked the total Ig antibody production to vaccination most closely. Vaccination also induced short-lasting IgG1 antibodies to gC, but not to gD. EHV-1-specific cellular immunity induced by vaccination developed slower than antibodies, was dominated by IFN-γ producing T-helper 1 (Th1) cells, and was significantly increased compared to pre-vaccination values after administration of 3 vaccine doses. Decreased IFN-γ production and reduced Th1-cell induction were also observed after the second and fourth vaccination. Overall, repeated EHV vaccine administration did not always result in increasing immunity. The adverse effects on antibody and cellular immunity that were observed here when the EHV vaccine was given in short intervals might in part explain why EHV-1 outbreaks are observed worldwide despite widely used vaccination. The findings warrant further evaluation of immune responses to EHV vaccines to optimize vaccination protocols for different vaccines and horse groups at risk.

  11. Knocking on Heaven's Door: Are Novel Invaders Necessarily Facing Naïve Native Species on Islands?

    PubMed Central

    Gérard, Agathe; Jourdan, Hervé; Millon, Alexandre; Vidal, Eric

    2016-01-01

    The impact of alien predator species on insular native biota has often been attributed to island prey naïveté (i.e. lack of, or inefficient, anti-predator behavior). Only rarely, however, has the concept of island prey naïveté been tested, and then only a posteriori (i.e. hundreds or thousands of years after alien species introduction). The presence of native or anciently introduced predators or competitors may be crucial for the recognition and development of adaptive behavior toward unknown predators or competitors of the same archetype (i.e. a set of species that occupy a similar ecological niche and show similar morphological and behavioral traits when interacting with other species). Here, we tested whether two squamates endemic to New Caledonia, a skink, Caledoniscincus austrocaledonicus, and a gecko, Bavayia septuiclavis, recognized and responded to the odor of two major invaders introduced into the Pacific islands, but not yet into New Caledonia. We chose one predator, the small Indian mongoose Herpestes javanicus and one competitor, the cane toad Rhinella marina, which belong respectively to the same archetype as the following two species already introduced into New Caledonia in the nineteenth century: the feral cat Felis catus and the golden bell frog Litoria aurea. Our experiment reveals that geckos are naïve with respect to the odors of both an unknown predator and an unknown competitor, as well as to the odors of a predator and a competitor they have lived with for centuries. In contrast, skinks seem to have lost some naïveté regarding the odor of a predator they have lived with for centuries and seem “predisposed” to avoid the odor of an unknown potential competitor. These results indicate that insular species living in contact with invasive alien species for centuries may be, although not systematically, predisposed toward developing adaptive behavior with respect to species belonging to the same archetype and introduced into their native

  12. Immunologic response in treatment-naïve HIV-2-infected patients: the IeDEA West Africa cohort

    PubMed Central

    Balestre, Eric; Ekouevi, Didier Koumavi; Tchounga, Boris; Eholie, Serge Paul; Messou, Eugène; Sawadogo, Adrien; Thiébaut, Rodolphe; May, Margaret T; Sterne, Jonathan Ac; Dabis, François

    2016-01-01

    Introduction Response to antiretroviral therapy (ART) among individuals infected with HIV-2 is poorly described. We compared the immunological response among patients treated with three nucleoside reverse-transcriptase inhibitors (NRTIs) to boosted protease inhibitor (PI) and unboosted PI-based regimens in West Africa. Methods This prospective cohort study enrolled treatment-naïve HIV-2-infected patients within the International Epidemiological Databases to Evaluate AIDS collaboration in West Africa. We used mixed models to compare the CD4 count response to treatment over 12 months between regimens. Results Of 422 HIV-2-infected patients, 285 (67.5%) were treated with a boosted PI-based regimen, 104 (24.6%) with an unboosted PI-based regimen and 33 (7.8%) with three NRTIs. Treatment groups were comparable with regard to gender (54.5% female) and median age at ART initiation (45.3 years; interquartile range 38.3 to 51.8). Treatment groups differed by clinical stage (21.2%, 16.8% and 17.3% at CDC Stage C or World Health Organization Stage IV for the triple NRTI, boosted PI and unboosted PI groups, respectively, p=0.02), median length of follow-up (12.9, 17.7 and 44.0 months for the triple NRTI, the boosted PI and the unboosted PI groups, respectively, p<0.001) and baseline median CD4 count (192, 173 and 129 cells/µl in the triple NRTI, the boosted PI and the unboosted PI-based regimen groups, respectively, p=0.003). CD4 count recovery at 12 months was higher for patients treated with boosted PI-based regimens than those treated with three NRTIs or with unboosted PI-based regimens (191 cells/µl, 95% CI 142 to 241; 110 cells/µl, 95% CI 29 to 192; 133 cells/µl, 95% CI 80 to 186, respectively, p=0.004). Conclusions In this observational study using African data, boosted PI-containing regimens had better immunological response compared to triple NRTI combinations and unboosted PI-based regimens at 12 months. A randomized clinical trial is still required to determine

  13. Naïve Learners Show Cross-Domain Transfer after Distributional Learning: The Case of Lexical and Musical Pitch

    PubMed Central

    Ong, Jia Hoong; Burnham, Denis; Stevens, Catherine J.; Escudero, Paola

    2016-01-01

    Experienced listeners of a particular acoustic cue in either speech or music appear to have an advantage when perceiving a similar cue in the other domain (i.e., they exhibit cross-domain transfer). One explanation for cross-domain transfer relates to the acquisition of the foundations of speech and music: if acquiring pitch-based elements in speech or music results in heightened attention to pitch in general, then cross-domain transfer of pitch may be observed, which may explain the cross-domain phenomenon seen among listeners of a tone language and listeners with musical training. Here, we investigate this possibility in naïve adult learners, who were trained to acquire pitch-based elements using a distributional learning paradigm, to provide a proof-of-concept for the explanation. Learners were exposed to a stimulus distribution spanning either a Thai lexical tone minimal pair or a novel musical chord minimal pair. Within each domain, the distribution highlights pitch to facilitate learning of two different sounds (Bimodal distribution) or the distribution minimizes pitch so that the input is inferred to be from a single sound (Unimodal distribution). Learning was assessed before and after exposure to the distribution using discrimination tasks with both Thai tone and musical chord minimal pairs. We hypothesize: (i) distributional learning for learners in both the tone and the chord distributions, that is, pre-to-post improvement in discrimination after exposure to the Bimodal but not the Unimodal distribution; and (ii) for both the tone and chord conditions, learners in the Bimodal conditions but not those in the Unimodal conditions will show cross-domain transfer, as indexed by improvement in discrimination of test items in the domain other than what they were trained on. The results support both hypotheses, suggesting that distributional learning is not only used to acquire the foundations of speech and music, but may also play a role in cross

  14. Telbivudine versus lamivudine and entecavir for treatment-naïve decompensated hepatitis B virus-related cirrhosis.

    PubMed

    Yue-Meng, Wan; Li, Yu-Hua; Wu, Hua-Mei; Yang, Jing; Xu, Ying; Yang, Li-Hong; Yang, Jin-Hui

    2016-04-19

    The long-term effects of telbivudine (TBV) on decompensated hepatitis B virus (HBV)-related cirrhosis were still not established. This study aimed to investigate the efficacy and safety of TBV in such cohort of patients as compared to lamivudine (LAM) and entecavir (ETV). We retrospectively evaluated 130 treatment-naïve patients with HBV-related decompensated cirrhosis who started treatment with TBV (n = 31), LAM (n = 45) or ETV (n = 54). After 24 months of treatment, cumulative virological response (VR) rates (HBV DNA <500 copies/mL) were 83.7, 65.3 and 89.1 % in TBV, LAM and ETV groups, respectively (p = 0.009). Reduction in HBV DNA levels in TBV was -3.66 ± 0.56, significantly higher than LAM (-3.34 ± 0.59; p < 0.05) and lower than ETV group (-3.98 ± 0.52; p < 0.05). The rates of HBeAg loss or seroconversion and normalization of alanine aminotransferase (ALT) were similar among the groups. Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease score in TBV were significantly improved compared to at baseline without difference among the groups. TBV resulted in similar cumulative rates of survival and incidence of hepatocellular carcinoma (HCC) to LAM and ETV. Frequencies of complications from cirrhosis, including variceal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis, were comparable among the groups. Four patients (16.7 %) in TBV displayed virological breakthrough, lower than LAM and higher than ETV (p = 0.004). Cox regression analysis showed that baseline HBV DNA (hazard ratio 0.743; 95 % confidence interval 0.582-949, p = 0.017) was an independent predictor for VR at 24 months. Long-term therapy with TBV was effective and safe in HBV-related decompensated cirrhosis.

  15. Phase-1 study of abiraterone acetate in chemotherapy-naïve Japanese patients with castration-resistant prostate cancer

    PubMed Central

    Matsubara, Nobuaki; Uemura, Hiroji; Fukui, Iwao; Niwakawa, Masashi; Yamaguchi, Akito; Iizuka, Koho; Akaza, Hideyuki

    2014-01-01

    Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1–7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2–3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484. PMID:25117615

  16. Caffeine affects CD8+ lymphocyte apoptosis and migration differently in naïve and familiar individuals following moderate intensity exercise.

    PubMed

    Navalta, James W; Fedor, Elizabeth A; Schafer, Mark A; Lyons, T Scott; Tibana, Ramires A; Pereira, Guilherme B; Prestes, Jonato

    2016-06-01

    The purpose of this investigation was to determine the lymphocyte subset response to 30 min of moderate treadmill exercise during caffeine supplemented (6.0 mg.kg(-1)) and placebo conditions in caffeine-naïve and -familiar individuals. Seventeen individuals participated (caffeine-familiar = 8, caffeine-naïve = 9) completing two exercise bouts (caffeine supplemented and placebo control) 48 h apart in a counterbalanced and double-blinded fashion. Individuals were classified as follows: caffeine-naive <50 mg.d(-1) and caffeine-familiar >200 mg.d(-1) Whole blood samples were obtained at rest, 30 min after caffeine or placebo ingestion, immediately following exercise, and 1 h post exercise. Blood was used to analyze apoptosis (annexin V) and cellular migration (CX3CR1) responses in lymphocyte subsets (CD4+, CD8+, CD19+). Absolute changes from rest values were calculated and differences between conditions were determined through Chi-squared analysis with significance accepted at P <0.05. With regard to CD4+ and CD19+ lymphocytes, the interaction of caffeine and exercise did not affect naïve individuals to a greater extent immediately post exercise when compared to familiar, as similar apoptotic and migratory responses were observed (P >0.05). However, CD8+ lymphocyte cell death and migration responses were observed to be significantly greater at each sampling point in caffeine-familiar individuals (P <0.05). It is possible that chronic caffeine supplementation may prime CD8+ cell receptors for responsiveness to apoptosis and migration and the consequence of this form of immunosuppression in the post-exercise period should be determined.

  17. High- and ultrahigh-field magnetic resonance imaging of naïve, injured and scarred vocal fold mucosae in rats

    PubMed Central

    Kishimoto, Ayami Ohno; Kishimoto, Yo; Young, David L.; Zhang, Jinjin

    2016-01-01

    ABSTRACT Subepithelial changes to the vocal fold mucosa, such as fibrosis, are difficult to identify using visual assessment of the tissue surface. Moreover, without suspicion of neoplasm, mucosal biopsy is not a viable clinical option, as it carries its own risk of iatrogenic injury and scar formation. Given these challenges, we assessed the ability of high- (4.7 T) and ultrahigh-field (9.4 T) magnetic resonance imaging to resolve key vocal fold subepithelial tissue structures in the rat, an important and widely used preclinical model in vocal fold biology. We conducted serial in vivo and ex vivo imaging, evaluated an array of acquisition sequences and contrast agents, and successfully resolved key anatomic features of naïve, acutely injured, and chronically scarred vocal fold mucosae on the ex vivo scans. Naïve lamina propria was hyperintense on T1-weighted imaging with gadobenate dimeglumine contrast enhancement, whereas chronic scar was characterized by reduced lamina propria T1 signal intensity and mucosal volume. Acutely injured mucosa was hypointense on T2-weighted imaging; lesion volume steadily increased, peaked at 5 days post-injury, and then decreased – consistent with the physiology of acute, followed by subacute, hemorrhage and associated changes in the magnetic state of hemoglobin and its degradation products. Intravenous administration of superparamagnetic iron oxide conferred no T2 contrast enhancement during the acute injury period. These findings confirm that magnetic resonance imaging can resolve anatomic substructures within naïve vocal fold mucosa, qualitative and quantitative features of acute injury, and the presence of chronic scar. PMID:27638667

  18. Modulation of the Default Mode Network in First-Episode, Drug-Naïve Major Depressive Disorder via Acupuncture at Baihui (GV20) Acupoint

    PubMed Central

    Deng, Demao; Liao, Hai; Duan, Gaoxiong; Liu, Yanfei; He, Qianchao; Liu, Huimei; Tang, Lijun; Pang, Yong; Tao, Jien

    2016-01-01

    Background: Previous neuroimaging studies have revealed that acupuncture modulates the default mode network (DMN) in healthy subjects and patients with certain disorder. However, few studies have been performed to investigate whether or not acupuncture might modulate the DMN in patients with major depressive disorder (MDD). Thereby, the aim of the present study was to assess alterations of the DMN induced by acupuncture stimulation in patients with first-episode, drug-naïve MDD. Materials and Methods: Twenty nine patients with first-episode, drug-naïve MDD and 29 healthy subjects were enrolled in this study. All the healthy subjects underwent 6-min resting-state functional magnetic resonance imaging (R-fMRI) scan. While patients underwent acupuncture stimulation for 20-min electro-acupuncture stimulation (EAS) at Baihui acupoint (GV20) and two 6-min R-fMRI scans before and after EAS. Based on the precuneus/posterior cingulate cortex (PC/PCC) as the seed region, functional connectivity (FC) method was adopted to examine abnormal DMN in patients by comparing with healthy subjects and to evaluate the influence of EAS on intrinsic connectivity within the DMN in patients with MDD. Results: Compared to healthy subjects, MDD patients had abnormal DMN. Moreover, results showed that EAS at GV20 induced increased FC between the PC/PCC and bilateral anterior cingulate cortex (ACC), and decreased FC between the PC/PCC and left middle prefrontal cortex, left angualr gyrus and bilateral hippocampus/parahippocampus (HIPP/paraHIPP) in patients with MDD, which were the main brain regions showing significant differences between the patients and healthy subjects. Conclusion: Our findings provide imaging evidence to support that GV20-related acupuncture stimulation may modulate the DMN in patients with first-episode, drug-naïve MDD. This study may partly interpret the neural mechanisms of acupuncture at GV20 which is used to treat patients with MDD in clinical. PMID:27242492

  19. ChemStable: a web server for rule-embedded naïve Bayesian learning approach to predict compound stability.

    PubMed

    Liu, Zhihong; Zheng, Minghao; Yan, Xin; Gu, Qiong; Gasteiger, Johann; Tijhuis, Johan; Maas, Peter; Li, Jiabo; Xu, Jun

    2014-09-01

    Predicting compound chemical stability is important because unstable compounds can lead to either false positive or to false negative conclusions in bioassays. Experimental data (COMDECOM) measured from DMSO/H2O solutions stored at 50 °C for 105 days were used to predicted stability by applying rule-embedded naïve Bayesian learning, based upon atom center fragment (ACF) features. To build the naïve Bayesian classifier, we derived ACF features from 9,746 compounds in the COMDECOM dataset. By recursively applying naïve Bayesian learning from the data set, each ACF is assigned with an expected stable probability (p(s)) and an unstable probability (p(uns)). 13,340 ACFs, together with their p(s) and p(uns) data, were stored in a knowledge base for use by the Bayesian classifier. For a given compound, its ACFs were derived from its structure connection table with the same protocol used to drive ACFs from the training data. Then, the Bayesian classifier assigned p(s) and p(uns) values to the compound ACFs by a structural pattern recognition algorithm, which was implemented in-house. Compound instability is calculated, with Bayes' theorem, based upon the p(s) and p(uns) values of the compound ACFs. We were able to achieve performance with an AUC value of 84% and a tenfold cross validation accuracy of 76.5%. To reduce false negatives, a rule-based approach has been embedded in the classifier. The rule-based module allows the program to improve its predictivity by expanding its compound instability knowledge base, thus further reducing the possibility of false negatives. To our knowledge, this is the first in silico prediction service for the prediction of the stabilities of organic compounds.

  20. ChemStable: a web server for rule-embedded naïve Bayesian learning approach to predict compound stability

    NASA Astrophysics Data System (ADS)

    Liu, Zhihong; Zheng, Minghao; Yan, Xin; Gu, Qiong; Gasteiger, Johann; Tijhuis, Johan; Maas, Peter; Li, Jiabo; Xu, Jun

    2014-09-01

    Predicting compound chemical stability is important because unstable compounds can lead to either false positive or to false negative conclusions in bioassays. Experimental data (COMDECOM) measured from DMSO/H2O solutions stored at 50 °C for 105 days were used to predicted stability by applying rule-embedded naïve Bayesian learning, based upon atom center fragment (ACF) features. To build the naïve Bayesian classifier, we derived ACF features from 9,746 compounds in the COMDECOM dataset. By recursively applying naïve Bayesian learning from the data set, each ACF is assigned with an expected stable probability ( p s ) and an unstable probability ( p uns ). 13,340 ACFs, together with their p s and p uns data, were stored in a knowledge base for use by the Bayesian classifier. For a given compound, its ACFs were derived from its structure connection table with the same protocol used to drive ACFs from the training data. Then, the Bayesian classifier assigned p s and p uns values to the compound ACFs by a structural pattern recognition algorithm, which was implemented in-house. Compound instability is calculated, with Bayes' theorem, based upon the p s and p uns values of the compound ACFs. We were able to achieve performance with an AUC value of 84 % and a tenfold cross validation accuracy of 76.5 %. To reduce false negatives, a rule-based approach has been embedded in the classifier. The rule-based module allows the program to improve its predictivity by expanding its compound instability knowledge base, thus further reducing the possibility of false negatives. To our knowledge, this is the first in silico prediction service for the prediction of the stabilities of organic compounds.

  1. The impact of 6-month training preparation for an Ironman triathlon on the proportions of naïve, memory and senescent T cells in resting blood.

    PubMed

    Cosgrove, Cormac; Galloway, Stuart D R; Neal, Craig; Hunter, Angus M; McFarlin, Brian K; Spielmann, Guilllaume; Simpson, Richard J

    2012-08-01

    Athletes appear to be at a greater risk of illness while undertaking arduous training regimens in preparation for endurance events. As infection susceptibility has been linked with increased proportions of differentiated and senescent T cells in the periphery, changes in the proportions of these cell types due to long-term high-volume exercise training could have important implications for athlete infection risk. This study examined the effects of 6-month training preparation for an Ironman triathlon on the proportions of naïve, memory and senescent T cells in resting blood. Ten club-level triathletes (9 males; 1 female: 43 ± 3 years) were sampled at 27 (December), 21 (January), 15 (March), 9 (May) and 3 (June) weeks before an Ironman Triathlon. An additional sample was collected 2-week post-competition (August). Four-colour flow cytometry was used for the phenotypic analysis of CD4+ and CD8+ blood T cells. Proportions of differentiated (KLRG1+/CD57-) CD8+ T cells and "transitional" (CD45RA+/CD45RO+) CD4+ and CD8+ T cells increased with training, as the values in June were elevated 37, 142 and 116%, respectively, from those observed in December. Proportions of senescent (KLRG1+/CD57+) CD4+ or CD8+ T cells did not change during the training phase. Two weeks post-race, proportions of differentiated CD8+ T cells had returned to baseline values, while the proportions of senescent CD4+ T cells increased 192% alongside a 31% reduction in naïve (CD45RA+/CD45RO-) cells. In conclusion, increases in differentiated and "transitional" T cells due to arduous exercise training could compromise host protection to novel pathogens and increase athlete infection risk, although whether or not the composition of naïve and differentiated T cells in blood can serve as prognostic biomarkers in athletes remains to be established.

  2. Low-frequency NNRTI-resistant HIV-1 variants and relationship to mutational load in antiretroviral-naïve subjects.

    PubMed

    Gupta, Shaili; Lataillade, Max; Kyriakides, Tassos C; Chiarella, Jennifer; St John, Elizabeth P; Webb, Suzin; Moreno, Elizabeth A; Simen, Birgitte B; Kozal, Michael J

    2014-09-16

    Low-frequency HIV variants possessing resistance mutations against non‑nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes.

  3. Peptide-pulsed dendritic cells induce the hepatitis C viral epitope-specific responses of naïve human T cells.

    PubMed

    Mishra, Sasmita; Losikoff, Phyllis T; Self, Alyssa A; Terry, Frances; Ardito, Matthew T; Tassone, Ryan; Martin, William D; De Groot, Anne S; Gregory, Stephen H

    2014-05-30

    Hepatitis C virus (HCV) is a major cause of liver disease. Spontaneous resolution of infection is associated with broad, MHC class I- (CD8(+)) and class II-restricted (CD4(+)) T cell responses to multiple viral epitopes. Only 20% of patients clear infection spontaneously, however, most develop chronic disease. The response to chemotherapy varies; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success in clinical trials. Vector-mediated vaccination with multi-epitope-expressing DNA constructs provides an improved approach. Highly-conserved, HLA-A2-restricted HCV epitopes and HLA-DRB1-restricted immunogenic consensus sequences (ICS, each composed of multiple overlapping and highly conserved epitopes) were predicted using bioinformatics tools and synthesized as peptides. HLA binding activity was determined in competitive binding assays. Immunogenicity and the ability of each peptide to stimulate naïve human T cell recognition and IFN-γ production were assessed in cultures of total PBMCs and in co-cultures composed of peptide-pulsed dendritic cells (DCs) and purified T lymphocytes, cell populations derived from normal blood donors. Essentially all predicted HLA-A2-restricted epitopes and HLA-DRB1-restricted ICS exhibited HLA binding activity and the ability to elicit immune recognition and IFN-γ production by naïve human T cells. The ability of DCs pulsed with these highly-conserved HLA-A2- and -DRB1-restricted peptides to induce naïve human T cell reactivity and IFN-γ production ex vivo demonstrates the potential efficacy of a multi-epitope-based HCV vaccine targeted to dendritic cells.

  4. Magnitude of cytopenias among HIV-infected children in Bahir Dar, northwest Ethiopia: a comparison of HAART-naïve and HAART-experienced children

    PubMed Central

    Tsegay, Yakob Gebregziabher; Tadele, Agerie; Addis, Zelalem; Alemu, Agersew; Melku, Mulugeta

    2017-01-01

    Background AIDS, caused by HIV, is a multisystem disease that affects hematopoiesis. The aim of this study was to assess cytopenias among HIV-infected children who had a follow-up at Felege Hiwot Referral Hospital, Bahir Dar, northwest Ethiopia. Methods An institution-based cross-sectional study was conducted between April and May 2013. Systematic random sampling method was used to select the study participants. Descriptive statistics, independent t-test as well as chi-square and logistic regression were used for analysis. A p-value <0.05 was considered as statistically significant. Results A total of 224 children (112 highly active antiretroviral therapy [HAART]-naïve and 112 HAART-experienced) participated in the study. The magnitude of anemia, thrombocytopenia, neutropenia, leukopenia and pancytopenia among HAART-naïve HIV-infected children were 30.4%, 9.8%, 8%, 4.5% and 1.8%, respectively. The overall prevalence of anemia, neutropenia, thrombocytopenia, leukopenia and pancytopenia were 29.5%, 8.9%, 8%, 4.5% and 1.4%, respectively. Cluster of differentiation-4 percentage and mean corpuscular volume were significantly different between HAART-experienced and HAART-naïve children. Being of younger age and severely immunosuppressed were risk factors of anemia. Conclusion Anemia was the most common cytopenia, followed by neutropenia. Severe immunosuppression and younger age were significantly associated with anemia. Therefore, emphasis should be given for investigation and management of cytopenias in HIV-infected children, particularly for those who are immunosuppressed and of younger age. PMID:28260948

  5. Tenofovir in the Treatment of Naïve and Refractory Chronic Hepatitis B: A Single Center Experience in Saudi Arabia

    PubMed Central

    Alsohaibani, Fahad; Alturaif, Noura; Abdulshakour, Ahmed; Alghamdi, Saad; Alshaibani, Alfadel; Alashgar, Hamad; Alkahtani, Khalid; Kagevi, Ingvar

    2015-01-01

    Background/Aims: Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used in the treatment of chronic hepatitis B (CHB) infection. This study evaluated the efficacy of TDF in achieving undetectable HBV DNA after 48 weeks of treatment in a Saudi cohort of CHB patients. Patients and Methods: This retrospective study included patients treated at a tertiary care center in Saudi Arabia from January 2009 to December 2012. Of the 68 eligible patients, 51 were treatment naïve and 17 were treatment-refractory. Twenty-three patients tested positive for HBeAg. The remaining 45 patients were HBeAg-negative. Results: The mean HBV DNA viral load decreased from 95 million IU/mL at baseline to 263 IU/mL after 48 weeks of treatment (P < 0.001). Overall, 62% of patients achieved a complete virological response (CVR) and 37% a partial virological response (PVR). Respective CVR and PVR rates according to subgroup were: HBeAg-positive (21.7% and 78.3%) and HBeAg-negative (84.4% and 15.6%). At 48 weeks, HBV DNA was undetectable in 66.7% of treatment-naïve and 53% of treatment-refractory patients (P = 0.3). Seroconversion occurred in 13 (57%) of HBeAg-positive patients. Two (3%) of the HBeAg-negative patients lost HBsAg at follow up. Mean alanine aminotransferase decreased significantly from 134 U/L before treatment to 37 U/L at 48 weeks (P < 0.001). Significant adverse events were not encountered during the study period. Conclusion: Forty-eight weeks of treatment with TDF reduced HBV DNA to undetectable levels in more than half of our patients regardless of whether they were treatment-naïve or refractory. HBeAg-negative (vs positive) patients experienced a better response rate. PMID:26458856

  6. Decreased Numbers of CD4+ Naive and Effector Memory T Cells, and CD8+ Naïve T Cells, are Associated with Trichloroethylene Exposure

    PubMed Central

    Hosgood, H. Dean; Zhang, Luoping; Tang, Xiaojiang; Vermeulen, Roel; Qiu, Chuangyi; Shen, Min; Smith, Martyn T.; Ge, Yichen; Ji, Zhiying; Xiong, Jun; He, Jian; Reiss, Boris; Liu, Songwang; Xie, Yuxuan; Guo, Weihong; Galvan, Noe; Li, Laiyu; Hao, Zhenyue; Rothman, Nathaniel; Huang, Hanlin; Lan, Qing

    2012-01-01

    Trichloroethylene (TCE) is a volatile chlorinated organic compound that is commonly used as a solvent for lipophilic compounds. Although recognized as an animal carcinogen, TCE’s carcinogenic potential in humans is still uncertain. We have carried out a cross-sectional study of 80 workers exposed to TCE and 96 unexposed controls matched on age and sex in Guangdong, China to study TCE’s early biologic effects. We previously reported that the total lymphocyte count and each of the major lymphocyte subsets (i.e., CD4+ T cells, CD8+ T cells, natural killer cells, and B cells) were decreased in TCE-exposed workers compared to controls, suggesting a selective effect on lymphoid progenitors, and/or lymphocyte survival. To explore which T lymphocyte subsets are affected in the same study population, we investigated the effect of TCE exposure on the numbers of CD4+ naïve and memory T cells, CD8+ naïve and memory T cells, and regulatory T cells by FACS analysis. Linear regression of each subset was used to test for differences between exposed workers and controls adjusting for potential confounders. We observed that CD4+ and CD8+ naïve T cell counts were about 8% (p = 0.056) and 17% (p = 0.0002) lower, respectively, among exposed workers. CD4+ effector memory T cell counts were decreased by about 20% among TCE-exposed workers compared to controls (p = 0.001). The selective targeting of TCE on CD8+ naive and possibly CD4+ naive T cells, and CD4+ effector memory T cells, provide further insights into the immunosuppression-related response of human immune cells upon TCE exposure. PMID:22649769

  7. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes

    PubMed Central

    Mendoza, Yaxelis; Castillo Mewa, Juan; Martínez, Alexander A.; Zaldívar, Yamitzel; Sosa, Néstor; Arteaga, Griselda; Armién, Blas; Bautista, Christian T.; García-Morales, Claudia; Tapia-Trejo, Daniela; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo; Bello, Gonzalo; Pascale, Juan M.

    2016-01-01

    The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug-experienced and 250 ARV drug-naïve HIV-1 subtypes B infected subjects during 2007–2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR-CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naïve and ARV drug-experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naïve subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5–10%) to Efavirenz/Nevirapine in ARV drug-naïve subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first-line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV. PMID:27119150

  8. Increasing HIV-1 pretreatment drug resistance among antiretroviral-naïve adults initiating treatment between 2006 and 2014 in Nairobi, Kenya.

    PubMed

    Chung, Michael H; Silverman, Rachel; Beck, Ingrid A; Yatich, Nelly; Dross, Sandra; McKernan-Mullin, Jennifer; Bii, Stephen; Tapia, Kenneth; Stern, Joshua; Chohan, Bhavna; Sakr, Samah R; Kiarie, James N; Frenkel, Lisa M

    2016-06-19

    Antiretroviral-naïve adults initiating antiretroviral therapy in Nairobi, Kenya were tested for HIV-1 drug resistance at codons K103N, Y181C, G190A, M184V, and K65R using an oligonucleotide ligation assay. Prevalence of pretreatment drug resistance increased from 3.89% in 2006 to 10.93% in 2014 (P < 0.001), and 95% of those with resistance had at least one nonnucleoside reverse transcriptase inhibitor mutation. Resistance to tenofovir (K65R) was found in 2014 but not in 2006.

  9. Loss of naïve T-cells and repertoire constriction predict poor response to vaccination in old primates1

    PubMed Central

    Čičin-Šain, Luka; Smyk-Paerson, Sue; Currier, Noreen; Byrd, Laura; Koudelka, Caroline; Robinson, Tammie; Swarbrick, Gwendolyn; Tackitt, Shane; Legasse, Alfred; Fischer, Miranda; Nikolich-Zugich, Dragana; Park, Byung; Hobbs, Theodore; Doane, Cynthia J.; Mori, Motomi; Axthelm, Michael T.; Lewinsohn, Deborah A.; Nikolich-Žugich, Janko

    2012-01-01

    Aging is usually accompanied by diminished immune protection upon infection or vaccination. While aging results in well-characterized changes in the T-cell compartment of long-lived, outbred, and pathogen-exposed organisms, their relevance for primary antigen responses remain unclear. Therefore, it remains unclear whether and to what extent the loss of naïve T-cells, their partial replacement by oligoclonal memory populations, and the consequent constriction of T-cell receptor (TCR) repertoire, limit the antigen responses in aging primates. PMID:20483749

  10. Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax challenge in vaccinia-naïve and vaccinia-immune individuals.

    PubMed

    Parrino, Janie; McCurdy, Lewis H; Larkin, Brenda D; Gordon, Ingelise J; Rucker, Steven E; Enama, Mary E; Koup, Richard A; Roederer, Mario; Bailer, Robert T; Moodie, Zoe; Gu, Lin; Yan, Lihan; Graham, Barney S

    2007-02-09

    Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax in vaccinia-naïve and vaccinia-immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax challenge at 3 months. Two or more doses of MVA prior to Dryvax reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax vaccinia-specific CD8(+) T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses.

  11. The transition of mouse pluripotent stem cells from the naïve to the primed state requires Fas signaling through 3-O sulfated heparan sulfate structures recognized by the HS4C3 antibody

    SciTech Connect

    Hirano, Kazumi; Van Kuppevelt, Toin H.; Nishihara, Shoko

    2013-01-18

    Highlights: ► Fas transcript increases during the transition from the naïve to the primed state. ► 3OST-5 transcript, the HS4C3 epitope synthesis gene, increases during the transition. ► Fas signaling regulates the transition from the naïve to the primed state. ► HS4C3-binding epitope regulates the transition from the naïve to the primed state. ► Fas signaling is regulated by the HS4C3 epitope during the transition. -- Abstract: The characteristics of pluripotent embryonic stem cells of human and mouse are different. The properties of human embryonic stem cells (hESCs) are similar to those of mouse epiblast stem cells (mEpiSCs), which are in a later developmental pluripotency state, the so-called “primed state” compared to mouse embryonic stem cells (mESCs) which are in a naïve state. As a result of the properties of the primed state, hESCs proliferate slowly, cannot survive as single cells, and can only be transfected with genes at low efficiency. Generating hESCs in the naïve state is necessary to overcome these problems and allow their application in regenerative medicine. Therefore, clarifying the mechanism of the transition between the naïve and primed states in pluripotent stem cells is important for the establishment of stable methods of generating naïve state hESCs. However, the signaling pathways which contribute to the transition between the naïve and primed states are still unclear. In this study, we carried out induction from mESCs to mEpiSC-like cells (mEpiSCLCs), and observed an increase in the activation of Fas signaling during the induction. The expression of Fgf5, an epiblast marker, was diminished by inhibition of Fas signaling using the caspase-8 and -3 blocking peptides, IETD and DEVD, respectively. Furthermore, during the induction, we observed increased expression of 3-O sulfated heparan sulfate (HS) structures synthesized by HS 3-O-sulfotransferase (3OST), which are recognized by the HS4C3 antibody (HS4C3-binding epitope

  12. Wood identification of Dalbergia nigra (CITES Appendix I) using quantitative wood anatomy, principal components analysis and naïve Bayes classification

    PubMed Central

    Gasson, Peter; Miller, Regis; Stekel, Dov J.; Whinder, Frances; Ziemińska, Kasia

    2010-01-01

    Background and Aims Dalbergia nigra is one of the most valuable timber species of its genus, having been traded for over 300 years. Due to over-exploitation it is facing extinction and trade has been banned under CITES Appendix I since 1992. Current methods, primarily comparative wood anatomy, are inadequate for conclusive species identification. This study aims to find a set of anatomical characters that distinguish the wood of D. nigra from other commercially important species of Dalbergia from Latin America. Methods Qualitative and quantitative wood anatomy, principal components analysis and naïve Bayes classification were conducted on 43 specimens of Dalbergia, eight D. nigra and 35 from six other Latin American species. Key Results Dalbergia cearensis and D. miscolobium can be distinguished from D. nigra on the basis of vessel frequency for the former, and ray frequency for the latter. Principal components analysis was unable to provide any further basis for separating the species. Naïve Bayes classification using the four characters: minimum vessel diameter; frequency of solitary vessels; mean ray width; and frequency of axially fused rays, classified all eight D. nigra correctly with no false negatives, but there was a false positive rate of 36·36 %. Conclusions Wood anatomy alone cannot distinguish D. nigra from all other commercially important Dalbergia species likely to be encountered by customs officials, but can be used to reduce the number of specimens that would need further study. PMID:19884155

  13. Raltegravir and Abacavir/Lamivudine in Japanese Treatment-Naïve and Treatment-Experienced Patients with HIV Infection: a 48-Week Retrospective Pilot Analysis.

    PubMed

    Suzuki, Akihito; Uehara, Yuki; Saita, Mizue; Inui, Akihiro; Isonuma, Hiroshi; Naito, Toshio

    2016-01-01

    Abacavir/lamivudine (ABC/3TC) is a nucleoside reverse transcriptase inhibitor used for treating human immunodeficiency viral (HIV) infections. Hypersensitivity reactions such as skin eruptions caused by ABC are well-known, but rarely occur in Asians. Raltegravir (RAL) is an integrase strand transfer inhibitor, that is now increasingly, used for treating HIV infections because it has few adverse effects. This retrospective analysis assessed the efficacy and safety of combined ABC/3TC and RAL in both treatment-naïve and -experienced Japanese patients with HIV infections. In all 11 treatment-naïve patients (100%), virological suppression to undetectable level was achieved. Liver transaminases, renal function, and serum lipid profiles showed no exacerbations up to 48 weeks of treatment. In 12 patients who were switched from previous regimens to ABC/3TC and RAL, HIV viral load was undetectable in 11 patients (91.6%), but remained detectable in 1 patient with poor adherence. Major reasons for switching regimens to ABC/3TC and RAL were hyperlipidemia and nausea. After switching, these adverse effects improved, and no new adverse effects were observed. Despite the small number of participants in this study, the results support the combination of ABC/3TC and RAL as a possible treatment choice in Japanese individuals with HIV-infection.

  14. The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression

    PubMed Central

    de Bruin, Ruben G.; van der Veer, Eric P.; Prins, Jurriën; Lee, Dae Hyun; Dane, Martijn J. C.; Zhang, Huayu; Roeten, Marko K.; Bijkerk, Roel; de Boer, Hetty C.; Rabelink, Ton J.; van Zonneveld, Anton Jan; van Gils, Janine M.

    2016-01-01

    Proper regulation of endothelial cell-cell contacts is essential for physiological functioning of the endothelium. Interendothelial junctions are actively involved in the control of vascular leakage, leukocyte diapedesis, and the initiation and progression of angiogenesis. We found that the RNA-binding protein quaking is highly expressed by endothelial cells, and that its expression was augmented by prolonged culture under laminar flow and the transcription factor KLF2 binding to the promoter. Moreover, we demonstrated that quaking directly binds to the mRNA of VE-cadherin and β-catenin and can induce mRNA translation mediated by the 3′UTR of these genes. Reduced quaking levels attenuated VE-cadherin and β-catenin expression and endothelial barrier function in vitro and resulted in increased bradykinin-induced vascular leakage in vivo. Taken together, we report that quaking is essential in maintaining endothelial barrier function. Our results provide novel insight into the importance of post-transcriptional regulation in controlling vascular integrity. PMID:26905650

  15. Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

    PubMed Central

    Myers, Darienne R; Polakos, Noelle K; Enders, Anselm; Roots, Carla; Balakishnan, Bhavani; Miosge, Lisa A; Sjollema, Geoff; Bertram, Edward M; Field, Matthew A; Shao, Yunli; Andrews, T Daniel; Whittle, Belinda; Barnes, S Whitney; Walker, John R; Cyster, Jason G

    2013-01-01

    Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation. DOI: http://dx.doi.org/10.7554/eLife.01020.001 PMID:24336796

  16. Inability to demonstrate fish-to-fish transmission of Ichthyophonus from laboratory infected Pacific herring Clupea pallasii to naïve conspecifics

    USGS Publications Warehouse

    Gregg, J.L.; Grady, C.A.; Friedman, C.S.; Hershberger, P.K.

    2012-01-01

    The parasite Ichthyophonus is enzootic in many marine fish populations of the northern Atlantic and Pacific Oceans. Forage fishes are a likely source of infection for higher trophic level predators; however, the processes that maintain Ichthyophonus in forage fish populations (primarily clupeids) are not well understood. Lack of an identified intermediate host has led to the convenient hypothesis that the parasite can be maintained within populations of schooling fishes by waterborne fish-to-fish transmission. To test this hypothesis we established Ichthyophonus infections in Age-1 and young-of-the-year (YOY) Pacific herring Clupea pallasii (Valenciennes) via intraperitoneal (IP) injection and cohabitated these donors with naïve conspecifics (sentinels) in the laboratory. IP injections established infection in 75 to 84% of donor herring, and this exposure led to clinical disease and mortality in the YOY cohort. However, after cohabitation for 113 d no infections were detected in naïve sentinels. These data do not preclude the possibility of fish-to-fish transmission, but they do suggest that other transmission processes are necessary to maintain Ichthyophonus in wild Pacific herring populations.

  17. ve-SEQ: Robust, unbiased enrichment for streamlined detection and whole-genome sequencing of HCV and other highly diverse pathogens

    PubMed Central

    Trebes, Amy; Brown, Anthony; Klenerman, Paul; Buck, David; Piazza, Paolo; Barnes, Eleanor; Bowden, Rory

    2015-01-01

    The routine availability of high-depth virus sequence data would allow the sensitive detection of resistance-associated variants that can jeopardize HIV or hepatitis C virus (HCV) treatment. We introduce ve-SEQ, a high-throughput method for sequence-specific enrichment and characterization of whole-virus genomes at up to 20% divergence from a reference sequence and 1,000-fold greater sensitivity than direct sequencing. The extreme genetic diversity of HCV led us to implement an algorithm for the efficient design of panels of oligonucleotide probes to capture any sequence among a defined set of targets without detectable bias. ve-SEQ enables efficient detection and sequencing of any HCV genome, including mixtures and intra-host variants, in a single experiment, with greater tolerance of sequence diversity than standard amplification methods and greater sensitivity than metagenomic sequencing, features that are directly applicable to other pathogens or arbitrary groups of target organisms, allowing the combination of sensitive detection with sequencing in many settings. PMID:27092241

  18. Endobronchial valves for patients with heterogeneous emphysema and without interlobar collateral ventilation: open label treatment following the BeLieVeR-HIFi study

    PubMed Central

    Zoumot, Zaid; Davey, Claire; Jordan, Simon; McNulty, William H; Carr, Denis H; Hind, Matthew D; Polkey, Michael I; Shah, Pallav L

    2017-01-01

    Outcomes in early trials of bronchoscopic lung volume reduction using endobronchial valves for the treatment of patients with advanced emphysema were inconsistent. However improvements in patient selection with focus on excluding those with interlobar collateral ventilation and homogeneous emphysema resulted in significant benefits in the BeLieVeR-HIFi study compared with sham treated controls. In this manuscript we present data from the control patients in the BeLieVeR-HIFi study who went on to have open label endobronchial valve treatment after completion of the clinical trial (n=12), combined with data from those in the treatment arm who did not have collateral ventilation (n=19). Three months after treatment FEV1 increased by 27.3 (36.4)%, residual volume reduced by 0.49 (0.76) L, the 6 min walk distance increased by 32.6 (68.7) m and the St George Respiratory Questionnaire for COPD score improved by 8.2 (20.2) points. These data extend the evidence for endobronchial valve placement in appropriately selected patients with COPD. Trial registration number: ISRCTN04761234; Results. PMID:27999170

  19. Similarities and differences of functional connectivity in drug-naïve, first-episode adolescent and young adult with major depressive disorder and schizophrenia

    PubMed Central

    Wei, Shengnan; Womer, Fay; Geng, Haiyang; Jiang, Xiaowei; Zhou, Qian; Chang, Miao; Zhou, Yifang; Tang, Yanqing; Wang, Fei

    2017-01-01

    Major depressive disorder (MDD) and schizophrenia (SZ) are considered two distinct psychiatric disorders. Yet, they have considerable overlap in symptomatology and clinical features, particularly in the initial phases of illness. The amygdala and prefrontal cortex (PFC) appear to have critical roles in these disorders; however, abnormalities appear to manifest differently. In our study forty-nine drug-naïve, first-episode MDD, 45 drug-naïve, first-episode SZ, and 50 healthy control (HC) participants from 13 to 30 years old underwent resting-state functional magnetic resonance imaging. Functional connectivity (FC) between the amygdala and PFC was compared among the three groups. Significant differences in FC were observed between the amygdala and ventral PFC (VPFC), dorsolateral PFC (DLPFC), and dorsal anterior cingulated cortex (dACC) among the three groups. Further analyses demonstrated that MDD showed decreased amygdala-VPFC FC and SZ had reductions in amygdala-dACC FC. Both the diagnostic groups had significantly decreased amygdala-DLPFC FC. These indicate abnormalities in amygdala-PFC FC and further support the importance of the interaction between the amygdala and PFC in adolescents and young adults with these disorders. Additionally, the alterations in amygdala-PFC FC may underlie the initial similarities observed between MDD and SZ and suggest potential markers of differentiation between the disorders at first onset. PMID:28287187

  20. Chilades pandava mothers discriminate among Cycas species during oviposition choice tests, but only in an endemic naïve population.

    PubMed

    Marler, Thomas E; Lindström, Anders J; Marler, Paris N

    2016-08-02

    Host and non-host plant species communicate with insect herbivores to influence oviposition decisions. We studied if Chilades pandava female adults expressed oviposition preferences among host Cycas species in 2 choice tests, counting 39,420 eggs among assays from 4 butterfly populations. A naïve butterfly population from Cycas nongnoochiae habitat oviposited 2.2-fold more eggs on leaves of Cycas species that are susceptible to butterfly herbivory than on leaves of its native host Cycas nongnoochiae. In contrast, Chilades pandava populations experienced with novel Cycas species in Thailand, Philippines, and Guam exhibited no preference in choice tests between leaves of susceptible versus leaves of minimally damaged Cycas species. The results indicated that oviposition deterrents and/or stimulants partly mediate the sustainable relationship between an endemic Cycas species and the naïve Chilades pandava population from its habitat. Alternatively, differences in infochemicals among Cycas species do not enable discrimination in oviposition choices for Chilades pandava populations that have experienced Cycas species exhibiting no evolutionary history with Chilades pandava.

  1. Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.

    PubMed

    Zimran, Ari; Durán, Gloria; Mehta, Atul; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Amato, Dominick J; Petakov, Milan; Muñoz, Eduardo Terreros; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Chertkoff, Raul; Brill-Almon, Einat

    2016-07-01

    Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc.

  2. Long‐term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment‐naïve patients with Gaucher disease

    PubMed Central

    Durán, Gloria; Mehta, Atul; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Amato, Dominick J.; Petakov, Milan; Muñoz, Eduardo Terreros; Solorio‐Meza, Sergio Eduardo; Cooper, Peter A.; Varughese, Sheeba; Chertkoff, Raul; Brill‐Almon, Einat

    2016-01-01

    Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell–expressed recombinant therapeutic protein. Herein, we report long‐term safety and efficacy results of taliglucerase alfa in treatment‐naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment‐related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36‐month results of taliglucerase alfa in treatment‐naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656–660, 2016. © 2016 Wiley Periodicals, Inc. PMID:27174694

  3. Tumor-associated mesenchymal stem cells inhibit naïve T cell expansion by blocking cysteine export from dendritic cells.

    PubMed

    Ghosh, Tithi; Barik, Subhasis; Bhuniya, Avishek; Dhar, Jesmita; Dasgupta, Shayani; Ghosh, Sarbari; Sarkar, Madhurima; Guha, Ipsita; Sarkar, Koustav; Chakrabarti, Pinak; Saha, Bhaskar; Storkus, Walter J; Baral, Rathindranath; Bose, Anamika

    2016-11-01

    Mesenchymal stem cells (MSCs) represent an important cellular constituent of the tumor microenvironment, which along with tumor cells themselves, serve to regulate protective immune responses in support of progressive disease. We report that tumor MSCs prevent the ability of dendritic cells (DC) to promote naïve CD4(+) and CD8(+) T cell expansion, interferon gamma secretion and cytotoxicity against tumor cells, which are critical to immune-mediated tumor eradication. Notably, tumor MSCs fail to prevent DC-mediated early T cell activation events or the ability of responder T cells to produce IL-2. The immunoregulatory activity of tumor MSCs is IL-10- and STAT3-dependent, with STAT3 repressing DC expression of cystathionase, a critical enzyme that converts methionine-to-cysteine. Under cysteine-deficient priming conditions, naïve T cells exhibit defective cellular metabolism and proliferation. Bioinformatics analyses as well as in vitro observations suggest that STAT3 may directly bind to a GAS-like motif within the cystathionase promoter (-269 to -261) leading to IL-10-STAT3 mediated repression of cystathionase gene transcription. Our collective results provide evidence for a novel mechanism of tumor MSC-mediated T cell inhibition within tumor microenvironment.

  4. TCR sequences and tissue distribution discriminate the subsets of naïve and activated/memory Treg cells in mice.

    PubMed

    Bergot, Anne-Sophie; Chaara, Wahiba; Ruggiero, Eliana; Mariotti-Ferrandiz, Encarnita; Dulauroy, Sophie; Schmidt, Manfred; von Kalle, Christof; Six, Adrien; Klatzmann, David

    2015-05-01

    Analyses of the regulatory T (Treg) cell TCR repertoire should help elucidate the nature and diversity of their cognate antigens and thus how Treg cells protect us from autoimmune diseases. We earlier identified CD44(hi) CD62L(low) activated/memory (am) Treg cells as a Treg-cell subset with a high turnover and possible self-specificity. We now report that amTreg cells are predominantly distributed in lymph nodes (LNs) draining deep tissues. Multivariate analyses of CDR3 spectratyping first revealed that amTreg TCR repertoire is different from that of naïve Treg cells (nTreg cells) and effector T (Teff) cells. Furthermore, in deep- versus superficial LNs, TCR-β deep sequencing further revealed diversified nTreg-cell and amTreg-cell repertoires, although twofold less diverse than that of Teff cells, and with repertoire richness significantly lower in deep-LN versus superficial-LN Treg cells. Importantly, expanded clonotypes were mostly detected in deep-LN amTreg cells, some accounting for 20% of the repertoire. Strikingly, these clonotypes were absent from nTreg cells, but found at low frequency in Teff cells. Our results, obtained in nonmanipulated mice, indicate different antigenic targets for naïve and amTreg cells and that amTreg cells are self-specific. The data we present are consistent with an instructive component in Treg-cell differentiation.

  5. A practical tool for public health surveillance: Semi-automated coding of short injury narratives from large administrative databases using Naïve Bayes algorithms.

    PubMed

    Marucci-Wellman, Helen R; Lehto, Mark R; Corns, Helen L

    2015-11-01

    Public health surveillance programs in the U.S. are undergoing landmark changes with the availability of electronic health records and advancements in information technology. Injury narratives gathered from hospital records, workers compensation claims or national surveys can be very useful for identifying antecedents to injury or emerging risks. However, classifying narratives manually can become prohibitive for large datasets. The purpose of this study was to develop a human-machine system that could be relatively easily tailored to routinely and accurately classify injury narratives from large administrative databases such as workers compensation. We used a semi-automated approach based on two Naïve Bayesian algorithms to classify 15,000 workers compensation narratives into two-digit Bureau of Labor Statistics (BLS) event (leading to injury) codes. Narratives were filtered out for manual review if the algorithms disagreed or made weak predictions. This approach resulted in an overall accuracy of 87%, with consistently high positive predictive values across all two-digit BLS event categories including the very small categories (e.g., exposure to noise, needle sticks). The Naïve Bayes algorithms were able to identify and accurately machine code most narratives leaving only 32% (4853) for manual review. This strategy substantially reduces the need for resources compared with manual review alone.

  6. Live imaging of X chromosome reactivation dynamics in early mouse development can discriminate naïve from primed pluripotent stem cells.

    PubMed

    Kobayashi, Shin; Hosoi, Yusuke; Shiura, Hirosuke; Yamagata, Kazuo; Takahashi, Saori; Fujihara, Yoshitaka; Kohda, Takashi; Okabe, Masaru; Ishino, Fumitoshi

    2016-08-15

    Pluripotent stem cells can be classified into two distinct states, naïve and primed, which show different degrees of potency. One difficulty in stem cell research is the inability to distinguish these states in live cells. Studies on female mice have shown that reactivation of inactive X chromosomes occurs in the naïve state, while one of the X chromosomes is inactivated in the primed state. Therefore, we aimed to distinguish the two states by monitoring X chromosome reactivation. Thus far, X chromosome reactivation has been analysed using fixed cells; here, we inserted different fluorescent reporter gene cassettes (mCherry and eGFP) into each X chromosome. Using these knock-in 'Momiji' mice, we detected X chromosome reactivation accurately in live embryos, and confirmed that the pluripotent states of embryos were stable ex vivo, as represented by embryonic and epiblast stem cells in terms of X chromosome reactivation. Thus, Momiji mice provide a simple and accurate method for identifying stem cell status based on X chromosome reactivation.

  7. The TLR9 ligand CpG promotes the acquisition of Plasmodium falciparum-specific memory B cells in malaria-naïve individuals

    PubMed Central

    Crompton, Peter D.; Mircetic, Marko; Weiss, Greta; Baughman, Amy; Huang, Chiung-Yu; Topham, David J.; Treanor, John J.; Sanz, Iñaki; Lee, F. Eun-Hyung; Durbin, Anna P.; Miura, Kazutoyo; Narum, David L.; Ellis, Ruth D.; Malkin, Elissa; Mullen, Gregory E.D.; Miller, Louis H.; Martin, Laura B.; Pierce, Susan K.

    2009-01-01

    Despite the central role of memory B cells (MBC) in protective immune responses, little is understood about how they are acquired in naïve individuals in response to antigen exposure, and how this process is influenced by concurrent activation of the innate immune system’s Toll-like receptors (TLR). In this longitudinal study of malaria-naïve individuals, we examined the MBC response to two candidate malaria vaccines administered with or without CpG, a TLR9 ligand. We show that the acquisition of MBC is a dynamic process in which the vaccine-specific MBC pool rapidly expands and then contracts, and that CpG enhances the kinetics, magnitude, and longevity of this response. We observed that the percentage of vaccine-specific MBC present at the time of re-immunization predicts vaccine-specific Ab levels 14 days later; and that at steady state, there is a positive correlation between vaccine-specific MBC and Ab levels. An examination of the total circulating MBC and plasma cell (PC) pools also suggests that MBC differentiate into PC through polyclonal activation, independent of antigen specificity. These results provide important insights into the human MBC response which can inform the development of vaccines against malaria and other pathogens that disrupt immunological memory. PMID:19234231

  8. Activation Outcomes Induced in Naïve CD8 T-Cells by Macrophages Primed via “Phagocytic” and Nonphagocytic Pathways

    PubMed Central

    Olazabal, Isabel María; Martín-Cofreces, Noa Beatriz; Mittelbrunn, María; Martínez del Hoyo, Gloria; Alarcón, Balbino

    2008-01-01

    The array of phagocytic receptors expressed by macrophages make them very efficient at pathogen clearance, and the phagocytic process links innate with adaptive immunity. Primary macrophages modulate antigen cross-presentation and T-cell activation. We assessed ex vivo the putative role of different phagocytic receptors in immune synapse formation with CD8 naïve T-cells from OT-I transgenic mice and compared this with the administration of antigen as a soluble peptide. Macrophages that have phagocytosed antigen induce T-cell microtubule-organizing center and F-actin cytoskeleton relocalization to the contact site, as well as the recruitment of proximal T-cell receptor signals such as activated Vav1 and PKCθ. At the same doses of loaded antigen (1 μM), “phagocytic” macrophages were more efficient than peptide-antigen–loaded macrophages at forming productive immune synapses with T-cells, as indicated by active T-cell TCR/CD3 conformation, LAT phosphorylation, IL-2 production, and T-cell proliferation. Similar T-cell proliferation efficiency was obtained when low doses of soluble peptide (3–30 nM) were loaded on macrophages. These results suggest that the pathway used for antigen uptake may modulate the antigen density presented on MHC-I, resulting in different signals induced in naïve CD8 T-cells, leading either to CD8 T-cell activation or anergy. PMID:18077558

  9. Naïve adult stem cells from patients with Hutchinson-Gilford progeria syndrome express low levels of progerin in vivo.

    PubMed

    Wenzel, Vera; Roedl, Daniela; Gabriel, Diana; Gordon, Leslie B; Herlyn, Meenhard; Schneider, Reinhard; Ring, Johannes; Djabali, Karima

    2012-06-15

    Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by segmental accelerated aging and early death from coronary artery disease or stroke. Nearly 90% of HGPS sufferers carry a G608G mutation within exon 11 of LMNA, producing a truncated form of prelamin A, referred to as "progerin". Here, we report the isolation of naïve multipotent skin-derived precursor (SKP) cells from dermal fibroblast cultures from HGPS donors. These cells form spheres and express the neural crest marker, nestin, in addition to the multipotent markers, OCT4, Sox2, Nanog and TG30; these cells can self-renew and differentiate into smooth muscle cells (SMCs) and fibroblasts. The SMCs derived from the HGPS-SKPs accumulate nuclear progerin with increasing passages. A subset of the HGPS-naïve SKPs express progerin in vitro and in situ in HGPS skin sections. This is the first in vivo evidence that progerin is produced in adult stem cells, and implies that this protein could induce stem cells exhaustion as a mechanism contributing to aging. Our study provides a basis on which to explore therapeutic applications for HGPS stem cells and opens avenues for investigating the pathogenesis of other genetic diseases.

  10. HIV-derived lentiviral particles promote T-cell independent activation and differentiation of naïve cognate conventional B2-cells in vitro.

    PubMed

    Gardt, Oliver; Grewe, Bastian; Tippler, Bettina G; Überla, Klaus; Temchura, Vladimir V

    2013-10-17

    In animal models, lentiviral particles (LP) were shown to be promising HIV vaccine candidates. Since little is known about the direct impact of LP on antigen-specific B cells, we incorporated Hen Egg Lysozyme (HEL) into LP (HEL-LP) derived from HIV to study their effect on HEL-specific, B cell receptor-transgenic B-cells (HEL(+)B-cells) in vitro. We observed preferential binding of HEL-LP to HEL(+)B-cells and their efficient internalization. HEL-LP were able to effectively cross-link B-cell receptors as indicated by the loss of surface CD62L. In the absence of CD4(+) T-cells, other activation events induced by LP in cognate naïve B-cells included increased expression of activation and co-stimulatory molecules as well as an enhanced proliferative response. Additionally, the B-cell phenotype shifted toward a germinal center pattern with further differentiation into memory and IgG3- and IgA-producing cells. The observed CD4(+) T-cell independent activation and differentiation may be due to LP-induced expression of CD40L by a subset of cognate B-cells. Thus, even in the absence of CD4(+) T-cells LP provide strong direct activation signals to cognate naïve B-cells, which may contribute to the strong humoral immune responses observed after LP immunization.

  11. The decays of three top contributors to the reactor ve high-energy spectrum, 92Rb, 96gsY, and 142Cs, studied with total absorption spectroscopy

    NASA Astrophysics Data System (ADS)

    Rasco, Bertis; MTAS Collaboration

    2016-09-01

    We report total absorption spectroscopy measurements of 92Rb, 96gsY, and 142Cs β decays, which are the most important contributors to the high energy ve spectral shape in nuclear reactors. The measurements were performed with the NaI(Tl) based Modular Total Absorption Spectrometer (MTAS). MTAS was constructed specifically to measure improved β-decay feeding patterns from neutron-rich nuclei, because it is difficult to measure β-decay feeding intensities with high energy precision γ-ray measurements due to the low efficiency of high precision detectors. Besides the impact to the high energy ve spectral shape in nuclear reactors, there are several other important applications of improved measurements of β-decay feeding patterns by total absorption spectroscopy; improve understanding of elemental abundances in the universe, help with stockpile stewardship, contribute to understanding of underlying nuclear structure, and improve measurements of decay heat. We will demonstrate some of the techniques for analyzing MTAS γ-decay data. This research was also sponsored by the Office of Nuclear Physics, U. S. Department of Energy under Contracts DE-AC05-00OR22725, DE-FG02-96ER40983, DE-FG02-96ER40978, and by the Polish National Science Center under Contract UMO-2013/08/T/ST2/00624.

  12. Successful closure of treatment-naïve, flat edge (Type II), full-thickness macular hole using inverted internal limiting membrane flap technique

    PubMed Central

    Hussain, Nazimul; Hussain, Anjli

    2016-01-01

    Objective The objective of this study was to present the outcome of the internal limiting membrane (ILM) peeling flap technique for a treatment-naïve, flat edge (Type II), full-thickness macular hole (MH). Methods A 52-year-old man presented with complaints of decreased vision and seeing black spot. He was diagnosed to have a flat edge, full-thickness MH, which was confirmed by optical coherence tomography (OCT). He underwent 23G vitrectomy with brilliant blue G-assisted inverted ILM peeling with an inverted flap over the hole followed by fluid gas exchange. Results Postoperative follow-up until 3 months showed successful closure of the MH, which was confirmed by OCT. The best-corrected visual acuity improved from baseline 6/60 to 6/12 at the final follow-up. Conclusion Using the inverted ILM flap technique, a treatment-naïve, flat edge (Type II), full thickness MH achieved successful anatomical and functional outcomes. PMID:27785110

  13. The VeTOOLS Project: an example of how to strengthen collaboration between scientists and Civil Protections in disaster risk reduction

    NASA Astrophysics Data System (ADS)

    Marti, Joan; Bartolini, Stefania; Becerril, Laura

    2016-04-01

    VeTOOLS is a project funded by the European Commission's Humanitarian Aid and Civil Protection department (ECHO), and aims at creating an integrated software platform specially designed to assess and manage volcanic risk. The project facilitates interaction and cooperation between scientists and Civil Protection Agencies in order to share, unify, and exchange procedures, methodologies and technologies to effectively reduce the impacts of volcanic disasters. The project aims at 1) improving and developing volcanic risk assessment and management capacities in active volcanic regions; 2) developing universal methodologies, scenario definitions, response strategies and alert protocols to cope with the full range of volcanic threats; 4) improving quantitative methods and tools for vulnerability and risk assessment; and 5) defining thresholds and protocols for civil protection. With these objectives, the VeTOOLS project points to two of the Sendai Framework resolutions for implementing it: i) Provide guidance on methodologies and standards for risk assessments, disaster risk modelling and the use of data; ii) Promote and support the availability and application of science and technology to decision-making, and offers a good example on how a close collaboration between science and civil protection is an effective way to contribute to DRR. European Commission ECHO Grant SI2.695524

  14. The prognostic value of DNA damage level in peripheral blood lymphocytes of chemotherapy-naïve patients with germ cell cancer

    PubMed Central

    Sestakova, Zuzana; Kalavska, Katarina; Hurbanova, Lenka; Jurkovicova, Dana; Gursky, Jan; Chovanec, Michal; Svetlovska, Daniela; Miskovska, Vera; Obertova, Jana; Palacka, Patrik; Rejlekova, Katarina; Sycova-Mila, Zuzana; Cingelova, Silvia; Spanik, Stanislav; Mardiak, Jozef; Chovanec, Miroslav; Mego, Michal

    2016-01-01

    Germ cell tumors (GCTs) are extraordinarily sensitive to cisplatin (CDDP)-based chemotherapy. DNA damage represents one of the most important factors contributing to toxic effects of CDDP-based chemotherapy. This study was aimed to evaluate the prognostic value of DNA damage level in peripheral blood lymphocytes (PBLs) from chemo-naïve GCT patients. PBLs isolated from 59 chemotherapy-naïve GCT patients were included into this prospective study. DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage tail DNA by the Metafer-MetaCyte analyzing software. The mean ± SEM (standard error of the mean) of endogenous DNA damage level was 5.25 ± 0.64. Patients with DNA damage levels lower than mean had significantly better progression free survival (hazard ratio [HR] = 0.19, 95% CI (0.04 – 0.96), P = 0.01) and overall survival (HR = 0.00, 95% CI (0.00 – 0.0), P < 0.001) compared to patients with DNA damage levels higher than mean. Moreover, there was significant correlation between the DNA damage level and presence of mediastinal lymph nodes metastases, IGCCCG (International Germ Cell Cancer Collaborative Group) risk group, and serum tumor markers level. These data suggest that DNA damage levels in PBLs of GCT patients may serve as an important prognostic marker early identifying patients with poor outcome. PMID:27732956

  15. The frequency of naïve and early-activated hapten-specific B cell subsets dictates the efficacy of a therapeutic vaccine against prescription opioid abuse

    PubMed Central

    Laudenbach, Megan; Baruffaldi, Federico; Vervacke, Jeffrey S; Distefano, Mark D; Titcombe, Philip J; Mueller, Daniel L; Tubo, Noah J; Griffith, Thomas S; Pravetoni, Marco

    2015-01-01

    Translation of therapeutic vaccines for addiction, cancer or other chronic non-communicable diseases has been slow because only a small subset of immunized subjects achieved effective antibody levels. We hypothesize that individual variability in the number of naïve and early-activated hapten-specific B cells determines post-vaccination serum antibody levels and vaccine efficacy. Using a model vaccine against the highly abused prescription opioid oxycodone, the polyclonal B cell population specific for an oxycodone-based hapten (6OXY) was analyzed by flow cytometry paired with antigen-based magnetic enrichment. A higher frequency of 6OXY-specific B cells in either spleen biopsies or blood, before and after immunization, correlated to subsequent greater oxycodone-specific serum antibody titers and their efficacy in blocking oxycodone distribution to the brain and oxycodone-induced behavior in mice. The magnitude of 6OXY-specific B cell activation and vaccine efficacy was tightly correlated to the size of the CD4+ T cell population. The frequency of enriched 6OXY-specific B cells was consistent across various mouse tissues. These data provide novel evidence that variations in the frequency of naïve or early-activated vaccine-specific B and T cells can account for individual responses to vaccines and may predict the clinical efficacy of a therapeutic vaccine. PMID:25972483

  16. Numerical and physical modelling of coastal cliff retreat processes between La Hève and Antifer capes, Normandy (NW France)

    NASA Astrophysics Data System (ADS)

    Le Cossec, Jérôme; Duperret, Anne; Vendeville, Bruno C.; Taibi, Said

    2011-09-01

    The study area is located along the French eastern Channel coastline, in Upper Normandy, between the La Hève and Antifer capes. The sedimentary series dip North-Eastward by 0.7° and comprise clay layers (Kimmeridgian and Albian clays) located at varying vertical elevation along the cliff (about 90 m high). This coastal cliff section is undergoing slow gravitational deformation, assumed to take place along the clay layers. Using numerical and experimental models, we investigated the role of clay layers, acting as potential detachment layers, on the development of gravitational instabilities. In order to properly design our models, we characterized the rock mechanical parameters using triaxial shear tests on in-situ samples dated from Kimmeridgian to Cenomanian. We ran a series of numerical simulations using a finite-element code applied to 2-D cliff cross section having varying lithological and mechanical layering. Under the sole effect of gravity forces, the plastic strains are mainly localised along the two clay layers, and the predicted displacements evidence a seaward sliding of the cliff. We further investigated gravitational deformation in the cliff using experimental models subjected to high pore-fluid pressure using by injecting compressed air at the base of the model. The presence of fluid overpressure can trigger spontaneous dismemberment of a cliff that would otherwise remain stable. The region of the model located near the initial cliff spread seaward, which generated a set of normal faults that propagated landward and create a frontal toe bulge. We modelled a more complex initial geometry closer that observed in the field by simulating the northward progressive deepening of a potential décollement (the Gault clay). In the segment of the model where the potential décollement layer lay above or at the cliff's base, the absence of frontal buttress allowed for a large part of the cliff to slide seaward. The compressional toe of the deformed wedge

  17. Associations of HIV infection with insulin and glucose levels in antiretroviral-naïve Rwandan women: a cross-sectional analysis

    PubMed Central

    Dusingize, Jean Claude; Hoover, Donald R; Shi, Qiuhu; Mutimura, Eugene; Kiefer, Elizabeth; Anastos, Kathryn

    2013-01-01

    Objectives The purpose of these analyses was to determine the associations of HIV infection and related immune dysfunction with a glucose homeostasis in the population of antiretroviral-naïve HIV-infected and uninfected Rwandan women. We hypothesise that insulin resistance and its consequences in the developing countries may be further elevated with HIV infection itself regardless of antiretroviral therapy. Study design Cross-sectional analysis of a longitudinal cohort. Setting Community-based women's associations. Participants In 2005, 710 HIV-infected (HIV positive) antiretroviral naïve and 226 HIV-uninfected (HIV negative) women were enrolled in the Rwanda Women's Interassociation Study and Assessment (RWISA). Clinical and demographic parameters, CD4 count, fasting insulin and glucose levels, anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were obtained. Linear models were fit to log-transformed Homeostasis Model Assessment (HOMA) with results exponentiated back to a multiplicative effect on the original scale. Primary outcome measures The outcome, insulin resistance, was measured by the HOMA, calculated as fasting insulin (μU/mL)×fasting glucose (mmol/L)⁄22.5. Results In adjusted models, HIV-positive women were less insulin resistant than HIV-negative; an HIV-positive woman tended to have 0.728 times as much (95% CI 0.681 to 0.861) HOMA than a comparable HIV-negative woman. Among the HIV-positive women, those with CD4 <200 cells/µL tended to have 0.741 times as much HOMA (95% CI 0.601 to 0.912) as did comparable women with CD4 >350 cells/µL. The older age was independently associated with a lower HOMA insulin resistance. After adjusting for body mass index, fat and fat-free mass were not independently associated with HOMA. Conclusions This study found that HIV infection and more advanced HIV infection (CD4 counts <200 cells/µL) were associated with greater insulin sensitivity in antiretroviral naïve African women. These

  18. Effect of Linagliptin on Glycemic Control in Chinese Patients with Newly-Diagnosed, Drug-Naïve Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

    PubMed

    Wu, Wenjun; Li, Ying; Chen, Xiong; Lin, Dini; Xiang, Songying; Shen, Feixia; Gu, Xuemei

    2015-09-09

    BACKGROUND This study aimed to evaluate the efficacy and safety of linagliptin (a novel dipeptidyl peptidase (DPP)-4 inhibitor) on glucose metabolism and β-cell function in Chinese patients with newly-diagnosed, drug-naïve type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS Newly-diagnosed and drug-naïve T2DM patients were enrolled. After 4-week lifestyle modulation and 2-week placebo run-in, 57 patients were randomized to double-blind treatment with linagliptin (n=34) or placebo (n=23). The primary endpoint was the change from baseline in glycosylated hemoglobin A1c (HbA1c) after 24 weeks. Fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2h-PPG), fasting insulin, proinsulin-to-insulin ratio, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) were also evaluated. RESULTS Baseline characteristics were similar between the 2 groups. Compared with placebo, linagliptin therapy resulted in a significant decrease in HbA1C (-1.2±0.7% vs. -0.4±0.4%, P<0.001), FBG (-0.98±1.17 vs. -0.32±0.51 mmol/L, P=0.011, and 2h-PPG (-2.02±0.94 vs. -0.97±0.63 mmol/L, P<0.001). Significant differences were observed for the proinsulin/insulin ratio (P<0.001) and HOMA-β index (P=0.001). Rates of adverse events were similar between the 2 groups (30.3% vs. 27.3%). All adverse events were mild. One patient discontinued participation due to pregnancy. CONCLUSIONS Linagliptin treatment resulted in a significant and clinically meaningful improvement of glycemic control in drug-naïve Chinese patients with T2DM, as well as improved parameters of b-cell function. Linagliptin had an excellent safety profile.

  19. HIV-1 drug resistance genotyping from antiretroviral therapy (ART) naïve and first-line treatment failures in Djiboutian patients

    PubMed Central

    2012-01-01

    Abstract In this study we report the prevalence of antiretroviral drug resistant HIV-1 genotypes of virus isolated from Djiboutian patients who failed first-line antiretroviral therapy (ART) and from ART naïve patients. Patients and methods A total of 35 blood samples from 16 patients who showed first-line ART failure (>1000 viral genome copies/ml) and 19 ART-naïve patients were collected in Djibouti from October 2009 to December 2009. Both the protease (PR) and reverse transcriptase (RT) genes were amplified and sequenced using National Agency for AIDS Research (ANRS) protocols. The Stanford HIV database algorithm was used for interpretation of resistance data and genotyping. Results Among the 16 patients with first-line ART failure, nine (56.2%) showed reverse transcriptase inhibitor-resistant HIV-1 strains: two (12.5%) were resistant to nucleoside (NRTI), one (6.25%) to non-nucleoside (NNRTI) reverse transcriptase inhibitors, and six (37.5%) to both. Analysis of the DNA sequencing data indicated that the most common mutations conferring drug resistance were M184V (38%) for NRTI and K103N (25%) for NNRTI. Only NRTI primary mutations K101Q, K103N and the PI minor mutation L10V were found in ART naïve individuals. No protease inhibitor resistant strains were detected. In our study, we found no detectable resistance in ∼ 44% of all patients who experienced therapeutic failure which was explained by low compliance, co-infection with tuberculosis and malnutrition. Genotyping revealed that 65.7% of samples were infected with subtype C, 20% with CRF02_AG, 8.5% with B, 2.9% with CRF02_AG/C and 2.9% with K/C. Conclusion The results of this first study about drug resistance mutations in first-line ART failures show the importance of performing drug resistance mutation test which guides the choice of a second-line regimen. This will improve the management of HIV-infected Djiboutian patients. Virtual slides The virtual slide(s) for this article can be found here

  20. 25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients

    PubMed Central

    Belle, Arthur; Gizard, Emmanuel; Conroy, Guillaume; Lopez, Anthony; Bouvier-Alias, Magali; Rouanet, Stéphanie; Peyrin-Biroulet, Laurent; Pawlotsky, Jean-Michel

    2016-01-01

    Background and aim The impact of 25-OH vitamin D on sustained viral response (SVR) to antiviral therapy and on fibrosis progression in hepatitis C is debated. We assessed the impact of 25-OH vitamin D concentration on the efficacy of antiviral therapy in naïve genotype 1 hepatitis C virus (HCV)-infected patients. Methods The study population consisted of treatment-naïve genotype 1 patients enrolled in a randomised controlled trial. A total of 516 patients received peginterferon α-2a 180 µg/week plus ribavirin 800 mg/day for 24 weeks. There were 349 patients with undetectable HCV RNA (<50 IU/ml) at week 24 (W24) who were randomised to continue dual therapy (n = 173) or to continue peginterferon alone (n = 176) until week 48. 25-OH vitamin D concentration was measured at baseline in frozen serum. Results A total of 461 patients could be analysed for virologic response at W24, and 285 (119 non-responders at W24 + 166 responders who continued dual therapy until W48) for the impact of SVR. There were 487 patients who could be analysed for fibrosis progression. Metavir fibrosis scores (centralised analysis) were: F1 30%, F2 34%, F3 27% and F4 9%. Median 25-OH vitamin D concentrations were similar in virologic responders (13.5 ng/ml) and in non-responders at W24 (12.6 ng/ml), as well as in patients with SVR (12.8 ng/ml) and without SVR (12.8 ng/ml, 3.99) at W72. Median 25-OH vitamin D concentrations were: F1: 14.30 ng/ml, F2: 13.50 ng/ml, F3: 13.30 ng/ml and F4: 12.80 ng/ml. Conclusion In this study, 25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients.

  1. Dysfunction of the Default Mode Network in Drug-Naïve Parkinson’s Disease with Mild Cognitive Impairments: A Resting-State fMRI Study

    PubMed Central

    Hou, Yanbing; Yang, Jing; Luo, Chunyan; Song, Wei; Ou, Ruwei; Liu, Wanglin; Gong, Qiyong; Shang, Huifang

    2016-01-01

    Objective: Cognitive impairments are common in Parkinson’s disease (PD) and can even occur in the early stages. The default mode network (DMN) is highly relevant for cognitive processes; however, it remains largely unknown if changes in the DMN connectivity are related to the cognitive decline in drug-naïve early stage PD patients with a mild cognitive impairment (MCI). This study used resting-state functional MRI (fMRI) to explore the brain connectivity of the DMN in early stage drug-naïve PD patients with MCI. Method: We recruited 32 early stage drug-naïve PD patients and 22 matched healthy controls (HC). Among the PD patients, 14 were classified as having MCI (PD-MCI) and 18 were classified as having unimpaired cognition (PD-CU). The functional integration of the DMN was evaluated by a seed-based correlation approach. Results: The brain connectivity analysis revealed reduced functional connectivity (FC) in both PD subgroups compared with HC. The PD-MCI group showed a significant reduction in FC between the DMN and a set of regions, including the precentral gyrus, middle temporal gyrus, insula, anterior inferior parietal lobule and middle frontal gyrus. Compared to the PD-CU group, the PD-MCI group demonstrated a significantly decreased FC in the middle frontal and middle temporal gyri. Additionally, compared to HC, the PD-MCI group had a significantly decreased FC within the DMN, mainly in the FC between the hippocampal formation and inferior frontal gyrus, between the posterior cingulate cortex and posterior inferior parietal lobule, and between the anterior temporal lobe and inferior frontal gyrus. Compared to the PD-CU group, the only significantly decreased FC within the DMN in the PD-MCI group was between the anterior temporal lobe and inferior frontal gyrus. In all PD patients, the decreased FC between anterior temporal lobe and middle temporal gyrus was positively correlated with attention/working performance, and the reduced FC between the

  2. Extensive scaling and nonuniformity of the Karhunen-Lo{grave e}ve decomposition for the spiral-defect chaos state

    SciTech Connect

    Zoldi, S.M.; Liu, J.; Liu, J.; Greenside, H.S.

    1998-12-01

    By analyzing large-aspect-ratio spiral-defect chaos (SDC) convection images, we show that the Karhunen-Lo{grave e}ve decomposition (KLD) scales extensively for subsystem sizes larger than 4d ({ital d} is the fluid depth), which strongly suggests that SDC is extensively chaotic. From this extensive scaling, the intensive length {xi}{sub KLD} is computed and found to have a different dependence on the Rayleigh number than the two-point correlation length {xi}{sub 2}. Local computations of {xi}{sub KLD} reveal a spatial nonuniformity of SDC images that extends over radii 18d{lt}r{lt}45d in a {Gamma}=109 aspect-ratio cell. {copyright} {ital 1998} {ital The American Physical Society}

  3. Safety, Immunogenicity and Efficacy of Modified Vaccinia Ankara (MVA) Against Dryvax® Challenge in Vaccinia-Naïve and Vaccinia-Immune Individuals

    PubMed Central

    Parrino, Janie; McCurdy, Lewis H.; Larkin, Brenda D.; Gordon, Ingelise J.; Rucker, Steven E.; Enama, Mary E.; Koup, Richard A.; Roederer, Mario; Bailer, Robert T.; Moodie, Zoe; Gu, Lin; Yan, Lihan; Graham, Barney S.

    2007-01-01

    Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax® in vaccinia-naïve and immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax® challenge at 3 months. Two or more doses of MVA prior to Dryvax® reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax® vaccinia-specific CD8+ T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax® vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses. PMID:17126963

  4. HIV reverse transcriptase gene mutations in anti-retroviral treatment naïve rural people living with HIV/AIDS.

    PubMed

    Mohanakrishnan, K; Kasthuri, A; Amsavathani, S K; Sumathi, G

    2015-01-01

    This study is designed to find out the mutational variations of reverse transcriptase (RT) gene of HIV, after the traditional drug usage among anti-retroviral therapy naïve rural people living with HIV/AIDS. HIV Reactive patients, who were exposed for indigenous medicines such as Siddha, Ayurveda etc., for a minimum period of 6 months were taken for this study. Among 40 patients, two samples (5.55%) demonstrated high-level mutational resistance variations for nucleoside RT inhibitor (NRTI) and non-NRTI. The predominant polymorphisms detected were K122E (91.7%), V60I (91.7%), V35T (89%), Q207E (89%), D177E (89%), T200A (86.1%), S48T (83.33%), K173A (80.6%).

  5. Having students create short video clips to help transition from naïve conceptions about mechanics to true Newtonian physics

    NASA Astrophysics Data System (ADS)

    Corten-Gualtieri, Pascale; Ritter, Christian; Plumat, Jim; Keunings, Roland; Lebrun, Marcel; Raucent, Benoit

    2016-07-01

    Most students enter their first university physics course with a system of beliefs and intuitions which are often inconsistent with the Newtonian frame of reference. This article presents an experiment of collaborative learning aiming at helping first-year students in an engineering programme to transition from their naïve intuition about dynamics to the Newtonian way of thinking. In a first activity, students were asked to critically analyse the contents of two video clips from the point of view of Newtonian mechanics. In a second activity, students had to design and realise their own video clip to illustrate a given aspect of Newtonian mechanics. The preparation of the scenario for the second activity required looking up and assimilating scientific knowledge. The efficiency of the activity was assessed on an enhanced version of the statistical analysis method proposed by Hestenes and Halloun, which relies on a pre-test and a post-test to measure individual learning.

  6. Eosinophils from Murine Lamina Propria Induce Differentiation of Naïve T Cells into Regulatory T Cells via TGF-β1 and Retinoic Acid.

    PubMed

    Chen, Hong-Hu; Sun, Ai-Hua; Ojcius, David M; Hu, Wei-Lin; Ge, Yu-Mei; Lin, Xu'ai; Li, Lan-Juan; Pan, Jian-Ping; Yan, Jie

    2015-01-01

    Treg cells play a crucial role in immune tolerance, but mechanisms that induce Treg cells are poorly understood. We here have described eosinophils in lamina propria (LP) that displayed high aldehyde dehydrogenase (ALDH) activity, a rate-limiting step during all-trans retinoic acid (ATRA) synthesis, and expressed TGF-β1 mRNA and high levels of ATRA. Co-incubation assay confirmed that LP eosinophils induced the differentiation of naïve T cells into Treg cells. Differentiation promoted by LP eosinophils were inhibited by blocked either TGF-β1 or ATRA. Peripheral blood (PB) eosinophils did not produce ATRA and could not induce Treg differentiation. These data identifies LP eosinophils as effective inducers of Treg cell differentiation through a mechanism dependent on TGF-β1 and ATRA.

  7. Habit learning by naïve macaques is marked by response sharpening of striatal neurons representing the cost and outcome of acquired action sequences

    PubMed Central

    Desrochers, Theresa M.; Amemori, Ken-ichi; Graybiel, Ann M.

    2015-01-01

    SUMMARY Over a century of scientific work has focused on defining the factors motivating behavioral learning. Observations in animals and humans trained on a wide range of tasks support reinforcement learning (RL) algorithms as accounting for the learning. Still unknown, however, are the signals that drive learning in naïve, untrained subjects. Here, we capitalized on a sequential saccade task in which macaque monkeys acquired repetitive scanning sequences without instruction. We found that spike activity in the caudate nucleus after each trial corresponded to an integrated cost-benefit signal that was highly correlated with the degree of naturalistic untutored learning by the monkeys. Across learning, neurons encoding both cost and outcome gradually acquired increasingly sharp phasic trial-end responses that paralleled the development of the habit-like, repetitive saccade sequences. Our findings demonstrate a novel integrated cost-benefit signal by which RL and its neural correlates could drive naturalistic behaviors in freely behaving primates. PMID:26291166

  8. Clinical outcomes and virology of equine influenza in a naïve population and in horses infected soon after receiving one dose of vaccine.

    PubMed

    Kannegieter, N J; Frogley, A; Crispe, E; Kirkland, P D

    2011-07-01

    As part of the control measures of the equine influenza (EI) outbreak, in addition to the strategic use of vaccination to provide buffer zones around infected populations, approval was obtained to vaccinate Thoroughbred racing horses. We review the clinical expression of the disease and virus excretion in a population of racehorses that were exposed to EI approximately 7 days after administration of a single dose of the canarypox-vectored recombinant compared with a similar unvaccinated population of horses at a nearby racetrack. Although this study was undertaken opportunistically and under the difficult field conditions that prevailed during the outbreak, our observations demonstrate that an appropriate vaccine can be effectively used as a disease control measure, even in the face of an outbreak, and therefore should be rapidly implemented as soon as there is evidence of infection in a naïve population.

  9. Loss of CCR2 expressing non-classical monocytes are associated with cognitive impairment in antiretroviral therapy-naïve HIV-infected Thais.

    PubMed

    Ndhlovu, Lishomwa C; D'Antoni, Michelle L; Ananworanich, Jintanat; Byron, Mary Margaret; Chalermchai, Thep; Sithinamsuwan, Pasiri; Tipsuk, Somporn; Ho, Erika; Slike, Bonnie M; Schuetz, Alexandra; Zhang, Guangxiang; Agsalda-Garcia, Melissa; Shiramizu, Bruce; Shikuma, Cecilia M; Valcour, Victor

    2015-11-15

    HIV DNA in monocytes has been linked to HIV-associated neurocognitive disorders (HAND), however, characterization of monocyte subsets associated with HAND remains unclear. We completed a prospective study of antiretroviral therapy-naïve, HIV-infected Thais, with varying degrees of cognitive impairment, compared to HIV-uninfected controls. Monocyte subsets' CCR2, CCR5 and CD163 expression were profiled and inflammatory markers in plasma and cerebrospinal fluid (CSF), measured. Lower numbers of CCR2(+)non-classical monocytes were associated with worse neuropsychological test performance (r=0.43, p=0.024). CCR2(+)non-classical monocyte count inversely correlated with CSF neopterin (r=-0.43, p=0.035) and plasma TNF-α levels (r=-0.40, p=0.041). These data benchmark CCR2(+)non-classical monocytes as an independent index of cognitive impairment.

  10. A Discrete Choice Conjoint Experiment to Evaluate Parent Preferences for Treatment of Young, Medication Naïve Children with ADHD

    PubMed Central

    Waschbusch, Daniel A.; Cunningham, Charles E.; Pelham, William E.; Rimas, Heather L.; Greiner, Andrew R.; Gnagy, Elizabeth M.; Waxmonsky, James; Fabiano, Gregory A.; Robb, Jessica A.; Burrows-MacLean, Lisa; Scime, Mindy; Hoffman, Martin T.

    2014-01-01

    The current study examined treatment preferences of 183 parents of young (average age = 5.8 years; SD = 0.6), medication naïve children with ADHD. Preferences were evaluated using a discrete choice experiment in which parents made choices between different combinations of treatment characteristics, outcomes, and costs. Latent class analysis yielded two segments of parents: (1) Medication Avoidant parents constituted 70.5% of the sample whose treatment decisions were strongly influenced by a desire to avoid medication; (2) Outcome Oriented parents constituted 29.5% of the sample whose treatment decisions were most influenced by a desire for positive treatment outcomes. Parents in the Outcome Oriented segment were more stressed and depressed, had lower socioeconomic status and education, were more likely to be single parents, and had more disruptive and impaired children. Simulations predicted that parents would prefer treatments with behavior therapy over treatments with stimulant medication only. PMID:21722027

  11. First exposure to an alive conspecific activates septal and amygdaloid nuclei in visually-naïve domestic chicks (Gallus gallus).

    PubMed

    Mayer, Uwe; Rosa-Salva, Orsola; Vallortigara, Giorgio

    2017-01-15

    The septal nuclei are an evolutionarily well-conserved part of the limbic system, present in all vertebrate groups. Functionally, septal nuclei are involved in many important aspects of social behavior and lateral septum is considered a node of the social decision making network, together with amygdaloid nuclei. Given the importance of septal nuclei for social behaviors, it is somewhat surprising that it has never been investigated whether they are involved in early social responses of naïve animals. In the present study we wanted to know if simple exposure of visually naïve newly hatched chicks to a visual object (an alive, behaving conspecific), that also contains all features to which chicks are known to express early social predispositions, will selectively activate septal areas. We measured brain activity by visualizing the immediate early gene product c-Fos with a standard immunohistochemical procedure. Notably, after a brief visual exposure to an alive behaving conspecific septum showed higher activation in experimental subjects, compared to baseline animals that were exposed to the same environment in the absence of the conspecific. This is, to the best of our knowledge, the first demonstration of septal involvement in early social responses. We also found similar effects in the nucleus taeniae and arcopallium (amygdala homologues), but not in the medial striatum. This result indicates that at least some nuclei of the social decision making network may participate in early responses to social stimuli. Future studies could capitalize on these results, by identifying the specific visual cues eliciting this effect.

  12. Functional characterization of a veA-dependent polyketide synthase gene in Aspergillus flavus necessary for the synthesis of asparasone, a sclerotium-specific pigment.

    PubMed

    Cary, Jeffrey W; Harris-Coward, Pamela Y; Ehrlich, Kenneth C; Di Mavungu, José Diana; Malysheva, Svetlana V; De Saeger, Sarah; Dowd, Patrick F; Shantappa, Sourabha; Martens, Stacey L; Calvo, Ana M

    2014-03-01

    The filamentous fungus, Aspergillus flavus, produces the toxic and carcinogenic, polyketide synthase (PKS)-derived family of secondary metabolites termed aflatoxins. While analysis of the A. flavus genome has identified many other PKSs capable of producing secondary metabolites, to date, only a few other metabolites have been identified. In the process of studying how the developmental regulator, VeA, affects A. flavus secondary metabolism we discovered that mutation of veA caused a dramatic down-regulation of transcription of a polyketide synthase gene belonging to cluster 27 and the loss of the ability of the fungi to produce sclerotia. Inactivation of the cluster 27 pks (pks27) resulted in formation of greyish-yellow sclerotia rather than the dark brown sclerotia normally produced by A. flavus while conidial pigmentation was unaffected. One metabolite produced by Pks27 was identified by thin layer chromatography and mass spectral analysis as the known anthraquinone, asparasone A. Sclerotia produced by pks27 mutants were significantly less resistant to insect predation than were the sclerotia produced by the wild-type and more susceptible to the deleterious effects of ultraviolet light and heat. Normal sclerotia were previously thought to be resistant to damage because of a process of melanization similar to that known for pigmentation of conidia. Our results show that the dark brown pigments in sclerotia derive from anthraquinones produced by Pks27 rather than from the typical tetrahydronapthalene melanin production pathway. To our knowledge this is the first report on the genes involved in the biosynthesis of pigments important for sclerotial survival.

  13. Effects of 12-month, 2000IU/day vitamin D supplementation on treatment naïve and vitamin D deficient Saudi type 2 diabetic patients

    PubMed Central

    Al-Shahwan, May A.; Al-Othman, Abdulaziz M.; Al-Daghri, Nasser M.; Sabico, Shaun B.

    2015-01-01

    Objectives: To determine whether 12-month, 2000IU/day vitamin D supplementation cardiometabolically improves treatment naïve type 2 diabetes mellitus (T2DM) Saudi patients with vitamin D deficiency. Methods: This 12-month interventional study was conducted at primary health centers in 5 different residential areas in Riyadh, Saudi Arabia between January 2013 and January 2014. Forty-five Saudi T2DM patients were enrolled. Baseline anthropometrics, glycemic, and lipid profiles were measured and repeated after 6 and 12 months. All subjects were provided with 2000IU vitamin D supplements for one year. Results: Vitamin D deficiency at baseline was 46.7%, 31.8% after 6 months, and 35.6% after 12 months, indicating an overall improvement in the vitamin D status in the entire cohort. Insulin and homeostatic model assessment-insulin resistance (HOMA-IR) after 12 months were significantly lower than a 6 months (p<0.05), but comparable to baseline values. Mean levels of triglycerides increased overtime from baseline (1.9±0.01 mmol/l) to 12 months (2.1±0.2 mmol). This modest increase in serum triglycerides was parallel to the insignificant decrease in circulating high-density lipoprotein -cholesterol levels. Conclusion: Twelve-month vitamin D supplementation of 2000IU per day in a cohort of treatment naïve Saudi patients with T2DM resulted in improvement of several cardiometabolic parameters including systolic blood pressure, insulin, and HOMA-IR. Further studies that include a placebo group are suggested to reinforce findings. PMID:26620985

  14. Stressful presentations: mild cold stress in laboratory mice influences phenotype of dendritic cells in naïve and tumor-bearing mice.

    PubMed

    Kokolus, Kathleen M; Spangler, Haley M; Povinelli, Benjamin J; Farren, Matthew R; Lee, Kelvin P; Repasky, Elizabeth A

    2014-01-01

    The ability of dendritic cells (DCs) to stimulate and regulate T cells is critical to effective anti-tumor immunity. Therefore, it is important to fully recognize any inherent factors which may influence DC function under experimental conditions, especially in laboratory mice since they are used so heavily to model immune responses. The goals of this report are to 1) briefly summarize previous work revealing how DCs respond to various forms of physiological stress and 2) to present new data highlighting the potential for chronic mild cold stress inherent to mice housed at the required standard ambient temperatures to influence baseline DCs properties in naïve and tumor-bearing mice. As recent data from our group shows that CD8(+) T cell function is significantly altered by chronic mild cold stress and since DC function is crucial for CD8(+) T cell activation, we wondered whether housing temperature may also be influencing DC function. Here we report that there are several significant phenotypical and functional differences among DC subsets in naïve and tumor-bearing mice housed at either standard housing temperature or at a thermoneutral ambient temperature, which significantly reduces the extent of cold stress. The new data presented here strongly suggests that, by itself, the housing temperature of mice can affect fundamental properties and functions of DCs. Therefore differences in basal levels of stress due to housing should be taken into consideration when interpreting experiments designed to evaluate the impact of additional variables, including other stressors on DC function.

  15. Strong and sustained effector function of memory- versus naïve-derived T cells upon T-cell receptor RNA transfer: implications for cellular therapy.

    PubMed

    Thomas, Simone; Klobuch, Sebastian; Besold, Katrin; Plachter, Bodo; Dörrie, Jan; Schaft, Niels; Theobald, Matthias; Herr, Wolfgang

    2012-12-01

    Current protocols used to select CMV-specific T cells for adoptive immunotherapy focus on virus-specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem-cell transplantation (HSCT) from CMV-seronegative donors. Here, we redirected T cells of CMV-seronegative donors with a human genetically engineered TCR recognizing an HLA-A*0201-binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non-viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naïve-derived T-cell subsets were both efficiently transfected by TCR-RNA, memory-derived T cells showed much stronger levels of HLA-A*0201-restricted cytolytic activity to CMV-infected fibroblasts and maintained acquired function for 5-10 days. In addition to redirection of CD8(+) cytotoxic T cells, TCR-RNA transfection was capable of redirecting CD4(+) T cells into potent Ag-specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naïve-derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus-specific CD4(+) and CD8(+) T-cell function. CMV TCR-RNA may represent a suitable therapeutic 'off-the-shelf' reagent to be used in severe CMV infections of HSCT patients when endogenous CMV-specific T-cell immunity is insufficient.

  16. Interleukin‑33‑induced immune tolerance is associated with the imbalance of memory and naïve T‑lymphocyte subsets.

    PubMed

    Shi, Xu; Tang, Ying; Sun, Xiguang; Liu, Yufei; Sun, Ying; Sun, Munan; Jiang, Yanfang; Li, Yulin

    2016-11-01

    The current study aimed to investigate the distribution of memory and naïve T cell (TN) subsets in hepatitis B virus (HBV)‑infected patients at different immune stages and investigate the effect of interleukin 33 (IL‑33) on the regulation of the T‑cell subsets. The distributions of memory and naïve T cells were detected by flow cytometry. ELISA was conducted to assess the levels of IL‑4, IL‑5, IL‑10, IL‑12, interferon γ and tumor necrosis factor α. The expression levels of IL‑33 and HBV x protein (HBx) were measured by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. By detecting TNs, central memory T cells (TCM) and effector memory T cells (TEM), it was identified that the proportions of TCM and TEM in CD4+ T cells were increased in patients with HBV. The trend observed for levels of CD8+ TCM and TEM was similar to that of CD4+ T cells in the immune tolerance and immune activation groups, however CD8+ TCM and TEM were significantly reduced in patients who underwent treatment. The CD8+ TEM cells appeared to be more sensitive to HBV activation and drug therapy. In addition, IL‑33 stimulation was observed to induce imbalances of CD8+ TN and CD8+ TEM, and while the imbalances were directly regulated by HBx, IL‑33 was not a key factor for the expression of HBx. CD8+ TEM cells may be a sensitive marker to assess the immune state of patients with HBV and the effect of clinical therapy. Treatment targeting IL‑33 may be a potential method to reverse HBV‑induced immune tolerance.

  17. Naïve hosts of avian brood parasites accept foreign eggs, whereas older hosts fine-tune foreign egg discrimination during laying

    PubMed Central

    2014-01-01

    Background Many potential hosts of social parasites recognize and reject foreign intruders, and reduce or altogether escape the negative impacts of parasitism. The ontogenetic basis of whether and how avian hosts recognize their own and the brood parasitic eggs remains unclear. By repeatedly parasitizing the same hosts with a consistent parasitic egg type, and contrasting the responses of naïve and older breeders, we studied ontogenetic plasticity in the rejection of foreign eggs by the great reed warbler (Acrocephalus arundinaceus), a host species of the common cuckoo (Cuculus canorus). Results In response to experimental parasitism before the onset of laying, first time breeding hosts showed almost no egg ejection, compared to higher rates of ejection in older breeders. Young birds continued to accept foreign eggs when they were subjected to repeated parasitism, whereas older birds showed even higher ejection rates later in the same laying cycle. Conclusions Our results are consistent with the hypotheses that (i) naïve hosts need to see and learn the appearance of their own eggs to discriminate and reject foreign eggs, whereas (ii) experienced breeders possess a recognition template of their own eggs and reject parasitic eggs even without having to see their own eggs. However, we cannot exclude the possibility that other external cues and internal processes, accumulated simply with increasing age, may also modify age-specific patterns in egg rejection (e.g. more sightings of the cuckoo by older breeders). Future research should specifically track the potential role of learning in responses of individual hosts between first and subsequent breeding attempts by testing whether imprinting on a parasitized clutch reduces the rates of rejecting foreign eggs in subsequent parasitized clutches. PMID:25024736

  18. Pseudo-continuous arterial spin labeling imaging of cerebral blood perfusion asymmetry in drug-naïve patients with first-episode major depression

    PubMed Central

    Chen, Guangdong; Bian, Haiman; Jiang, Deguo; Cui, Mingwei; Ji, Shengzhang; Liu, Mei; Lang, Xu; Zhuo, Chuanjun

    2016-01-01

    Many previous studies have reported that regional cerebral blood flow (rCBF) aberrations may be one of the pathological characteristics of depression and rCBF has demonstrated a certain degree of asymmetry. However, studies investigating the cerebral blood perfusion asymmetry changes of drug-naïve patients experiencing their first episode of major depression using pseudo-continuous arterial spin labeling (pCASL) are rare. Ten drug-naïve patients experiencing their first major depression episode and 15 healthy volunteers were enrolled in the current study. A novel pCASL method was applied to whole brain MRI scans of all of the samples. The Statistics Parameter Mapping and Relative Expression Software Tool software packages were used for the pre-processing and statistical analysis of the two sets of images, and the differences in the cerebral blood perfusion at the whole brain level were compared between the two groups. Compared with the healthy control group, the cerebral perfusion of the depression patients showed an asymmetric pattern. Decreased cerebral blood perfusion regions were primarily located in the left hemisphere, specifically in the left temporal lobe, frontal lobe and cingulate cortex [P<0.05 and cluster size ≥30 with false discovery rate (FDR) correction]. Simultaneously, increased perfusion regions were predominantly located in the right hemisphere, specifically in the right cerebellum, thalamus, frontal lobe and anterior cingulate cortex (P<0.05 and cluster size ≥30, with FDR correction). Thus, pCASL may characterize the alterations in cerebral blood perfusion of patients with depression. PMID:28101340

  19. Late-onset myasthenia gravis - CTLA4(low) genotype association and low-for-age thymic output of naïve T cells.

    PubMed

    Chuang, Wen-Yu; Ströbel, Philipp; Bohlender-Willke, Anna-Lena; Rieckmann, Peter; Nix, Wilfred; Schalke, Berthold; Gold, Ralf; Opitz, Andreas; Klinker, Erdwine; Inoue, Masayoshi; Müller-Hermelink, Hans Konrad; Saruhan-Direskeneli, Güher; Bugert, Peter; Willcox, Nick; Marx, Alexander

    2014-08-01

    Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60.

  20. Natural Polymorphisms Conferring Resistance to HCV Protease and Polymerase Inhibitors in Treatment-Naïve HIV/HCV Co-Infected Patients in China

    PubMed Central

    Wang, Charles; Hu, Fengyu; Ning, Chuanyi; Lan, Yun; Tang, Xiaoping; Tucker, Joseph D.; Cai, Weiping

    2016-01-01

    Background The advent of direct-acting agents (DAAs) has improved treatment of HCV in HIV co-infection, but may be limited by primary drug resistance. This study reports the prevalence of natural polymorphisms conferring resistance to NS3/4A protease inhibitors and NS5B polymerase inhibitors in treatment-naïve HIV/HCV co-infected individuals in China. Methods Population based NS3/4A sequencing was completed for 778 treatment-naïve HIV/HCV co-infected patients from twelve provinces. NS3 sequences were amplified by nested PCR using in-house primers for genotypes 1–6. NS5B sequencing was completed for genotyping in 350 sequences. Resistance-associated variants (RAVs) were identified in positions associated with HCV resistance. Results Overall, 72.8% (566/778) of all HCV sequences had at least one RAV associated with HCV NS3/4A protease inhibitor resistance. Variants were found in 3.6% (7/193) of genotype 1, 100% (23/23) of genotype 2, 100% (237/237) of genotype 3 and 92% (299/325) of genotype 6 sequences. The Q80K variant was present in 98.4% of genotype 6a sequences. High-level RAVs were rare, occurring in only 0.8% of patients. 93% (64/69) patients with genotype 1b also carried the C316N variant associated with NS5B low-level resistance. Conclusions The low frequency of high-level RAVs associated with primary HCV DAA resistance among all genotypes in HIV/HCV co-infected patients is encouraging. Further phenotypic studies and clinical research are needed. PMID:27341031

  1. Stochastic uncertainty analysis for solute transport in randomly heterogeneous media using a Karhunen-Loève-based moment equation approach

    USGS Publications Warehouse

    Liu, Gaisheng; Lu, Zhiming; Zhang, Dongxiao

    2007-01-01

    A new approach has been developed for solving solute transport problems in randomly heterogeneous media using the Karhunen-Loève-based moment equation (KLME) technique proposed by Zhang and Lu (2004). The KLME approach combines the Karhunen-Loève decomposition of the underlying random conductivity field and the perturbative and polynomial expansions of dependent variables including the hydraulic head, flow velocity, dispersion coefficient, and solute concentration. The equations obtained in this approach are sequential, and their structure is formulated in the same form as the original governing equations such that any existing simulator, such as Modular Three-Dimensional Multispecies Transport Model for Simulation of Advection, Dispersion, and Chemical Reactions of Contaminants in Groundwater Systems (MT3DMS), can be directly applied as the solver. Through a series of two-dimensional examples, the validity of the KLME approach is evaluated against the classical Monte Carlo simulations. Results indicate that under the flow and transport conditions examined in this work, the KLME approach provides an accurate representation of the mean concentration. For the concentration variance, the accuracy of the KLME approach is good when the conductivity variance is 0.5. As the conductivity variance increases up to 1.0, the mismatch on the concentration variance becomes large, although the mean concentration can still be accurately reproduced by the KLME approach. Our results also indicate that when the conductivity variance is relatively large, neglecting the effects of the cross terms between velocity fluctuations and local dispersivities, as done in some previous studies, can produce noticeable errors, and a rigorous treatment of the dispersion terms becomes more appropriate.

  2. BLyS-mediated modulation of naïve B cell subsets impacts HIV Env-induced antibody responses1

    PubMed Central

    Dosenovic, Pia; Soldemo, Martina; Scholz, Jean L.; O’Dell, Sijy; Grasset, Emilie K.; Pelletier, Nadège; Karlsson, Mikael C. I.; Mascola, John R.; Wyatt, Richard T.; Cancro, Michael P.; Karlsson Hedestam, Gunilla B.

    2012-01-01

    Neutralizing Abs provide the protective effect of the majority of existing human vaccines. For a prophylactic vaccine against HIV-1, broadly neutralizing Abs (bNAbs) targeting conserved epitopes of the viral envelope glycoproteins (Env) are likely required, as the pool of circulating HIV-1 variants is extremely diverse. The failure to efficiently induce bNAbs by vaccination may be due to the use of sub-optimal immunogens or immunization regimens, or it may indicate that B cells specific for broadly neutralizing Env determinants are selected against during peripheral checkpoints, either before or after antigen encounter. To investigate if perturbation of B cell subsets prior to immunization with recombinant Env protein affects the vaccine-induced Ab response in mice, we used B Lymphocyte Stimulator (BLyS), a cytokine that regulates survival and selection of peripheral B cells. We show that the transient BLyS treatment used here substantially affected naïve B cell populations; in particular, it resulted in an increased number of B cells surviving counter-selection at the transitional stages. We also observed an increased number of mature naïve B cells, especially marginal zone B cells, in BLyS-treated mice. Intriguingly, provision of excess BLyS prior to immunization led to a consistent improvement in the frequency and potency of HIV-1 Env vaccine-induced neutralizing Ab responses, without increasing the number of Env-specific Ab-secreting cells or the Ab binding titers measured after boosting. The results presented here suggest that an increased understanding of BLyS-regulated processes may help the design of vaccine regimens aimed at eliciting improved neutralizing Ab responses against HIV-1. PMID:22561155

  3. Türk Lise Öğrencilerinde Okul Terkinin Yordanması: Aracı ve Etkileşim Değişkenleri ile Bir Model Testi

    PubMed Central

    Özer, Arif; Gençtanirim, Dilek; Ergene, Tuncay

    2011-01-01

    Bu araştırmada ilk olarak, dürtüsel davranma ile okulu terk etme riski arasındaki ilişkiye disiplin cezası almanın, antisosyal davranışların ve sigara-alkol kullanımının aracılık edip etmediği incelenmiştir. İkinci olarak, öğretmen desteği ve antisosyal davranış etkileşiminin okulu terk etme riski üzerindeki etkisi test edilmiştir. Araştırma grubunu 2009-2010 yılında Ankara İlinde genel liselere devam eden 478 öğrenci oluşturmuştur. Sonuçlar okulu terk etme riskini aile ve arkadaş desteğinin azalttığını, dürtüsel davranmanın ise artırdığını göstermiştir. Ayrıca disiplin cezası, alkol-sigara kullanma ve antisosyal davranışlar okulu terk etme riskini artıran aracı değişkenlerdir. Antisosyal davranışlarla okulu terk etme arasındaki ilişki öğretmen desteğine bağlı olarak değişmektedir. Öğrencilerin cinsiyet ve başarıları ile okulu terk etme riskleri arasında anlamlı bir ilişki bulunmamaktadır. PMID:22003257

  4. Information seeking and anxiety among colonoscopy-naïve adults: Direct-to-colonoscopy vs traditional consult-first pathways

    PubMed Central

    Silvester, Jocelyn A; Kalkat, Harmandeep; Graff, Lesley A; Walker, John R; Singh, Harminder; Duerksen, Donald R

    2016-01-01

    AIM To investigate the effects of direct to colonoscopy pathways on information seeking behaviors and anxiety among colonoscopy-naïve patients. METHODS Colonoscopy-naïve patients at two tertiary care hospitals completed a survey immediately prior to their scheduled outpatient procedure and before receiving sedation. Survey items included clinical pathway (direct or consult), procedure indication (cancer screening or symptom investigation), telephone and written contact from the physician endoscopist office, information sources, and pre-procedure anxiety. Participants reported pre-procedure anxiety using a 10 point scale anchored by “very relaxed” (1) and “very nervous” (10). At least three months following the procedure, patient medical records were reviewed to determine sedative dose, procedure indications and any adverse events. The primary comparison was between the direct and consult pathways. Given the very different implications, a secondary analysis considering the patient-reported indication for the procedure (symptoms or screening). Effects of pathway (direct vs consult) were compared both within and between the screening and symptom subgroups. RESULTS Of 409 patients who completed the survey, 34% followed a direct pathway. Indications for colonoscopy were similar in each group. The majority of the participants were women (58%), married (61%), and internet users (81%). The most important information source was family physicians (Direct) and specialist physicians (Consult). Use of other information sources, including the internet (20% vs 18%) and Direct family and friends (64% vs 53%), was similar in the Direct and Consult groups, respectively. Only 31% of the 81% who were internet users accessed internet health information. Most sought fundamental information such as what a colonoscopy is or why it is done. Pre-procedure anxiety did not differ between care pathways. Those undergoing colonoscopy for symptoms reported greater anxiety [mean 5.3, 95

  5. Aboriginal status is a prognostic factor for mortality among antiretroviral naïve HIV-positive individuals first initiating HAART

    PubMed Central

    Lima, Viviane D; Kretz, Patricia; Palepu, Anita; Bonner, Simon; Kerr, Thomas; Moore, David; Daniel, Mark; Montaner, Julio SG; Hogg, Robert S

    2006-01-01

    Background Although the impact of Aboriginal status on HIV incidence, HIV disease progression, and access to treatment has been investigated previously, little is known about the relationship between Aboriginal ethnicity and outcomes associated with highly active antiretroviral therapy (HAART). We undertook the present analysis to determine if Aboriginal and non-Aboriginal persons respond differently to HAART by measuring HIV plasma viral load response, CD4 cell response and time to all-cause mortality. Methods A population-based analysis of a cohort of antiretroviral therapy naïve HIV-positive Aboriginal men and women 18 years or older in British Columbia, Canada. Participants were antiretroviral therapy naïve, initiated triple combination therapy between August 1, 1996 and September 30, 1999. Participants had to complete a baseline questionnaire as well as have at least two follow-up CD4 and HIV plasma viral load measures. The primary endpoints were CD4 and HIV plasma viral load response and all cause mortality. Cox proportional hazards models were used to determine the association between Aboriginal status and CD4 cell response, HIV plasma viral load response and all-cause mortality while controlling for several confounder variables. Results A total of 622 participants met the study criteria. Aboriginal status was significantly associated with no AIDS diagnosis at baseline (p = 0.0296), having protease inhibitor in the first therapy (p = 0.0209), lower baseline HIV plasma viral load (p < 0.001), less experienced HIV physicians (P = 0.0133), history of IDU (p < 0.001), not completing high school (p = 0.0046), and an income of less than $10,000 per year (p = 0.0115). Cox proportional hazards models controlling for clinical characteristics found that Aboriginal status had an increased hazard of mortality (HR = 3.12, 95% CI: 1.77–5.48) but did not with HIV plasma viral load response (HR = 1.15, 95% CI: 0.89–1.48) or CD4 cell response (HR = 0.95, 95% CI: 0.73

  6. Imaging Characteristics of Driver Mutations in EGFR, KRAS, and ALK among Treatment-Naïve Patients with Advanced Lung Adenocarcinoma

    PubMed Central

    Park, Jangchul; Kobayashi, Yoshihisa; Urayama, Kevin Y.; Yamaura, Hidekazu; Yatabe, Yasushi; Hida, Toyoaki

    2016-01-01

    This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB–IV) and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups’ characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159), KRAS mutations (n = 55), or ALK rearrangements (n = 51). Among the three groups, we evaluated only patients with stage IIIB–IV lung adenocarcinoma who had EGFR mutations (n = 126), KRAS mutations (n = 35), or ALK rearrangements (n = 47). We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009). Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003). Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively). Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049). Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively). Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively). In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal

  7. HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection

    PubMed Central

    Sarrazin, Christoph; Castelli, Francesco; Andreone, Pietro; Buti, Maria; Colombo, Massimo; Pol, Stanislas; Calinas, Filipe; Puoti, Massimo; Olveira, Antonio; Shiffman, Mitchell; Stern, Jerry O; Kukolj, George; Roehrle, Michael; Aslanyan, Stella; Deng, Qiqi; Vinisko, Richard; Mensa, Federico J; Nelson, David R

    2016-01-01

    The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72). Primary endpoints were comparisons of adjusted sustained virologic response (SVR) rates with historical rates: 71% (HCVerso1) and 68% (HCVerso2). Adjusted SVR12 rates were significantly greater than historical controls for Arms 1 and 2 in HCVerso2 (76%, 95% confidence interval [CI] 71–81, P=0.002; 81%, 95% CI 76–86, P<0.0001) and Arm 2 in HCVerso1 (81%, 95% CI 77–86, P<0.0001), but not for Arm 1 of HCVerso1 (72%, 95% CI 66–77, P=0.3989). Unadjusted SVR12 rates in Arms 1, 2, and 3 were 71.6%, 82.5%, and 72.5%, respectively, in HCVerso1 and 75.6%, 82.0%, and 73.6%, respectively, in HCVerso2. Virologic breakthrough and relapse occurred in 24-week arms in 8%–9% and 1% of patients, respectively, and in 16-week arms in 7%–8% and 9%–11% of patients, respectively. The most common adverse events were nausea (46%–61%) and vomiting (29%–35%). Adverse events resulted in discontinuation of all medications in 6%–8% of patients. In treatment-naïve patients with hepatitis C virus genotype-1b infection, with or without cirrhosis, faldaprevir + deleobuvir + ribavirin treatment for 24 weeks resulted in adjusted SVR12 rates significantly higher than historical controls. Both studies were registered in ClinicalTrials.gov (NCT01732796, NCT01728324). PMID:27920566

  8. Coupling Self-Organizing Maps with a Naïve Bayesian classifier: A case study for classifying Vermont streams using geomorphic, habitat and biological assessment data

    NASA Astrophysics Data System (ADS)

    Fytilis, N.; Rizzo, D. M.

    2012-12-01

    Environmental managers are increasingly required to forecast the long-term effects and the resilience or vulnerability of biophysical systems to human-generated stresses. Mitigation strategies for hydrological and environmental systems need to be assessed in the presence of uncertainty. An important aspect of such complex systems is the assessment of variable uncertainty on the model response outputs. We develop a new classification tool that couples a Naïve Bayesian Classifier with a modified Kohonen Self-Organizing Map to tackle this challenge. For proof-of-concept, we use rapid geomorphic and reach-scale habitat assessments data from over 2500 Vermont stream reaches (~1371 stream miles) assessed by the Vermont Agency of Natural Resources (VTANR). In addition, the Vermont Department of Environmental Conservation (VTDEC) estimates stream habitat biodiversity indices (macro-invertebrates and fish) and a variety of water quality data. Our approach fully utilizes the existing VTANR and VTDEC data sets to improve classification of stream-reach habitat and biological integrity. The combined SOM-Naïve Bayesian architecture is sufficiently flexible to allow for continual updates and increased accuracy associated with acquiring new data. The Kohonen Self-Organizing Map (SOM) is an unsupervised artificial neural network that autonomously analyzes properties inherent in a given a set of data. It is typically used to cluster data vectors into similar categories when a priori classes do not exist. The ability of the SOM to convert nonlinear, high dimensional data to some user-defined lower dimension and mine large amounts of data types (i.e., discrete or continuous, biological or geomorphic data) makes it ideal for characterizing the sensitivity of river networks in a variety of contexts. The procedure is data-driven, and therefore does not require the development of site-specific, process-based classification stream models, or sets of if-then-else rules associated with

  9. HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection.

    PubMed

    Sarrazin, Christoph; Castelli, Francesco; Andreone, Pietro; Buti, Maria; Colombo, Massimo; Pol, Stanislas; Calinas, Filipe; Puoti, Massimo; Olveira, Antonio; Shiffman, Mitchell; Stern, Jerry O; Kukolj, George; Roehrle, Michael; Aslanyan, Stella; Deng, Qiqi; Vinisko, Richard; Mensa, Federico J; Nelson, David R

    2016-01-01

    The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72). Primary endpoints were comparisons of adjusted sustained virologic response (SVR) rates with historical rates: 71% (HCVerso1) and 68% (HCVerso2). Adjusted SVR12 rates were significantly greater than historical controls for Arms 1 and 2 in HCVerso2 (76%, 95% confidence interval [CI] 71-81, P=0.002; 81%, 95% CI 76-86, P<0.0001) and Arm 2 in HCVerso1 (81%, 95% CI 77-86, P<0.0001), but not for Arm 1 of HCVerso1 (72%, 95% CI 66-77, P=0.3989). Unadjusted SVR12 rates in Arms 1, 2, and 3 were 71.6%, 82.5%, and 72.5%, respectively, in HCVerso1 and 75.6%, 82.0%, and 73.6%, respectively, in HCVerso2. Virologic breakthrough and relapse occurred in 24-week arms in 8%-9% and 1% of patients, respectively, and in 16-week arms in 7%-8% and 9%-11% of patients, respectively. The most common adverse events were nausea (46%-61%) and vomiting (29%-35%). Adverse events resulted in discontinuation of all medications in 6%-8% of patients. In treatment-naïve patients with hepatitis C virus genotype-1b infection, with or without cirrhosis, faldaprevir + deleobuvir + ribavirin treatment for 24 weeks resulted in adjusted SVR12 rates significantly higher than historical controls. Both studies were registered in ClinicalTrials.gov (NCT01732796, NCT01728324).

  10. Differential activation of dendritic cells by toll-like receptors causes diverse differentiation of naïve CD4+ T cells from allergic patients

    PubMed Central

    Deifl, S.; Kitzmüller, C.; Steinberger, P.; Himly, M.; Jahn-Schmid, B.; Fischer, G. F.; Zlabinger, G. J.; Bohle, B.

    2014-01-01

    Background To avert the differentiation of allergen-specific Th2 cells in atopic individuals is a major goal in the prevention and therapy of IgE-mediated allergy. We aimed to compare different toll-like receptor (TLR) agonists regarding their effects on antigen-presenting cells and the differentiation of naïve T cells from allergic patients. Methods Monocytes and monocyte-derived dendritic cells (mdDC) from allergic patients were stimulated with Pam3CSK4 (TLR1/2 ligand), FSL-1 (TLR2/6 ligand), monophosphoryl lipid (MPL)-A, lipopolysaccharide (LPS, both TLR4 ligands), and flagellin (TLR5 ligand). Allergen uptake and upregulation of CD40, CD80, CD83, CD86, CD58, CCR7 and PD-L1 were analyzed by flow cytometry. Functional maturation of mdDC was tested in mixed leukocyte reactions, and the synthesis of proinflammatory cytokines, IL-10 and members of the IL-12 family was assessed. TLR-ligand-activated mdDC were used to stimulate naïve CD4+ T cells, and cytokine responses were assessed in supernatants and intracellularly. Results All TLR ligands except flagellin enhanced allergen uptake. All TLR ligands induced functional maturation of mdDC with differential expression of surface molecules and cytokines and promoted the differentiation of IFN-γ-producing T cells. LPS-matured mdDC exclusively induced Th1-like responses, whereas mdDC stimulated with the other TLR ligands induced both Th1- and Th0-like cells. Pam3CSK4 and flagellin additionally induced Th2-like cells. Th1-like responses were associated with higher expression levels of co-stimulatory molecules, PD-L1, IL-6, TNF-α, and IL-12p70. None of the TLR-ligand-stimulated mdDC induced IL-10- or IL-17-producing T cells. Conclusion Different TLR ligands differently influence T-cell responses due to varying activation of the three signals relevant for T-cell activation, that is, antigen presentation, co-stimulation and cytokine milieu. PMID:25093709

  11. Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection.

    PubMed

    Ribichini, Danilo; Fiorini, Giulia; Repaci, Andrea; Castelli, Valentina; Gatta, Luigi; Vaira, Dino; Pasquali, Renato

    2016-11-15

    To compare the clinical efficacy of tablet and oral liquid L-thyroxine (LT4) formulation in naïve hypothyroid subjects with Helicobacter pylori infection. Forty-seven adult naïve hypothyroid subjects with dyspeptic symptoms were investigated with upper endoscopy and divided into: 28 patients with Helicobacter pylori infection (Group A); 15 patients without gastric alterations (group B); 4 patients with autoimmune gastritis were excluded from the study. Subjects were randomly treated with a same dose of LT4 tablet (TAB) or oral liquid formulation (SOL), for 9 months on group A and 6 months on group B. Helicobacter pylori infection was eradicated after 3 months of LT4 treatment. On group A, after 3 months (before Helicobacter pylori eradication), subjects treated with SOL showed a greater thyroid-stimulating hormone reduction (ΔTSH3-0: TAB = -4.1 ± 4.6 mU/L; SOL = -7.7 ± 2.5 mU/L; p = 0.029) and a greater homogeneity in the thyroid-stimulating hormone values (TSH3mo: TAB = 5.7 ± 4.9 mU/L; SOL = 4.1 ± 2.0 mU/L; p = 0.025), compared to LT4 tablet. At 9 months (after 6 months of Helicobacter pylori eradication) mean thyroid-stimulating hormone values were lower in subjects treated with LT4 tablet (TSH9mo: TAB = 1.8 ± 1.2 mU/L; SOL = 3.2 ± 1.7 mU/L; p = 0.006). On group B no difference were observed, at each time point, in the mean thyroid-stimulating hormone values and thyroid-stimulating hormone variations between two LT4 formulations. LT4 liquid formulation may produce a better clinical response compared to the tablet formulation in hypothyroid subjects with Helicobacter pylori infection.

  12. Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial.

    PubMed

    Kutoh, Eiji; Ukai, Yasuhiro

    2012-06-01

    The objectives of this study is to evaluate the efficacy and safety of alogliptin versus very low fat/calorie traditional Japanese diet (non-inferiority trial) as an initial therapy for newly diagnosed, drug naïve subjects with type 2 diabetes (T2DM). Study design was prospective, randomized, non-double-blind, controlled trial. The study was conducted at outpatient units of municipal hospital. Patients were newly diagnosed, drug naïve patients who visited the outpatient units. The patients randomly received 12.5-25 mg/day alogliptin (n = 25) or severe low calorie traditional Japanese diet (n = 26). The procedure of this trial was assessed by the consolidated standards of reporting trials statement. The primary end point was the change of HbA1c at 3 months. Secondary end points included the changes of fasting blood glucose, insulin, homeostasis model assessment-R (HOMA-R), HOMA-B, body mass index (BMI), and lipid parameters. Similar, significant reductions of HbA1c levels were observed in both groups (from 10.51 to 8.74% for alogliptin and from 10.01 to 8.39% for traditional Japanese diet) without any clinically significant adverse events. In the alogliptin group, some subjects (16%) had mild hypoglycemic evens which could be managed by taking glucose drinks by themselves. HOMA-B significantly increased in both groups with varying degrees, whereas HOMA-R significantly decreased only in the Japanese diet group. Atherogenic lipids, such as, total cholesterol, non-high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels significantly decreased in both groups. BMI had no change in the alogliptin group, whereas it significantly decreased in the Japanese diet group. (1) Concerning its glycemic efficacy, alogliptin is effective and non-inferior to traditional Japanese diet as an initial therapeutic option for newly diagnosed T2DM. However, regarding the reductions of body weight and insulin resistance, traditional Japanese diet is

  13. Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and "depressed" mice exposed to chronic mild stress.

    PubMed

    Franceschelli, A; Sens, J; Herchick, S; Thelen, C; Pitychoutis, P M

    2015-04-02

    During the past decade, one of the most striking discoveries in the treatment of major depression was the clinical finding that a single infusion of a sub-anesthetic dose of the N-methyl-d-aspartate receptor antagonist ketamine produces a rapid (i.e. within a few hours) and long-lasting (i.e. up to two weeks) antidepressant effect in both treatment-resistant depressed patients and in animal models of depression. Notably, converging clinical and preclinical evidence support that responsiveness to antidepressant drugs is sex-differentiated. Strikingly, research regarding the antidepressant-like effects of ketamine has focused almost exclusively on the male sex. Herein we report that female C57BL/6J stress-naïve mice are more sensitive to the rapid and the sustained antidepressant-like effects of ketamine in the forced swim test (FST). In particular, female mice responded to lower doses of ketamine (i.e. 3mg/kg at 30 min and 5mg/kg at 24h post-injection), doses that were not effective in their male counterparts. Moreover, tissue levels of the excitatory amino acids glutamate and aspartate, as well as serotonergic activity, were affected in a sex-dependent manner in the prefrontal cortex and the hippocampus, at the same time-points. Most importantly, a single injection of ketamine (10mg/kg) induced sex-dependent behavioral effects in mice subjected to the chronic mild stress (CMS) model of depression. Intriguingly, female mice were more reactive to the earlier effects of ketamine, as assessed in the open field and the FST (at 30 min and 24h post-treatment, respectively) but the antidepressant potential of the drug proved to be longer lasting in males, as assessed in the splash test and the FST (days 5 and 7 post-treatment, respectively). Taken together, present data revealed that ketamine treatment induces sex-dependent rapid and sustained neurochemical and behavioral antidepressant-like effects in stress-naïve and CMS-exposed C57BL/6J mice.

  14. Glycemic Effectiveness of Metformin-Based Dual-Combination Therapies with Sulphonylurea, Pioglitazone, or DPP4-Inhibitor in Drug-Naïve Korean Type 2 Diabetic Patients

    PubMed Central

    Lee, Young Ki; Song, Sun Ok; Kim, Kwang Joon; Cho, Yongin; Choi, Younjeong; Yun, Yujung; Kang, Eun-Seok; Cha, Bong Soo; Lee, Hyun Chul

    2013-01-01

    Background This study compared the glycemic effectiveness of three metformin-based dual therapies according to baseline hemoglobin A1c (HbA1c) to evaluate the appropriateness of the guideline enforced by the National Health Insurance Corporation of Korea for initial medication of type 2 diabetes (T2D). Methods This prospective observational study was conducted across 24 weeks for drug-naïve Korean T2D patients with HbA1c greater than 7.5%. Subjects were first divided into three groups based on the agent combined with metformin (group 1, gliclazide-modified release or glimepiride; group 2, pioglitazone; group 3, sitagliptin). Subjects were also classified into three categories according to baseline HbA1c (category I, 7.5%≤HbA1c<9.0%; category II, 9.0%≤HbA1c<11.0%; category III, 11.0%≤HbA1c). Results Among 116 subjects, 99 subjects completed the study, with 88 subjects maintaining the initial medication. While each of the metformin-based dual therapies showed a significant decrease in HbA1c (group 1, 8.9% to 6.4%; group 2, 9.0% to 6.6%; group 3, 9.3% to 6.3%; P<0.001 for each), there was no significant difference in the magnitude of HbA1c change among the groups. While the three HbA1c categories showed significantly different baseline HbA1c levels (8.2% vs. 9.9% vs. 11.9%; P<0.001), endpoint HbA1c was not different (6.4% vs. 6.6% vs. 6.0%; P=0.051). Conclusion The three dual therapies using a combination of metformin and either sulfonylurea, pioglitazone, or sitagliptin showed similar glycemic effectiveness among drug-naïve Korean T2D patients. In addition, these regimens were similarly effective across a wide range of baseline HbA1c levels. PMID:24404518

  15. Acceptability and efficacy of interactive short message service intervention in improving HIV medication adherence in Chinese antiretroviral treatment-naïve individuals

    PubMed Central

    Ruan, Ye; Xiao, Xueling; Chen, Jia; Li, Xianhong; Williams, Ann Bartley; Wang, Honghong

    2017-01-01

    Aim The aim of this study was to examine the acceptability and efficacy of interactive short message service (SMS) in improving medication adherence in antiretroviral treatment (ART)-naïve individuals living with HIV/AIDS in Hengyang, Hunan, China. Background SMS via mobile phone has emerged as a potential tool for improving ART adherence. However, most studies used SMS only as a medication reminder, with few studies exploring the effect of comprehensive, interactive SMS. Patients and methods In a randomized controlled trial, 100 HIV-positive patients on ART for <3 months were randomized into control or intervention arm. Participants in the control group received routine standard instruction for ART medication in the HIV clinics, while the intervention group received 6 months of an SMS intervention in addition to the standard care. A total of 124 text messages within 6 modules were edited, preinstalled, and sent to participants according to personalized schedules. Knowledge (of HIV and HIV medications), self-reported antiretroviral adherence (Visual Analog Scale [VAS] and Community Programs for Clinical Research on AIDS [CPCRA] Antiretroviral Medication Self-Report), and CD4 count were assessed at baseline and immediate post-intervention. Intervention participants were interviewed after completion of the study about their satisfaction with and acceptability of the SMS intervention. Results Baseline assessments were comparable between arms. Repeated-measures analysis showed that both HIV-related and ART medication knowledge of the intervention group showed better improvement over time than those of the control group after the intervention (P<0.0001). For the adherence measures, compared with the control group, participants in the intervention group had significantly higher VAS mean score (Z=2.735, P=0.006) and lower suboptimal adherence rate (Z=2.208, P=0.027) at the end of the study. The intervention had no effect on CD4 cell count. Almost all (96%) intervention

  16. Impact of telephonic interviews on persistence and daily adherence to insulin treatment in insulin-naïve type 2 diabetes patients: dropout study

    PubMed Central

    Yavuz, Dilek Gogas; Bilen, Habip; Sancak, Seda; Garip, Tayfun; Hekimsoy, Zeliha; Sahin, Ibrahim; Yilmaz, Murat; Aydin, Hasan; Atmaca, Aysegul; Sert, Murat; Karakaya, Pinar; Arpaci, Dilek; Oguz, Aytekin; Guvener, Nilgun

    2016-01-01

    Objective The objective of this study is to evaluate the impact of sequential telephonic interviews on treatment persistence and daily adherence to insulin injections among insulin-naïve type 2 diabetes patients initiated on different insulin regimens in a 3-month period. Methods A total of 1,456 insulin-naïve patients with type 2 diabetes (mean [standard deviation, SD] age: 56.0 [12.0] years, 49.1% were females) initiated on insulin therapy and consecutively randomized to sequential (n=733) and single (n=723) telephonic interview groups were included. Data on insulin treatment and self-reported blood glucose values were obtained via telephone interview. Logistic regression analysis was performed for factors predicting increased likelihood of persistence and skipping an injection. Results Overall, 76.8% patients (83.2% in sequential vs 70.3% in single interview group, (P<0.001) remained on insulin treatment at the third month. Significantly higher rate for skipping doses was noted in basal bolus than in other regimens (27.0% vs 15.0% for premixed and 15.8% basal insulin, respectively, P<0.0001). Logistic regression analysis revealed sequential telephonic interview (odds ratio [OR], 1.531; 95% confidence interval [CI], 1.093–2.143; P=0.013), higher hemoglobin A1c levels (OR, 1.090; 95% CI, 0.999–1.189; P=0.049), and less negative appraisal of insulin therapy as significant predictors of higher persistence. Basal bolus regimen (OR, 1.583; 95% CI, 1.011–2.479; P=0.045) and higher hemoglobin A1c levels (OR, 1.114; 95% CI, 1.028–1.207; P=0.008) were the significant predictors of increased likelihood of skipping an injection. Conclusion Our findings revealed positive influence of sequential telephonic interview, although including no intervention in treatment, on achieving better treatment persistence in type 2 diabetes patients initiating insulin. PMID:27274207

  17. Altered resting state functional connectivity of anterior cingulate cortex in drug naïve adolescents at the earliest stages of anorexia nervosa

    PubMed Central

    Gaudio, Santino; Piervincenzi, Claudia; Beomonte Zobel, Bruno; Romana Montecchi, Francesca; Riva, Giuseppe; Carducci, Filippo; Cosimo Quattrocchi, Carlo

    2015-01-01

    Previous Resting-State Functional Connectivity (RSFC) studies have shown several functional alterations in adults with or recovered from long Anorexia Nervosa (AN). The aim of this paper was to investigate whole brain RSFC in adolescents with AN in the earliest stages, less than 6 months, of the disorder. Sixteen drug-naïve outpatient female adolescents with AN-restrictive type (AN-r) (mean age: 15,8; SD 1,7) were compared to 16 age-matched healthy female (mean age: 16,3; SD 1,4). Relevant resting state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data; a dual regression technique was used to detect between-group differences in the RSNs. Between-group differences of the functional connectivity maps were found in the executive control network (ECN). Particularly, decreased temporal correlation was observed in AN-r patients relative to healthy controls between the ECN functional connectivity maps and the anterior cingulate cortex (p < 0.05 corrected). Our results in AN adolescents may represent an early trait-related biomarker of the disease. Considering that the above mentioned network and its area are mainly involved in cognitive control and emotional processing, our findings could explain the impaired cognitive flexibility in relation to body image and appetite in AN patients. PMID:26043139

  18. A preliminary study to understand the effect of Fasciola hepatica tegument on naïve macrophages and humoral responses in an ovine model.

    PubMed

    Haçarız, O; Sayers, G; Mulcahy, G

    2011-02-15

    Fasciola hepatica, the liver fluke, is a highly evolved endo-parasite that uses various mechanisms to evade the host immune system. The immunosuppressive capabilities of the parasite's excretory/secretory products have been well demonstrated by previous independent studies. However, the role of the parasite's tegument in the immune responses remains to be investigated. In this study, the effect of the tegument and other fractions of adult F. hepatica (excretory/secretory, liver fluke homogenate and liver fluke homogenate without tegument) in the activation of naïve macrophages in vitro was investigated using an ovine model. In addition, an immunoproteomic approach was used to investigate the characteristics of humoral antibody responses developed in sheep against the tegument fraction. The results indicated significantly increased arginase expression in macrophages incubated with the tegument and excretory/secretory fractions. Two dimensional gel electrophoresis of the tegument demonstrated approximately 100 protein spots, with only four of these spots were highly reactive with the positive serum as determined by 2-DE immunoblotting. These results give a preliminary indication that the liver fluke tegument may play role in avoiding hosts' protective immune responses against itself.

  19. Evaluation of the Effectiveness of a Psychoeducational Intervention in Treatment-Naïve Patients with Antidepressant Medication in Primary Care: A Randomized Controlled Trial

    PubMed Central

    Casañas, R.; Catalán, R.; Penadés, R.; Real, J.; Valero, S.; Muñoz, MA.; Lalucat-Jo, LL.; Casas, M.

    2015-01-01

    Background. There is evidence supporting the effectiveness of psychoeducation (PE) in patients with symptoms of depression in primary care (PC), but very few studies have assessed this intervention in antidepressant-naïve patients. The aim of this study is to assess the effectiveness of a PE program in these patients, since the use of antidepressant (AD) medication may interfere with the effects of the intervention. Methods. 106 participants were included, 50 from the PE program (12 weekly 1.5-hour sessions) and 56 from the control group (CG) that received the usual care. Patients were assessed at baseline and at 3, 6, and 9 months. The main outcome measures were the Beck Depression Inventory (BDI) and remission based on the BDI. The analysis was carried out on an intention-to-treat basis. Results. The PE program group showed remission of symptoms of 40% (P = 0.001) posttreatment and 42% (P = 0.012) at 6 months. The analysis only showed significant differences in the BDI score posttreatment (P = 0.008; effect size Cohen's d′ = 0.55). Conclusions. The PE intervention is an effective treatment in the depressive population not treated with AD medication. Before taking an AD, psychoeducational intervention should be considered. PMID:26380366

  20. Monitoring of local CD8β-expressing cell populations during Eimeria tenella infection of naïve and immune chickens.

    PubMed

    Wattrang, E; Thebo, P; Lundén, A; Dalgaard, T S

    2016-08-01

    The purpose of this study was to monitor abundance and activation of local CD8β-expressing T-cell populations during Eimeria tenella infections of naïve chickens and chickens immune by previous infections. Chickens were infected with E. tenella up to three times. Caecal T-cell receptor (TCR) γ/δ-CD8β+ cells (cytotoxic T lymphocytes; CTL) and TCRγ/δ+CD8β+ cells were characterized with respect to activation markers (blast transformation, CD25 and cell surface CD107a). Cells were also induced to degranulate in vitro as a measure of activation potential. Major findings included a prominent long-lasting, up to 6 weeks, increase in the proportion of CTL among caecal CD45+ cells in the later stages after primary E. tenella infection. These CTL also showed clear signs of activation, that is blast transformation and increased in vitro induced degranulation. At second and third E. tenella infection, chickens showed strong protective immunity but discrete signs of cellular activation were observed, for example increased in vitro induced degranulation of CTL. Thus, primary E. tenella infection induced clear recruitment and activation of local CTL. Upon subsequent infections of strongly immune chickens cellular changes were less prominent, possibly due to lower overall numbers of cells being activated because of the severe restriction of parasite replication.

  1. Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: A meta-analysis.

    PubMed

    Capuzzi, Enrico; Bartoli, Francesco; Crocamo, Cristina; Clerici, Massimo; Carrà, Giuseppe

    2017-03-08

    Schizophrenia is likely to be associated with immunological abnormalities. However, antipsychotics may induce immunomodulatory effects, by influencing plasma cytokines. In order to distinguish these influences, we carried out a systematic review and meta-analysis exploring the acute effect of antipsychotics on candidate cytokines plasma levels (IL-1β, IL-2, IL-6, IL-17, IFN-γ, TNF-α) among drug-naïve subjects with first episode psychosis. We searched main Electronic Databases, identifying eight studies meeting our inclusion criteria. Pre and post-treatment plasma cytokines values were used to estimate standardized mean differences. Heterogeneity was estimated using the I(2) index. Heterogeneity-based sensitivity analyses were performed. IL-2 (p=0.023) and IL-6 (p=0.012) levels showed a significant decrease after four weeks of antipsychotic treatment. Relevant sensitivity analysis confirmed these findings. IL-1β had high between-study heterogeneity. However, leaving out one study, significant after treatment decrease was found. IL-6 and IL-2, and possibly IL-1β, could be considered state markers, decreasing after antipsychotic treatment, whilst TNF-α, IL-17, and IFN-γ might be considered trait markers. Options for novel treatments in FEP, involving cytokine-modulating agents, should be further studied.

  2. Depression in Caregivers of Status-Naïve Pediatric HIV Patients Participating in a Status Disclosure Study in Haiti and the Dominican Republic: Preliminary Report

    PubMed Central

    Dévieux, Jessy G.; Pinzón-Iregui, María Claudia; Abreu-Pérez, Rosa; Lerebours-Nadal, Leonel; Gaston, Stephanie; Dean, Andrew G.; Halpern, Mina; Rouzier, Vanessa; Bertrand, Rachel; Rosenberg, Rhonda; Pape, Jean William; Nicholas, Stephen W.; Blasini, Ileana

    2015-01-01

    A pilot study is underway to assess safety and acceptability of an intervention to disclose their HIV infection status to status-naïve pediatric antiretroviral therapy patients in Hispaniola [the island shared by Haiti and the Dominican Republic (DR)]. Of 22 Haiti and 47 DR caregivers recruited to date, 68.2% Haiti and 34.0% DR caregivers had clinically significant depressive symptomatology at the time of enrollment (p = 0.008). Depressive symptom prevalence was higher in Haiti caregivers who were female (81.3% vs. 0 in males; p = 0.02) and in DR caregivers who were patients’ mothers (50.0%) or grandmothers (66.7%; 56.0% combined) than others (9.1%), (p < 0.001). Internalized stigma was more commonly reported by Haiti (85.7%) than DR (53.2%; p = 0.01) caregivers; 56.4% of Haiti and DR caregivers reporting internalized stigma vs. 26.1% of caregivers denying it had depressive symptoms (p = 0.02). Depression is common in Hispaniola caregivers possibly affecting disclosure timing. Study participation presents opportunities for addressing caregiver depression. PMID:25389181

  3. Voxel-based Gaussian naïve Bayes classification of ischemic stroke lesions in individual T1-weighted MRI scans

    PubMed Central

    Griffis, Joseph C.; Allendorfer, Jane B.; Szaflarski, Jerzy P.

    2015-01-01

    Background Manual lesion delineation by an expert is the standard for lesion identification in MRI scans, but is time-consuming and can introduce subjective bias. Alternative methods often require multi-modal MRI data, user interaction, scans from a control population, and/or arbitrary statistical thresholding. New Method We present an approach for automatically identifying stroke lesions in individual T1-weighted MRI scans using naïve Bayes classification. Probabilistic tissue segmentation and image algebra were used to create feature maps encoding information about missing and abnormal tissue. Leave-one-case-out training and cross-validation was used to obtain out-of-sample predictions for each of 30 cases with left hemisphere stroke lesions. Results Our method correctly predicted lesion locations for 30/30 un-trained cases. Post-processing with smoothing (8mm FWHM) and cluster-extent thresholding (100 voxels) was found to improve performance. Comparison with Existing Method Quantitative evaluations of post-processed out-of-sample predictions on 30 cases revealed high spatial overlap (mean Dice similarity coefficient = 0.66) and volume agreement (mean percent volume difference = 28.91; Pearson’s r = 0.97) with manual lesion delineations. Conclusions Our automated approach agrees with manual tracing. It provides an alternative to automated methods that require multi-modal MRI data, additional control scans, or user interaction to achieve optimal performance. Our fully trained classifier has applications in neuroimaging and clinical contexts. PMID:26432931

  4. Isolation and characterization of HIV-1 envelope glycoprotein specific B cell from immortalized human naïve B cell library.

    PubMed

    Sun, Zehua; Lu, Shiqiang; Yang, Zheng; Li, Jingjing; Zhang, Meiyun

    2017-01-10

    With the recent development of single B cell cloning techniques, an increasing number of HIV-1-specific broadly neutralizing antibodies (bNAbs) have been isolated since 2009. However, knowledge regarding HIV-1-specific B cells in vivo is limited. In this study, an HIV-1-specific B cell line has been established using healthy PBMC donors by the highly efficient EBV transformation method to generate immortalized human naïve B cell libraries. The enrichment of HIV-1 envelope-specific B cells was observed after four rounds of cell panning with the HIV-1 envelope glycoprotein. An HIV-1 envelope-specific stable B cell line (LCL-P4) was generated. Although this cell line acquired a lymphoblastic phenotype, no expression was observed for activation-induced cytidine deaminase (AID), an enzyme responsible for initiating somatic hypermutation and class switch recombination in B cells. This study describes a method that enables fast isolation of HIV-1-specific B cells, and this approach may extend to isolating other B cell-specific antigens for further experiments.

  5. Smaller Feedback ERN Amplitudes During the BART are Associated with a Greater Family History Density of Alcohol Problems in Treatment-Naïve Alcoholics

    PubMed Central

    Fein, George; Chang, Maria

    2008-01-01

    BACKGROUND Alcoholism is characterized by impaired decision-making (i.e., choosing intoxication in the face of mounting negative consequences). This impairment may involve a reduced brain response to the negative consequences of behavior, which supports an inclination to engage in risky behaviors. The feedback error-related negativity (F-ERN) is hypothesized to reflect the valence attached to the negative consequences of behavior. Performance on the Balloon Analogue Risk Task (BART) measures risk-taking propensity. We recorded F-ERNs during the BART and during a BART simulation, where individuals observed the rewards and consequences of (someone else’s) BART performance. METHODS EEGs were recorded on 22 actively drinking, treatment-naïve alcoholics during the BART and BART simulation. F-ERNs were measured and their association with psychological and alcohol use measures was examined. RESULTS F-ERNs over fronto-central electrode sites were observed to balloon pops in the BART and BART simulation. F-ERNs during the BART were more than twice the amplitude of F-ERNs during the BART simulation. Smaller F-ERN amplitudes from the BART (but not the BART simulation) were associated with a greater family history density of alcohol problems. CONCLUSION The results suggest a possible link between the genetic vulnerability toward developing alcoholism and the brain’s response to the negative consequences of behavior. PMID:17869027

  6. A Karhunen-Loève least-squares technique for optimization of geometry of a blunt body in supersonic flow

    NASA Astrophysics Data System (ADS)

    Brooks, Gregory P.; Powers, Joseph M.

    2004-03-01

    A novel Karhunen-Loève (KL) least-squares model for the supersonic flow of an inviscid, calorically perfect ideal gas about an axisymmetric blunt body employing shock-fitting is developed; the KL least-squares model is used to accurately select an optimal configuration which minimizes drag. Accuracy and efficiency of the KL method is compared to a pseudospectral method employing global Lagrange interpolating polynomials. KL modes are derived from pseudospectral solutions at Mach 3.5 from a uniform sampling of the design space and subsequently employed as the trial functions for a least-squares method of weighted residuals. Results are presented showing the high accuracy of the method with less than 10 KL modes. Close agreement is found between the optimal geometry found using the KL model to that found from the pseudospectral solver. Not including the cost of sampling the design space and building the KL model, the KL least-squares method requires less than half the central processing unit time as the pseudospectral method to achieve the same level of accuracy. A decrease in computational cost of several orders of magnitude as reported in the literature when comparing the KL method against discrete solvers is shown not to hold for the current problem. The efficiency is lost because the nature of the nonlinearity renders a priori evaluation of certain necessary integrals impossible, requiring as a consequence many costly reevaluations of the integrals.

  7. A functional connectivity comparison between attention deficit hyperactivity disorder and bipolar disorder in medication-naïve adolescents with mood fluctuation and attention problems.

    PubMed

    Son, Young Don; Han, Doug Hyun; Kim, Sun Mi; Min, Kyung Joon; Renshaw, Perry F

    2017-02-17

    In order to compare patterns of connectivity between affective and attention networks in adolescents with bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD), we investigated differences in resting state functional connectivity (RSFC) between these populations. Study participants were medication-naïve adolescents (aged 13-18 years) with BD (N=22) or ADHD (N=25) and age- and sex-matched healthy adolescents (healthy controls [HC]) (N=22). Forty-seven adolescents with mood fluctuation and attention problems showed increased functional correlation (FC) between two pairs of regions within the affective network (AFN), compared to 22 HC: the left orbitofrontal cortex (OFC) to the left thalamus and the left OFC to the right thalamus. In post-hoc testing, adolescents with BD showed increased FC between two pairs of regions compared to ADHD: the right amygdala to the left temporoparietal junction (TPJ) and the right amygdala to the right TPJ. Adolescents with BD showed increased FC within the attention network (ATN) as well as increased FC between the ATN and the AFN, while those with ADHD showed decreased FC within the ATN. The current suggests that these features could be used as biomarkers for differentiating BD from ADHD in adolescents.

  8. Comparison of naïve and central memory derived CD8(+) effector cell engraftment fitness and function following adoptive transfer.

    PubMed

    Wang, Xiuli; Wong, ChingLam W; Urak, Ryan; Taus, Ellie; Aguilar, Brenda; Chang, Wen-Chung; Mardiros, Armen; Budde, Lihua E; Brown, Christine E; Berger, Carolina; Forman, Stephen J; Jensen, Michael C

    Human CD8(+) effector T cells derived from CD45RO(+)CD62L(+) precursors enriched for central memory (TCM) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45RO(+)CD62L(-) precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8(+) effector T cells derived from CD45RA(+)CD62L(+) precursors enriched for naïve and stem cell memory precursors (TN/SCM) with that of TCM. We found that cytotoxic T cells (CTLs) derived from TCM transcribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from TN/SCM. Higher frequencies of CTLs derived from TCM retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/Scid IL-2RγC(null) mice, CD8(+) TCM derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8(+) TCM derived CD19CAR(+) CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8(+) TN/SCM derived counterparts. These studies support the use of TCM enriched cell products for adoptive therapy of cancer.

  9. Getting ready for invasions: can background level of risk predict the ability of naïve prey to survive novel predators?

    PubMed Central

    Ferrari, Maud C. O.; Crane, Adam L.; Brown, Grant E.; Chivers, Douglas P.

    2015-01-01

    Factors predicting the outcome of predator invasions on native prey communities are critical to our understanding of invasion ecology. Here, we tested whether background level of risk affected the survival of prey to novel predators, both native and invasive, predicting that high-risk environments would better prepare prey for invasions. We used naïve woodfrog as our prey and exposed them to a high or low risk regime either as embryos (prenatal exposure) or as larvae (recent exposure). Tadpoles were then tested for their survival in the presence of 4 novel predators: two dytiscid beetles, crayfish and trout. Survival was affected by both risk level and predator type. High risk was beneficial to prey exposed to the dytiscids larvae (ambush predators), but detrimental to prey exposed to crayfish or trout (pursuit predators). No effect of ontogeny of risk was found. We further documented that high-risk tadpoles were overall more active than their low-risk counterparts, explaining the patterns found with survival. Our results provide insights into the relationship between risk and resilience to predator invasions. PMID:25655436

  10. Naïve Bayes QSDR classification based on spiral-graph Shannon entropies for protein biomarkers in human colon cancer.

    PubMed

    Aguiar-Pulido, Vanessa; Munteanu, Cristian R; Seoane, José A; Fernández-Blanco, Enrique; Pérez-Montoto, Lázaro G; González-Díaz, Humberto; Dorado, Julián

    2012-06-01

    Fast cancer diagnosis represents a real necessity in applied medicine due to the importance of this disease. Thus, theoretical models can help as prediction tools. Graph theory representation is one option because it permits us to numerically describe any real system such as the protein macromolecules by transforming real properties into molecular graph topological indices. This study proposes a new classification model for proteins linked with human colon cancer by using spiral graph topological indices of protein amino acid sequences. The best quantitative structure-disease relationship model is based on eleven Shannon entropy indices. It was obtained with the Naïve Bayes method and shows excellent predictive ability (90.92%) for new proteins linked with this type of cancer. The statistical analysis confirms that this model allows diagnosing the absence of human colon cancer obtaining an area under receiver operating characteristic of 0.91. The methodology presented can be used for any type of sequential information such as any protein and nucleic acid sequence.

  11. Altered functional connectivity links in neuroleptic-naïve and neuroleptic-treated patients with schizophrenia, and their relation to symptoms including volition

    PubMed Central

    Pu, Weidan; Rolls, Edmund T.; Guo, Shuixia; Liu, Haihong; Yu, Yun; Xue, Zhimin; Feng, Jianfeng; Liu, Zhening

    2014-01-01

    In order to analyze functional connectivity in untreated and treated patients with schizophrenia, resting-state fMRI data were obtained for whole-brain functional connectivity analysis from 22 first-episode neuroleptic-naïve schizophrenia (NNS), 61 first-episode neuroleptic-treated schizophrenia (NTS) patients, and 60 healthy controls (HC). Reductions were found in untreated and treated patients in the functional connectivity between the posterior cingulate gyrus and precuneus, and this was correlated with the reduction in volition from the Positive and Negative Symptoms Scale (PANSS), that is in the willful initiation, sustenance, and control of thoughts, behavior, movements, and speech, and with the general and negative symptoms. In addition in both patient groups interhemispheric functional connectivity was weaker between the orbitofrontal cortex, amygdala and temporal pole. These functional connectivity changes and the related symptoms were not treated by the neuroleptics. Differences between the patient groups were that there were more strong functional connectivity links in the NNS patients (including in hippocampal, frontal, and striatal circuits) than in the NTS patients. These findings with a whole brain analysis in untreated and treated patients with schizophrenia provide evidence on some of the brain regions implicated in the volitional, other general, and negative symptoms, of schizophrenia that are not treated by neuroleptics so have implications for the development of other treatments; and provide evidence on some brain systems in which neuroleptics do alter the functional connectivity. PMID:25389520

  12. Causal connectivity alterations of cortical-subcortical circuit anchored on reduced hemodynamic response brain regions in first-episode drug-naïve major depressive disorder

    PubMed Central

    Gao, Qing; Zou, Ke; He, Zongling; Sun, Xueli; Chen, Huafu

    2016-01-01

    Some efforts were done to investigate the disruption of brain causal connectivity networks involved in major depressive disorder (MDD) using Granger causality (GC) analysis. However, the homogenous hemodynamic response function (HRF) assumption over the brain may disturb the inference of temporal precedence. Here we applied a blind deconvolution approach to examine the altered HRF shape in first-episode, drug-naïve MDD patients. The regions with abnormal HRF shape in patients were chosen as seeds to detect the GC alterations in MDD. The results demonstrated significantly decreased magnitude of spontaneous hemodynamic response of the orbital frontal cortex (OFC) and the caudate nucleus (CAU) in MDD comparing to healthy controls, suggesting MDD patients likely had alterations in neurovascular coupling and cerebrovascular physiology in these two regions. GC mapping showed increased/decreased GC in OFC-/CAU centered networks in MDD. The outgoing GC values from OFC to anterior cingulate cortex and occipital regions were positively correlated with Hamilton Depression Scale (HAMD) scores, while the incoming GC from insula, middle and superior temporal gyrus to CAU were negatively correlated with HAMD scores of MDD. The abnormalities of directional connections in the cortico-subcortico-cerebellar network may lead to unbalanced integrating the emotional-related information for MDD, and further exacerbating depressive symptoms. PMID:26911651

  13. Detection of Natural Resistance-Associated Substitutions by Ion Semiconductor Technology in HCV1b Positive, Direct-Acting Antiviral Agents-Naïve Patients

    PubMed Central

    Marascio, Nadia; Pavia, Grazia; Strazzulla, Alessio; Dierckx, Tim; Cuypers, Lize; Vrancken, Bram; Barreca, Giorgio Settimo; Mirante, Teresa; Malanga, Donatella; Oliveira, Duarte Mendes; Vandamme, Anne-Mieke; Torti, Carlo; Liberto, Maria Carla; Focà, Alfredo

    2016-01-01

    Naturally occurring resistance-associated substitutions (RASs) can negatively impact the response to direct-acting antivirals (DAAs) agents-based therapies for hepatitis C virus (HCV) infection. Herein, we set out to characterize the RASs in the HCV1b genome from serum samples of DAA-naïve patients in the context of the SINERGIE (South Italian Network for Rational Guidelines and International Epidemiology, 2014) project. We deep-sequenced the NS3/4A protease region of the viral population using the Ion Torrent Personal Genome Machine, and patient-specific majority rule consensus sequence summaries were constructed with a combination of freely available next generation sequencing data analysis software. We detected NS3/4A protease major and minor variants associated with resistance to boceprevir (V36L), telaprevir (V36L, I132V), simeprevir (V36L), and grazoprevir (V36L, V170I). Furthermore, we sequenced part of HCV NS5B polymerase using Sanger-sequencing and detected a natural RAS for dasabuvir (C316N). This mutation could be important for treatment strategies in cases of previous therapy failure. PMID:27618896

  14. Abnormal Glucose Tolerance, White Blood Cell Count, and Telomere Length in Newly Diagnosed, Antidepressant-Naïve Patients with Depression

    PubMed Central

    Garcia-Rizo, Clemente; Fernandez-Egea, Emilio; Miller, Brian J.; Oliveira, Cristina; Justicia, Azucena; Griffith, Jeffrey K.; Heaphy, Christopher M.; Bernardo, Miguel; Kirkpatrick, Brian

    2012-01-01

    Chronic mood disorders have been associated with a shortened telomere, a marker of increased mortality rate and ageing, and impaired cellular immunity. However, treatment may confound these relationships. We examined the relationship of glucose tolerance, white blood cell count and telomere length to depression in newly diagnosed, antidepressant-naïve patients. Subjects with major depression (n=15), and matched healthy control subjects (n=70) underwent a two-hour oral glucose tolerance test and evaluation of blood cell count and telomere content. The depression group had significantly higher two-hour glucose concentrations and a lower lymphocyte count than control subjects (respective means [SD] for two-hour glucose were 125.0 mg/dL [67.9] vs 84.6 [25.6] (p<.001); for lymphocyte count 2.1 × 109/L [0.6] vs. 2.5 ×109/L [0.7] p=.028).Telomere content was significantly shortened in the depression group (87.9 [7.6]) compared to control subjects (101.0 [14.3]; p<0.01). Abnormal glucose tolerance, lymphopenia and a shortened telomere are present early in the course of depression independently of the confounding effect of antidepressant treatment, supporting the concept of major depression as an accelerated ageing disease. PMID:23207109

  15. Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics.

    PubMed

    Ondondo, Beatrice; Jones, Emma; Hindley, James; Cutting, Scott; Smart, Kathryn; Bridgeman, Hayley; Matthews, Katherine K; Ladell, Kristin; Price, David A; Jackson, David G; Godkin, Andrew; Ager, Ann; Gallimore, Awen

    2014-05-01

    The tumor microenvironment comprises newly formed blood and lymphatic vessels which shape the influx, retention and departure of lymphocytes within the tumor mass. Thus, by influencing the intratumoral composition of lymphocytes, these vessels affect the manner in which the adaptive immune system responds to the tumor, either promoting or impairing effective antitumor immunity. In our study, we utilized a mouse model of carcinogen-induced fibrosarcoma to examine the composition of tumor-infiltrating lymphocytes during tumor progression. In particular, we sought to determine whether CD4(+) Foxp3(+) regulatory T cells (Tregs) became enriched during tumor progression thereby contributing to tumor-driven immunosuppression. This was not the case as the proportion of Tregs and effector CD4(+) T cells actually declined within the tumor owing to the unexpected accumulation of naïve T cells. However, we found no evidence for antigen-driven migration of these T cells or for their participation in an antitumor immune response. Our data support the notion that lymphocytes can enter tumors via aberrantly formed blood and lymphatic vessels. Such findings suggest that targeting both the tumor vasculature and lymphatics will alter the balance of lymphocyte subpopulations that enter the tumor mass. A consideration of this aspect of tumor immunology may be critical to the success of solid cancer immunotherapies.

  16. Responses of dopaminergic, serotonergic and noradrenergic networks to acute levo-tetrahydropalmatine administration in naïve rats detected at 9.4 T

    PubMed Central

    Liu, Xiping; Yang, Zheng; Li, Rupeng; Xie, Jun; Yin, Qian; Bloom, Alan S.; Li, Shi-Jiang

    2012-01-01

    Aim The aim of this study was to understand the neuropharmacological characteristics of levo-tetrahydropalmatine (l-THP), a recently found potential treatment for drug addiction, and discover its neural correlates and sites of action. Methods High-field pharmacological magnetic resonance imaging (phMRI) was used to detect activation induced by acute l-THP administration in the naïve rat brain at dose levels of 5, 10, 20 and 40 mg/kg. Results Interestingly, the pharmacological profile of l-THP selectively binds to the receptors of the dopaminergic, serotonergic and noradrenergic systems. Using the phMRI method, it was demonstrated that l-THP selectively activated the key brain regions of the dopaminergic, serotonergic and noradrenergic systems in a dose-dependent manner. Conclusion Numerous studies suggest a critical role of monoamines in the behavioral, pharmacological and addictive properties of psychostimulants. It is suggested that l-THP holds great potential to be a therapeutic medication for drug addiction. PMID:22079072

  17. Plasma aldosterone and left ventricular diastolic function in treatment-naïve patients with hypertension: tissue-Doppler imaging study.

    PubMed

    Catena, Cristiana; Verheyen, Nicolas; Pilz, Stefan; Kraigher-Krainer, Elisabeth; Tomaschitz, Andreas; Sechi, Leonardo A; Pieske, Burkert

    2015-06-01

    Aldosterone has hypertrophic and profibrotic effects on the heart. The relationship between plasma aldosterone levels and left ventricular diastolic function in hypertension, however, is unclear. The aim of this study was to examine this relationship in treatment-naïve hypertensive patients free of comorbidities that could affect left ventricular diastolic filling properties. In 115 patients with primary hypertension who were eating a standard diet and 100 matched normotensive controls, we measured plasma aldosterone and active renin levels and performed both conventional echocardiography and tissue-Doppler imaging for assessment of left ventricular diastolic function. Left ventricular hypertrophy was found in 21% of hypertensive patients, and diastolic dysfunction was detected in 20% by conventional echocardiography and in 58% by tissue-Doppler imaging. Patients with left ventricular diastolic dysfunction at tissue-Doppler imaging were older and more frequently men, had greater body mass index, blood pressure, alcohol intake, left ventricular mass index, relative wall thickness, and lower plasma aldosterone levels than patients with preserved diastolic function. Plasma aldosterone correlated directly with left ventricular mass index in addition to age, body mass index, and systolic blood pressure. Plasma aldosterone was also directly related to e' velocity at tissue-Doppler imaging, but this relationship was lost after multivariate adjustment. In conclusion, plasma aldosterone levels are associated with left ventricular hypertrophy but have no independent relationship with left ventricular diastolic properties in hypertensive patients.

  18. Prediction of Endocrine System Affectation in Fisher 344 Rats by Food Intake Exposed with Malathion, Applying Naïve Bayes Classifier and Genetic Algorithms

    PubMed Central

    Mora, Juan David Sandino; Hurtado, Darío Amaya; Sandoval, Olga Lucía Ramos

    2016-01-01

    Background: Reported cases of uncontrolled use of pesticides and its produced effects by direct or indirect exposition, represent a high risk for human health. Therefore, in this paper, it is shown the results of the development and execution of an algorithm that predicts the possible effects in endocrine system in Fisher 344 (F344) rats, occasioned by ingestion of malathion. Methods: It was referred to ToxRefDB database in which different case studies in F344 rats exposed to malathion were collected. The experimental data were processed using Naïve Bayes (NB) machine learning classifier, which was subsequently optimized using genetic algorithms (GAs). The model was executed in an application with a graphical user interface programmed in C#. Results: There was a tendency to suffer bigger alterations, increasing levels in the parathyroid gland in dosages between 4 and 5 mg/kg/day, in contrast to the thyroid gland for doses between 739 and 868 mg/kg/day. It was showed a greater resistance for females to contract effects on the endocrine system by the ingestion of malathion. Females were more susceptible to suffer alterations in the pituitary gland with exposure times between 3 and 6 months. Conclusions: The prediction model based on NB classifiers allowed to analyze all the possible combinations of the studied variables and improving its accuracy using GAs. Excepting the pituitary gland, females demonstrated better resistance to contract effects by increasing levels on the rest of endocrine system glands. PMID:27833725

  19. The effect of training set on the classification of honey bee gut microbiota using the Naïve Bayesian Classifier

    PubMed Central

    2012-01-01

    Background Microbial ecologists now routinely utilize next-generation sequencing methods to assess microbial diversity in the environment. One tool heavily utilized by many groups is the Naïve Bayesian Classifier developed by the Ribosomal Database Project (RDP-NBC). However, the consistency and confidence of classifications provided by the RDP-NBC is dependent on the training set utilized. Results We explored the stability of classification of honey bee gut microbiota sequences by the RDP-NBC utilizing three publically available ribosomal RNA sequence databases as training sets: ARB-SILVA, Greengenes and RDP. We found that the inclusion of previously published, high-quality, full-length sequences from 16S rRNA clone libraries improved the precision in classification of novel bee-associated sequences. Specifically, by including bee-specific 16S rRNA gene sequences a larger fraction of sequences were classified at a higher confidence by the RDP-NBC (based on bootstrap scores). Conclusions Results from the analysis of these bee-associated sequences have ramifications for other environments represented by few sequences in the public databases or few bacterial isolates. We conclude that for the exploration of relatively novel habitats, the inclusion of high-quality, full-length 16S rRNA gene sequences allows for a more confident taxonomic classification. PMID:23013113

  20. PD-1 is a marker for abnormal distribution of naïve/memory T cell subsets in HIV-1 infection

    PubMed Central

    Breton, Gaëlle; Chomont, Nicolas; Takata, Hiroshi; Fromentin, Rémi; Ahlers, Jeffrey; Filali-Mouhim, Abdelali; Riou, Catherine; Boulassel, Mohamed-Rachid; Routy, Jean-Pierre; Yassine-Diab, Bader; Sékaly, Rafick-Pierre

    2013-01-01

    Chronic activation of T cells is a hallmark of HIV-1 infection and plays an important role in disease progression. We previously showed that the engagement of the inhibitory receptor PD-1 on HIV-1 specific CD4+ and CD8+ T cells leads to their functional exhaustion in vitro. However, little is known about the impact of PD-1 expression on the turnover and maturation status of T cells during the course of the disease. Here, we show that PD-1 is up regulated on all T cell subsets including naïve, central memory and transitional memory T cells in HIV-1 infected subjects. PD-1 is expressed at similar levels on most CD4+ T cells during the acute and the chronic phase of disease and identifies cells that have recently entered the cell cycle. In contrast, PD-1 expression dramatically increased in CD8+ T cells during the transition from acute to chronic infection and this was associated with reduced levels of cell proliferation. The failure to down regulate expression of PD-1 in most T cells during chronic HIV-1 infection was associated to persistent alterations in the distribution of T cell subsets and was associated with impaired responses to IL-7. Our findings identify PD-1 as a marker for aberrant distribution of T cell subsets in HIV-1 infection. PMID:23918986

  1. Detection of Natural Resistance-Associated Substitutions by Ion Semiconductor Technology in HCV1b Positive, Direct-Acting Antiviral Agents-Naïve Patients.

    PubMed

    Marascio, Nadia; Pavia, Grazia; Strazzulla, Alessio; Dierckx, Tim; Cuypers, Lize; Vrancken, Bram; Barreca, Giorgio Settimo; Mirante, Teresa; Malanga, Donatella; Oliveira, Duarte Mendes; Vandamme, Anne-Mieke; Torti, Carlo; Liberto, Maria Carla; Focà, Alfredo; The Sinergie-Umg Study Group

    2016-08-27

    Naturally occurring resistance-associated substitutions (RASs) can negatively impact the response to direct-acting antivirals (DAAs) agents-based therapies for hepatitis C virus (HCV) infection. Herein, we set out to characterize the RASs in the HCV1b genome from serum samples of DAA-naïve patients in the context of the SINERGIE (South Italian Network for Rational Guidelines and International Epidemiology, 2014) project. We deep-sequenced the NS3/4A protease region of the viral population using the Ion Torrent Personal Genome Machine, and patient-specific majority rule consensus sequence summaries were constructed with a combination of freely available next generation sequencing data analysis software. We detected NS3/4A protease major and minor variants associated with resistance to boceprevir (V36L), telaprevir (V36L, I132V), simeprevir (V36L), and grazoprevir (V36L, V170I). Furthermore, we sequenced part of HCV NS5B polymerase using Sanger-sequencing and detected a natural RAS for dasabuvir (C316N). This mutation could be important for treatment strategies in cases of previous therapy failure.

  2. Association study between mannose-binding lectin haplotypes and X gene mutation of hepatitis B virus from treatment naïve patients

    PubMed Central

    Su, Chenghao; Lin, Yong; Mao, Qianguo; Wu, Daitze; Zhu, Lina; Najera, Isabel; Garcia-Alcalde, Fernando; Niu, Jianjun

    2016-01-01

    Mannose binding lectin (MBL) plays important role in the innate immunity of human. Mutations in the MBL2 gene can significantly change the serum level of MBL, and consequently alter the susceptibility and progression of infectious disease. However, the association between the MBL2 profile and the HBV mutation and quasispecies complexity has not yet been reported. Our approach includes the study of the MBL2 gene genotype as well as ultra-deep sequencing of the HBV viruses obtained from the plasma of 50 treatment naïve patients with chronic HBV infection. We found that the liver function was better among patients within the high MBL2 group with respect to those within the medium/low MBL2 group. Likewise, the number of mutations in the HBV X gene as well as the viral quasispecies complexity were significantly higher in medium/low MBL2 production group. Nucleotide substitution rates were also higher within the medium/low MBL2 production group in all positions described to have an influence in liver cancer development, except for A1499G. In this work we show that the MBL2 profile may have an impact on the HBV X gene mutations as well as on viral quasispecies complexity. PMID:27824315

  3. Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials.

    PubMed

    Zimran, Ari; Elstein, Deborah; Gonzalez, Derlis E; Lukina, Elena A; Qin, Yulin; Dinh, Quinn; Turkia, Hadhami Ben

    2016-10-21

    Gaucher disease is an inherited metabolic disease characterized by β-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427.

  4. Evaluation of dry powder inhalers with a focus on ease of use and user preference in inhaler-naïve individuals.

    PubMed

    von Schantz, Sofia; Katajavuori, Nina; Antikainen, Osmo; Juppo, Anne

    2016-07-25

    Inhaler errors are common amongst inhaler users. Therefore, in the development work of new inhalation devices, it is important to characterize the ease of use of the inhalers. In this study four dry powder inhalers, Diskus, Easyhaler, Ellipta and Turbuhaler, were evaluated, focusing on ease of use and patient preference. The study used a triangular methodology. The sample consisted of 31 inhaler naïve individuals. Educational videos for all inhalers were watched, and afterwards, the use of all four inhalers was demonstrated in a random order. The demonstrations were videotaped. Thereafter they were checked against a predefined checklist and all mistakes were recorded. Only 33% of inhaler demonstrations were completed without the participants making any mistakes. The proportions of subjects who used the devices correctly were as follows: Diskus 48%, Easyhaler 19%, Ellipta 55% and Turbuhaler 16%. When comparing correct and incorrect inhaler technique for each inhaler pair the following differences were statistically significant: Diskus vs. Easyhaler (p<0.05), Ellipta vs. Easyhaler (p<0.01), Diskus vs. Turbuhaler (p<0.01), Ellipta vs. Turbuhaler (p<0.01). In the participants' ranking, the inhalers Ellipta, followed by Turbuhaler, were most often ranked as most preferred. Participants' preference of Ellipta over Easyhaler (p<0.01) and over Diskus (p<0.001) were statistically significant.

  5. Short-term Effects of Risperidone Monotherapy on Spontaneous Brain Activity in First-episode Treatment-naïve Schizophrenia Patients: A Longitudinal fMRI Study

    PubMed Central

    Hu, Mao-Lin; Zong, Xiao-Fen; Zheng, Jun-Jie; Pantazatos, Spiro P.; Miller, Jeffrey M.; Li, Zong-Chang; Liao, Yan-Hui; He, Ying; Zhou, Jun; Sang, De-En; Zhao, Hong-Zeng; Lv, Lu-Xian; Tang, Jin-Song; Mann, J. John; Chen, Xiao-Gang

    2016-01-01

    It is unclear whether abnormal spontaneous neural activation patterns found in chronic schizophrenia patients (CSP) are part of the pathogenesis of disease, consequences of chronic illness, or effects of antipsychotic treatment. We performed a longitudinal resting-state functional magnetic resonance imaging (fMRI) study in 42 treatment-naïve first-episode schizophrenia patients (FESP) at baseline and then after 8-weeks of risperidone monotherapy, and compared the findings to 38 healthy volunteers. Spontaneous brain activity was quantified using the fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) and compared between patients and controls. Pretreatment, patients exhibited higher fALFF in left caudate compared with controls. After treatment, patients had elevated fALFF in bilateral putamen and right caudate, and increased ReHo in right caudate and left putamen. Greater increase of fALFF in the left putamen correlated with less improvement in positive symptoms. Thus, abnormalities of spontaneous neural activity in chronic schizophrenia is at least partly due to a medication effect. The observed post-treatment increase in striatal intrinsic activity may reflect counter-therapeutic functional adaptation to dopamine D2 receptor occupancy required for medication effects on psychosis. PMID:27698361

  6. Reduced γ-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk

    PubMed Central

    Tang, Yingying; Zhang, Tianhong; Cui, Huiru; Xu, Lihua; Zeng, Botao; Li, Yu; Li, Gaiying; Li, Chunbo; Liu, Hui; Zhang, Jianye

    2016-01-01

    Altered γ-aminobutyric acid (GABA), glutamate (Glu) levels, and an imbalance between GABAergic and glutamatergic neurotransmissions have been involved in the pathophysiology of schizophrenia. However, it remains unclear how these abnormalities impact the onset and course of psychosis. In the present study, 21 drug-naïve subjects at ultrahigh risk for psychosis (UHR), 16 drug-naïve patients with first-episode schizophrenia (FES), and 23 healthy controls (HC) were enrolled. In vivo GABA and glutamate+glutamine (Glx) levels in the medial prefrontal cortex were measured using proton magnetic resonance spectroscopy. Medial prefrontal GABA and Glx levels in FES patients were significantly lower than those in HC and UHR, respectively. GABA and Glx levels in UHR were comparable with those in HC. In each group, there was a positive correlation between GABA and Glx levels. Reduced medial prefrontal GABA and Glx levels thus may play an important role in the early stages of schizophrenia. PMID:28003912

  7. Assessment of the neurotoxic potential of exposure to 50Hz extremely low frequency electromagnetic fields (ELF-EMF) in naïve and chemically stressed PC12 cells.

    PubMed

    de Groot, Martje W G D M; Kock, Marjolijn D M; Westerink, Remco H S

    2014-09-01

    Increasing exposure to extremely low frequency electromagnetic fields (ELF-EMF), generated by power lines and electric appliances, raises concern about potential adverse health effects of ELF-EMF. The central nervous system is expected to be particularly vulnerable to ELF-EMF as its function strongly depends on electrical excitability. We therefore investigated effects of acute (30min) and sub-chronic (48h) exposure to 50Hz ELF-EMF on naïve and chemically stressed pheochromocytoma (PC12) cells. The latter have higher levels of iron and/or reactive oxygen species (ROS) and display increased vulnerability to environmental insults. Effects of ELF-EMF on Ca(2+)-homeostasis, ROS production and membrane integrity were assessed using Fura-2 single cell fluorescence microscopy, H2-DCFDA and CFDA assays, respectively. Our data demonstrate that acute exposure of naïve PC12 cells to 50Hz ELF-EMF up to 1000μT fails to affect basal or depolarization-evoked [Ca(2+)]i. Moreover, sub-chronic ELF-EMF exposure up to 1000μT has no consistent effects on Ca(2+)-homeostasis in naïve PC12 cells and does not affect ROS production and membrane integrity. Notably, in chemically stressed PC12 cells both acute and sub-chronic ELF-EMF exposure also failed to exert consistent effects on Ca(2+)-homeostasis, ROS production and membrane integrity. Our combined findings thus indicate that exposure to 50Hz ELF-EMF up to 1000μT, i.e. 10,000 times above background exposure, does not induce neurotoxic effects in vitro, neither in naïve nor in chemically stressed PC12 cells. Though our data require confirmation, e.g. in developing neuronal cells in vitro or (developing) animals, it appears that the neurotoxic risk of ELF-EMF exposure is limited.

  8. The cumulative effect of coffee and a mental stress task on heart rate, blood pressure, and mental alertness is similar in caffeine-naïve and caffeine-habituated females.

    PubMed

    Kennedy, Michael D; Galloway, Ashley V; Dickau, Leanne J; Hudson, Megan K

    2008-09-01

    Most North American workers drink coffee throughout their workday, although the cumulative effect of job stress and coffee is not well known. Research has shown that coffee affects the cardiovascular system and mental alertness primarily through the active ingredient caffeine; however, the dose of caffeine used in these studies is greater than a normal cup of coffee. In addition, these changes have been mostly determined in male caffeine-habituated consumers. Therefore, this study examined the effect of a normal cup of coffee on the cardiovascular and mental alertness response both before and after a mental stress task in 10 caffeine-naïve (23 +/- 5.0 years) and 10 caffeine-habituated (25 +/- 6 years) females. Blood pressure, heart rate, and mental alertness were taken at baseline (before coffee), 50 minutes after finishing coffee and immediately after a 9-minute mental stress task. The volume of coffee ingested for a 15-minute period was 350 mL (12 oz), which is equivalent to 140 mg of caffeine. The combined effect of coffee and mental stress significantly decreased diastolic blood pressure (Delta8 mm Hg) and increased heart rate (Delta6 beats per minute) and mental alertness (Delta67.3%) in caffeine-naïve and caffeine-habituated females, whereas systolic blood pressure (Delta10.3 mm Hg) only increased in the caffeine-naïve participants. Our results indicate that a normal cup of coffee can effect changes in blood pressure and mental alertness and that mental stress may alter the magnitude of change; however, the transient increase in systolic blood pressure after drinking coffee in caffeine-naïve participants requires further investigation.

  9. How skill expertise shapes the brain functional architecture: an fMRI study of visuo-spatial and motor processing in professional racing-car and naïve drivers.

    PubMed

    Bernardi, Giulio; Ricciardi, Emiliano; Sani, Lorenzo; Gaglianese, Anna; Papasogli, Alessandra; Ceccarelli, Riccardo; Franzoni, Ferdinando; Galetta, Fabio; Santoro, Gino; Goebel, Rainer; Pietrini, Pietro

    2013-01-01

    The present study was designed to investigate the brain functional architecture that subserves visuo-spatial and motor processing in highly skilled individuals. By using functional magnetic resonance imaging (fMRI), we measured brain activity while eleven Formula racing-car drivers and eleven 'naïve' volunteers performed a motor reaction and a visuo-spatial task. Tasks were set at a relatively low level of difficulty such to ensure a similar performance in the two groups and thus avoid any potential confounding effects on brain activity due to discrepancies in task execution. The brain functional organization was analyzed in terms of regional brain response, inter-regional interactions and blood oxygen level dependent (BOLD) signal variability. While performance levels were equal in the two groups, as compared to naïve drivers, professional drivers showed a smaller volume recruitment of task-related regions, stronger connections among task-related areas, and an increased information integration as reflected by a higher signal temporal variability. In conclusion, our results demonstrate that, as compared to naïve subjects, the brain functional architecture sustaining visuo-motor processing in professional racing-car drivers, trained to perform at the highest levels under extremely demanding conditions, undergoes both 'quantitative' and 'qualitative' modifications that are evident even when the brain is engaged in relatively simple, non-demanding tasks. These results provide novel evidence in favor of an increased 'neural efficiency' in the brain of highly skilled individuals.

  10. OREGANO_VE: a new parallelised 3D solver for the general (non-)linear Maxwell visco-elastic problem: validation and application to the calculation of surface deformation in the earthquake cycle

    NASA Astrophysics Data System (ADS)

    Yamasaki, Tadashi; Houseman, Gregory; Hamling, Ian; Postek, Elek

    2010-05-01

    We have developed a new parallelized 3-D numerical code, OREGANO_VE, for the solution of the general visco-elastic problem in a rectangular block domain. The mechanical equilibrium equation is solved using the finite element method for a (non-)linear Maxwell visco-elastic rheology. Time-dependent displacement and/or traction boundary conditions can be applied. Matrix assembly is based on a tetrahedral element defined by 4 vertex nodes and 6 nodes located at the midpoints of the edges, and within which displacement is described by a quadratic interpolation function. For evaluating viscoelastic relaxation, an explicit time-stepping algorithm (Zienkiewicz and Cormeau, Int. J. Num. Meth. Eng., 8, 821-845, 1974) is employed. We test the accurate implementation of the OREGANO_VE by comparing numerical and analytic (or semi-analytic half-space) solutions to different problems in a range of applications: (1) equilibration of stress in a constant density layer after gravity is switched on at t = 0 tests the implementation of spatially variable viscosity and non-Newtonian viscosity; (2) displacement of the welded interface between two blocks of differing viscosity tests the implementation of viscosity discontinuities, (3) displacement of the upper surface of a layer under applied normal load tests the implementation of time-dependent surface tractions (4) visco-elastic response to dyke intrusion (compared with the solution in a half-space) tests the implementation of all aspects. In each case, the accuracy of the code is validated subject to use of a sufficiently small time step, providing assurance that the OREGANO_VE code can be applied to a range of visco-elastic relaxation processes in three dimensions, including post-seismic deformation and post-glacial uplift. The OREGANO_VE code includes a capability for representation of prescribed fault slip on an internal fault. The surface displacement associated with large earthquakes can be detected by some geodetic observations

  11. Assessment and restoring soil functionality in degraded areas of organic vineyards. The preliminary results of the ReSolVe project in Italy

    NASA Astrophysics Data System (ADS)

    Priori, Simone; Agnelli, Alessandro; Castaldini, Maurizio; D'Avino, Lorenzo; D'Errico, Giada; Gagnarli, Elena; Giudi, Silvia; Goggioli, Donatella; Lagomarsino, Alessandra; Landi, Silvia; Leprini, Marco; Pellegrini, Sergio; Perria, Rita; Puccioni, Sergio; Simoni, Sauro; Storchi, Paolo; Valboa, Giuseppe; Zombardo, Alessandra; Costantini, Edoardo

    2016-04-01

    In both conventional and organic Italian vineyards, it is quite common to have areas characterized by problems in vine health, grape production and quality, often caused by improper land preparation before vine plantation and/or management. Causes for soil malfunctioning can include: reduced contribution of the soil fauna to the ecosystem services (i.e. nutrient cycles), poor organic matter content, imbalance of some element ratio, altered pH, water deficiency, soil compaction and/or scarce oxygenation. ReSolVe is a transnational and interdisciplinary 3-years research project aimed at testing the effects of selected organic strategies for restoring optimal soil functionality in degraded areas within vineyard. The different restoring strategies implemented in each plot will be: i) compost produced on farm by manure + pruning residue + grass, ii) faba bean and barley green manure, iii) sowing and dry mulching with Trifolium squarrosum L. During two years of such treatments, the trend of the soil features and the grapevine status will be monitored in detail, to reveal the positive and negative effects of such treatments. The project involves 8 research groups in 6 different EU countries (Italy, France, Spain, Sweden, Slovenia, and Turkey), with experts from several disciplines, including soil science, ecology, microbiology, grapevine physiology, viticulture, and biometry. The experimental vineyards are situated in Italy (Chianti hills and Maremma plain, Tuscany), France (Bordeaux and Languedoc), Spain (La Rioja) and Slovenia (Primorska) for winegrape, and in Turkey (Adana and Mersin) for table grape. Soil features before implementing restoring strategies showed lower content of soil organic matter and enzyme activities, and higher carbonates in degraded areas than in the non-degraded areas. The Biological Soil Quality values of microarthropods were always high, in comparison with data registered in similarly managed vineyards or stable ecosystems, and the data showed

  12. Lipid Peroxidation and Total Cholesterol in HAART-Naïve Patients Infected with Circulating Recombinant Forms of Human Immunodeficiency Virus Type-1 in Cameroon

    PubMed Central

    Teto, Georges; Kanmogne, Georgette D.; Torimiro, Judith N.; Alemnji, George; Nguemaim, Flore N.; Takou, Désiré; Nanfack, Aubin; Tazoacha, Asonganyi

    2013-01-01

    Background HIV infection has commonly been found to affect lipid profile and antioxidant defense. Objectives To determine the effects of Human Immunodeficiency Virus (HIV) infection and viral subtype on patient’s cholesterol and oxidative stress markers, and determine whether in the absence of Highly Active Antiretroviral Therapy (HAART), these biochemical parameters could be useful in patient’s management and monitoring disease progression in Cameroon. For this purpose, we measured total cholesterol (TC), LDL cholesterol (LDLC), HDL cholesterol (HDLC), total antioxidant ability (TAA), lipid peroxidation indices (LPI), and malondialdehyde (MDA) in HIV negative persons and HIV positive HAART-naïve patients infected with HIV-1 group M subtypes. Methods We measured serum TC, LDLC, HDLC, plasma MDA, and TAA concentrations, and calculated LPI indices in 151 HIV-positive HAART-naïve patients and 134 seronegative controls. We also performed gene sequence analysis on samples from 30 patients to determine the effect of viral genotypes on these biochemical parameters. We also determined the correlation between CD4 cell count and the above biochemical parameters. Results We obtained the following controls/patients values for TC (1.96±0.54/1. 12±0. 48 g/l), LDLC (0. 67±0. 46/0. 43±0. 36 g/l), HDLC (105. 51±28. 10/46. 54±23. 36 mg/dl) TAA (0. 63±0. 17/0. 16±0. 16 mM), MDA (0. 20±0. 07/0. 41±0. 10 µM) and LPI (0. 34±0. 14/26. 02±74. 40). In each case, the difference between the controls and patients was statistically significant (p<0.05). There was a positive and statistically significant Pearson correlation between CD4 cell count and HDLC (r = +0.272; p<0.01), TAA (r = +0.199; p<0.05) and a negative and statistically significant Pearson correlation between CD4 cell count and LPI (r = −0.166; p<0.05). Pearson correlation between CD4 cell count and TC, CD4cell count and LDLC was positive but not statistically significant while it was negative but

  13. VeWa: Assessing Vegetation Effects on Water Flows and Mixing in Northern Mountain Environments using Stable Isotopes and Conceptual Runoff Models

    NASA Astrophysics Data System (ADS)

    Tetzlaff, D.; Buttle, J. M.; Carey, S. K.; Laudon, H.; McDonnell, J.; McNamara, J. P.; Van Huijgevoort, M.; Spence, C.; Soulsby, C.

    2015-12-01

    The lack of comprehensive tracer data sets still hinders the development of a generalized understanding of how northern headwaters function hydrologically. As part of the ERC funded "VeWa" project, we combined a conceptual rainfall-runoff model and input-output relationships of stable isotopes to understand ecohydrological influences on hydrological partitioning in in six high-latitude experimental catchments located in the UK, USA, Sweden and Canada. We used stable isotope records from precipitation and stream flow to examine the effects of soils and landcover. A meta-analysis was carried out using the HBV-model to estimate the main storage changes characterising annual water balances. Annual snowpack storage importance was ranked differently across the sites, and the subsequent rate and longevity of melt was reflected in calibrated parameters that determine partitioning of waters between more rapid and slower flowpaths and associated variations in soil and groundwater storage. Variability of stream water isotopic composition depends on: (i) rate and duration of spring snowmelt; (ii) significance of summer/autumn rainfall; (iii) relative importance of near-surface and deeper flowpaths in routing water to the stream. Flowpath partitioning also regulates influences of summer evaporation on drainage waters. Deviations of isotope data from the Global Meteoric Water Line showed subtle effects of internal catchment processes on isotopic fractionation most likely through evaporation. After accounting for climate, evaporative fractionation is strongest at sites where lakes and near-surface runoff processes in wet riparian soils can mobilize isotopically-enriched water during summer and autumn. Given close soil-vegetation coupling, this may result in spatial variability in soil water isotope pools available for plant uptake. We argue that stable isotope studies are crucial in addressing the many open questions on hydrological functioning of northern environments.

  14. Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease.

    PubMed

    Zimran, Ari; Durán, Gloria; Giraldo, Pilar; Rosenbaum, Hanna; Giona, Fiorina; Petakov, Milan; Terreros Muñoz, Eduardo; Solorio-Meza, Sergio Eduardo; Cooper, Peter A; Varughese, Sheeba; Alon, Sari; Chertkoff, Raul

    2016-07-18

    Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm(3)). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187.

  15. Does Historical Coexistence with Dingoes Explain Current Avoidance of Domestic Dogs? Island Bandicoots Are Naïve to Dogs, unlike Their Mainland Counterparts.

    PubMed

    Frank, Anke S K; Carthey, Alexandra J R; Banks, Peter B

    2016-01-01

    Introduced predators have a global reputation for causing declines and extinctions of native species. Native prey naiveté towards novel predators is thought to be a key reason for predator impacts. However, naiveté is not necessarily forever: where coexistence establishes, it is likely that naiveté will be reduced through adaptation, and the once alien predator will eventually become recognised by prey. For example, native marsupial bandicoots in Sydney avoid backyards with domestic dogs (C. lupus familiaris), but not domestic cats (Felis catus), even though cats and dogs were both introduced about 200 years ago (Carthey and Banks 2012). The authors attributed bandicoots' recognition of dogs to long-term exposure to a close relative of dogs, dingoes that arrived in Australia 4000 years ago. Here, we test a prediction of this hypothesis by taking the study to Tasmania, where dingoes have never been present but where domestic dogs also arrived about 200 years ago. We use a similar survey design to that of Carthey and Banks (2012): asking Hobart residents to report on pet-ownership, bandicoot sightings and scats within their backyards, as well as an array of yard characteristic control variables. We predicted that if long term experience with dingoes enabled mainland bandicoots to recognise domestic dogs, then Tasmanian bandicoots, which are inexperienced with dingoes, would not recognise domestic dogs. Our results indicate that Tasmanian bandicoots are naïve to both dogs and cats after only 200 years of coexistence, supporting our hypothesis and the notion that naiveté in native prey towards alien predators (as observed on the mainland) may eventually be overcome.

  16. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.

    PubMed

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Evans, Christopher P; Kim, Choung-Soo; Kimura, Go; Miller, Kurt; Saad, Fred; Bjartell, Anders S; Borre, Michael; Mulders, Peter; Tammela, Teuvo L; Parli, Teresa; Sari, Suha; van Os, Steve; Theeuwes, Ad; Tombal, Bertrand

    2017-02-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p<0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67-0.88; p=0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9-22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1-5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2-not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8-34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991.

  17. Simeprevir plus sofosbuvir for eight or 12 weeks in treatment-naïve and treatment-experienced hepatitis C virus genotype 4 patients with or without cirrhosis.

    PubMed

    El Raziky, M; Gamil, M; Ashour, M K; Sameea, E A; Doss, W; Hamada, Y; Van Dooren, G; DeMasi, R; Keim, S; Lonjon-Domanec, I; Hammad, R; Hashim, M S; Hassany, M; Waked, I

    2017-02-01

    The OSIRIS study investigated efficacy and safety of simeprevir plus sofosbuvir for eight or 12 weeks in hepatitis C virus (HCV) genotype 4-infected patients with METAVIR F0-F4 fibrosis. Sixty-three patients (33 treatment-naïve and 30 peg-interferon/ribavirin (Peg-IFN/RBV)-experienced) enrolled in a partly randomized, open-label, multicentre, phase IIa study. Patients with F0-F3 fibrosis were randomized (1:1) into two groups (A1 and A2), stratified according to treatment experience and METAVIR score, to receive either eight weeks (Group A1, n=20) or 12 weeks (Group A2, n=20) of treatment. Patients with compensated cirrhosis (METAVIR F4) received 12 weeks of treatment (Group B, n=23). Treatment comprised simeprevir 150 mg and sofosbuvir 400 mg daily. The primary efficacy endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). Safety and tolerability were assessed throughout. Overall, 92% (95% CI: 82-97) of patients achieved SVR12; 75% (15/20) in Group A1 and 100% in groups A2 and B. Patients who did not achieve SVR12 (n=5) experienced viral relapse during the first 32 days following treatment and were all prior Peg-IFN/RBV null responders. The most commonly reported treatment-emergent adverse events (TEAEs) were asymptomatic lipase increase (14%), pruritus (14%), headache (13%) and hyperbilirubinaemia (11%). No patients discontinued due to TEAEs. In conclusion, simeprevir plus sofosbuvir for 12 weeks achieved a 100% SVR rate in HCV genotype 4-infected patients with or without compensated cirrhosis (ClinicalTrials.gov: NCT02278419). The AE and laboratory profile were favourable and consistent with previous data for simeprevir plus sofosbuvir in eight- and 12-week regimens.

  18. Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling.

    PubMed

    Gurnik, Stefanie; Devraj, Kavi; Macas, Jadranka; Yamaji, Maiko; Starke, Julia; Scholz, Alexander; Sommer, Kathleen; Di Tacchio, Mariangela; Vutukuri, Rajkumar; Beck, Heike; Mittelbronn, Michel; Foerch, Christian; Pfeilschifter, Waltraud; Liebner, Stefan; Peters, Kevin G; Plate, Karl H; Reiss, Yvonne

    2016-05-01

    The homeostasis of the central nervous system is maintained by the blood-brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear. We investigated the influence of Ang-2 on BBB permeability in wild-type and gain-of-function (GOF) mice and demonstrated an increase in permeability by Ang-2, both in vitro and in vivo. Expression analysis of brain endothelial cells from Ang-2 GOF mice showed a downregulation of tight/adherens junction molecules and increased caveolin-1, a vesicular permeability-related molecule. Immunohistochemistry revealed reduced pericyte coverage in Ang-2 GOF mice that was supported by electron microscopy analyses, which demonstrated defective intra-endothelial junctions with increased vesicles and decreased/disrupted glycocalyx. These results demonstrate that Ang-2 mediates permeability via paracellular and transcellular routes. In patients suffering from stroke, a cerebrovascular disorder associated with BBB disruption, Ang-2 levels were upregulated. In mice, Ang-2 GOF resulted in increased infarct sizes and vessel permeability upon experimental stroke, implicating a role of Ang-2 in stroke pathophysiology. Increased permeability and stroke size were rescued by activation of Tie2 signaling using a vascular endothelial protein tyrosine phosphatase inhibitor and were independent of VE-cadherin phosphorylation. We thus identified Ang-2 as an endothelial cell-derived regulator of BBB permeability. We postulate that novel therapeutics targeting Tie2 signaling could be of potential use for opening the BBB for increased CNS drug delivery or tighten it in neurological disorders associated with cerebrovascular leakage and brain edema.

  19. Identification and quantification of neuropeptides in naïve mouse spinal cord using mass spectrometry reveals [des-Ser1]-cerebellin as a novel modulator of nociception.

    PubMed

    Su, Jie; Sandor, Katalin; Sköld, Karl; Hökfelt, Tomas; Svensson, Camilla I; Kultima, Kim

    2014-07-01

    Neuropeptide transmitters involved in nociceptive processes are more likely to be expressed in the dorsal than the ventral horn of the spinal cord. This study was designed to examine the relative distribution of neuropeptides between the dorsal and ventral spinal cord in naïve mice using liquid chromatography, high-resolution mass spectrometry. We identified and relatively quantified 36 well-characterized full-length neuropeptides and an additional 168 not previously characterized peptides. By extraction with organic solvents we identified seven additional full-length neuropeptides. The peptide [des-Ser1]-cerebellin (desCER), originating from cerebellin precursor protein 1 (CBLN1), was predominantly expressed in the dorsal horn. Immunohistochemistry showed the presence of CBLN1 immunoreactivity with a punctate cytoplasmic pattern in neuronal cell bodies throughout the spinal gray matter. The signal was stronger in the dorsal compared to the ventral horn, with most CBLN1 positive cells present in outer laminae II/III, colocalizing with calbindin, a marker for excitatory interneurons. Intrathecal injection of desCER induced a dose-dependent mechanical hypersensitivity but not heat or cold hypersensitivity. This study provides evidence for involvement of desCER in nociception and provides a platform for continued exploration of involvement of novel neuropeptides in the regulation of nociceptive transmission. Neuropeptides involved in nociceptive processes are more likely to be expressed in the dorsal than the ventral horn of spinal cord. Well-characterized full-length neuropeptides as well as uncharacterized neuropeptides were quantified by mass spectrometry. The CBLN1-derived peptide [des-Ser1]-cerebellin (desCER) is predominantly expressed in the dorsal horn, and intrathecal injection of desCER induced a dose-dependent mechanical hypersensitivity.

  20. Entecavir Safety and Effectiveness in a National Cohort of Treatment-Naïve Chronic Hepatitis B Patients in the US - the ENUMERATE study

    PubMed Central

    Ahn, Joseph; Lee, Hannah M.; Lim, Joseph K.; Pan, Calvin Q.; Nguyen, Mindie H.; Kim, W. Ray; Mannalithara, Ajitha; Trinh, Huy; Chu, Danny; Tran, Tram; Min, Albert; Do, Son; Te, Helen; Reddy, K. Rajender; Lok, Anna S.

    2016-01-01

    Background Entecavir (ETV) has been shown to be safe and efficacious in randomized controlled trials in highly selected patients with hepatitis B virus (HBV) infection. Aim To determine the safety and effectiveness of ETV in “real-world” HBV patients in the United States (US). Methods Treatment-naïve HBV patients ≥ 18 years old who received ETV for ≥12 months between 2005 and 2013 were included in a retrospective, cohort study. Rates of ALT normalization, undetectable HBV DNA, HBeAg and HBsAg loss/seroconversion, adverse events (AE) and clinical outcomes were evaluated. Results Of 841 patients, 658 [65% male, 83% Asian; median age 47 years] met the inclusion criteria. 36% were HBeAg+ and 9.3% cirrhotic. 89% had abnormal ALT. Baseline median HBV DNA was 5.8 log 10 IU/mL. Median duration of ETV treatment was 4 years. Rates of ALT normalization at 1, 3, and 5 years were 37.2%, 48.7%, and 56.2% in HBeAg+ and 39.6%, 46.8 %, and 55.6% in HBeAg- patients. HBV DNA was undetectable at 1, 3, and 5 years in 34.6%, 64.7%, and 84.6% in HBeAg+ patients, and 81.9%, 90.3%, and 96.2% in HBeAg- patients. 5 year cumulative probability of HBeAg loss and seroconversion was 46% and 33.7% and HBsAg loss was 4.6%. ETV was discontinued due to adverse events in 1.2% of patients. Hepatic decompensation occurred in 0.8%, liver cancer in 2.7%, and death in 0.6%. Conclusion Entecavir treatment was safe in a large cohort of US patients, but ALT normalization and HBV DNA suppression rates were lower than previously reported in clinical trials. PMID:26510638

  1. Identification of Immunogenic Cytotoxic T Lymphocyte Epitopes Containing Drug Resistance Mutations in Antiretroviral Treatment-Naïve HIV-Infected Individuals

    PubMed Central

    Blanco-Heredia, Juan; Lecanda, Aarón; Valenzuela-Ponce, Humberto; Brander, Christian; Ávila-Ríos, Santiago; Reyes-Terán, Gustavo

    2016-01-01

    Background Therapeutic HIV vaccines may prove helpful to intensify antiretroviral treatment (ART) efficacy and may be an integral part of future cure strategies. Methods We examined IFN-gamma ELISpot responses to a panel of 218 HIV clade B consensus-based HIV protease-reverse transcriptase peptides, designed to mimic previously described and predicted cytotoxic T lymphocyte epitopes overlapping drug resistance (DR) positions, that either included the consensus sequence or the DR variant sequence, in 49 ART-naïve HIV-infected individuals. Next generation sequencing was used to assess the presence of minority DR variants in circulating viral populations. Results Although a wide spectrum of differential magnitudes of response to DR vs. WT peptide pairs was observed, responses to DR peptides were frequent and strong in the study cohort. No difference between the median magnitudes of response to DR vs. WT peptides was observed. Interestingly, of the 22 peptides that were recognized by >15% of the participants, two-thirds (64%) corresponded to DR peptides. When analysing responses per peptide pair per individual, responses to only WT (median 4 pairs/individual) or DR (median 6 pairs/individual) were more common than responses to both WT and DR (median 2 pairs/individual; p<0.001). While the presence of ELISpot responses to WT peptides was frequently associated with the presence of the corresponding peptide sequence in the patient’s virus (mean 68% of cases), responses to DR peptides were generally not associated with the presence of DR mutations in the viral population, even at low frequencies (mean 1.4% of cases; p = 0.0002). Conclusions Our data suggests that DR peptides are frequently immunogenic and raises the potential benefit of broadening the antigens included in a therapeutic vaccine approach to immunogenic epitopes containing common DR sequences. Further studies are needed to assess the quality of responses elicited by DR peptides. PMID:26808823

  2. Once-Daily Simeprevir (TMC435) With Pegylated Interferon and Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C: The Randomized PILLAR Study

    PubMed Central

    Fried, Michael W.; Buti, Maria; Dore, Gregory J.; Flisiak, Robert; Ferenci, Peter; Jacobson, Ira; Marcellin, Patrick; Manns, Michael; Nikitin, Igor; Poordad, Fred; Sherman, Morris; Zeuzem, Stefan; Scott, Jane; Gilles, Leen; Lenz, Oliver; Peeters, Monika; Sekar, Vanitha; De Smedt, Goedele; Beumont-Mauviel, Maria

    2014-01-01

    The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-α-2a and ribavirin (RBV) in treatment-naïve patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. Conclusion SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks. PMID:23907700

  3. The effects of tamoxifen on learning, memory and brain tissues oxidative damage in ovariectomized and naïve female rats

    PubMed Central

    Zabihi, Hoda; Hosseini, Mahmoud; Pourganji, Masoume; Oryan, Shahrbanoo; Soukhtanloo, Mohammad; Niazmand, Saeed

    2014-01-01

    Background: Regarding the modulatory effects of tamoxifen (TAM) on the actions of estrogen in the present study, the effects of TAM on learning, memory and brain tissues oxidative damage in ovariectomized (OVX) and naοve female rats was investigated. Materials and Methods: The animals were divided into: (1) Sham, (2) OVX, (3) Sham-tamoxifen (Sham-TAM) and (4) ovariectomized-tamoxifen (OVX-TAM). The animals of the Sham-TAM and OVX-TAM groups were treated by TAM (1 mg/kg; 4 weeks). Results: In Morris water maze, the escape latency in the OVX group was higher than in the Sham group (P < 0.01). The time latency in the animals of OVX-TAM group was lower than that of OVX group (P < 0.01); however, there were no significant differences between the Sham-TAM and Sham groups. In the probe trial, the time spent in target quadrant (Q1) by the animals of OVX group was lower than that of Sham group (P < 0.01). Interestingly, the animals of OVX-TAM group spent more times in target quadrant (Q1) compared with OVX group (P < 0.01). In passive avoidance test, the animals of OVX group had lower latencies to enter the dark compartment compared with the Sham group (P < 0.05). The time latency to enter the dark compartment by animals of OVX-TAM group was higher than in OVX group (P < 0.01). In OVX-TAM group, the total thiol concentration was significantly higher (P < 0.05) and malondialdehyde concentration was lower (P < 0.01) than OVX group. Conclusions: These results allow us to propose that TAM enhances learning and memory of OVX rats. The possible mechanism may be due to the protective effects against brain tissues oxidative damage. PMID:25371876

  4. Lipoprotein Changes in HIV-Infected Antiretroviral-Naïve Individuals after Starting Antiretroviral Therapy: ACTG Study A5152s Stein: Lipoprotein Changes on Antiretroviral Therapy.

    PubMed

    Stein, James H; Komarow, Lauren; Cotter, Bruno R; Currier, Judith S; Dubé, Michael P; Fichtenbaum, Carl J; Gerschenson, Mariana; Mitchell, Carol K C; Murphy, Robert L; Squires, Kathleen; Parker, Robert A; Torriani, Francesca J

    2008-12-01

    BACKGROUND: Dyslipidemia is a frequent complication of antiretroviral therapy (ART) for patients with human immunodeficiency virus infection (HIV). The effects of ART on lipoproteins are less well-understood, and have not been investigated in a prospective study where assignment to ART is randomized. OBJECTIVE: To evaluate the effects of three class-sparing ART regimens on lipids and lipoproteins. METHODS: This was a substudy of a prospective, multicenter study treatment-naïve HIV-infected individuals randomly assigned to receive a regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + the non-nucleoside reverse transcriptase inhibitor efavirenz, NRTIs + the protease inhibitor lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. Lipoproteins were measured by nuclear magnetic resonance spectroscopy. RESULTS: Among the 82 participants, total and small low-density lipoprotein concentrations increased (median, interquartile range) by 152 (-49 - +407, p<0.01) and 130 (-98 - +417, p<0.01) nmol/L, respectively, especially in the arms containing lopinavir/ritonavir (p(KW)<0.04). Very low-density lipoproteins also increased (p<0.01), with a larger increase in the arms that contained lopinavir/ritonavir (p=0.022). High-density lipoproteins increased by 6.0 nmol/L (2.8 - 10.4, p<0.01), but differences between arms were not significant (p(KW)=0.069). Changes were not related to changes in markers of insulin/glucose metabolism. CONCLUSIONS: Total and small low-density lipoprotein concentrations increased, especially in the arms containing lopinavir/ritonavir, as did increases in total very low-density lipoproteins. Adverse changes were especially prominent in the arm with efavirenz + lopinavir/ritonavir.

  5. Pain Flare Is a Common Adverse Event in Steroid-Naïve Patients After Spine Stereotactic Body Radiation Therapy: A Prospective Clinical Trial

    SciTech Connect

    Chiang, Andrew; Zeng, Liang; Zhang, Liying; Lochray, Fiona; Korol, Renee; Loblaw, Andrew; Chow, Edward; Sahgal, Arjun

    2013-07-15

    Purpose: To determine the incidence of pain flare after spine stereotactic body radiation therapy (SBRT) in steroid-naïve patients and identify predictive factors. Methods and Materials: Forty-one patients were treated with spine SBRT between February 2010 and April 2012. All patients had their pain assessed at baseline, during, and for 10 days after SBRT using the Brief Pain Inventory. All pain medications were recorded daily and narcotics converted to an oral morphine equivalent dose. Pain flare was defined as a 2-point increase in worst pain score as compared with baseline with no decrease in analgesic intake, a 25% increase in analgesic intake as compared with baseline with no decrease in worst pain score, or if corticosteroids were initiated at any point during or after SBRT because of pain. Results: The median age and Karnofsky performance status were 57.5 years (range, 27-80 years) and 80 (range, 50-100), respectively. Eighteen patients were treated with 20-24 Gy in a single fraction, whereas 23 patients were treated with 24-35 Gy in 2-5 fractions. Pain flare was observed in 68.3% of patients (28 of 41), most commonly on day 1 after SBRT (29%, 8 of 28). Multivariate analysis identified a higher Karnofsky performance status (P=.02) and cervical (P=.049) or lumbar (P=.02) locations as significant predictors of pain flare. In those rescued with dexamethasone, a significant decrease in pain scores over time was subsequently observed (P<.0001). Conclusions: Pain flare is a common adverse event after spine SBRT and occurs most commonly the day after treatment completion. Patients should be appropriately consented for this adverse event.

  6. Prospective study on the incidence and progression of clinical signs in naïve dogs naturally infected by Leishmania infantum.

    PubMed

    Foglia Manzillo, Valentina; Di Muccio, Trentina; Cappiello, Sivia; Scalone, Aldo; Paparcone, Rosa; Fiorentino, Eleonora; Gizzarelli, Manuela; Gramiccia, Marina; Gradoni, Luigi; Oliva, Gaetano

    2013-01-01

    The incidence of clinical and clinicopathological signs associated with the progression of infection was evaluated prospectively in 329 naïve young dogs exposed to Leishmania infantum transmission and examined periodically during 22 months (M). The dogs were part of Leishmania vaccine investigations performed under natural conditions. Vaccinated groups were considered in the evaluation when the vaccine resulted non-protective and the appearance and progression of signs did not differ statistically from controls at each time point, otherwise only control groups were included. 115 beagles were part of 3 studies (A to C) performed in the same kennel; 214 owned dogs (29 breeds, 2.3% beagles) were included in a study (D) performed in 45 endemic sites. At M22 the prevalence of any Leishmania infection stage classified as subpatent, active asymptomatic, or symptomatic was 59.8% in studies A-C and 29.2% in study D. Despite different breed composition and infection incidence, the relative proportion of active infections and the progression and type of clinical and clinicopathological signs have been similar in both study sets. All asymptomatic active infections recorded have invariably progressed to full-blown disease, resulting in 56 sick dogs at M22. In these dogs, lymph nodes enlargement and weight loss--recorded from M12--were the most common signs. Cutaneous signs were seen late (M18) and less frequently. Ocular signs appeared even later, being sporadically recorded at M22. Most clinicopathological alterations became evident from M12, although a few cases of thrombocytopenia or mild non-regenerative anemia were already observed at M6. Albumin/globulin inversions were recorded from M12 and urea/creatinine increase appeared mostly from M18. Altogether our findings indicate that any susceptible young dogs naturally infected by L. infantum present a common pattern of progression of signs during 2 years post infection, providing clues for medical and epidemiological

  7. Effect of Pioglitazone on Serum Uric Acid Levels in Newly Diagnosed, Drug-Naïve Patients with Type 2 Diabetes.

    PubMed

    Kutoh, Eiji; Hori, Tadataka

    2012-12-05

    Objectives. The aim of this study was to investigate the effect of pioglitazone on serum uric acid (UA) levels and several diabetic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM). Patients and Methods. The patients (n = 68) received 7.5-30 mg/day pioglitazone monotherapy. They were divided into three groups based on their baseline UA levels (low, medium, and high). These parameters were followed for 12 weeks. Results. At baseline, HbA1c and fasting blood glucose (FBG) levels were in negative proportion to those of UA, while homeostasis model assessment-beta (HOMA-B) levels were in proportion to those of UA. Insulin, homeostasis model assessment-R (HOMA-R), and body mass index (BMI) levels had a tendency to be in proportion to those of UA. While similar glycemic effects were observed in all the groups, UA levels significantly decreased in the high UA group while they insignificantly increased in the low UA group. Multiple regression analysis revealed that the baseline UA level and age were the significant determinants for the changes of UA levels. In the high UA group, significant decreases of insulin and HOMA-R levels were observed, and their changes (Δ) were significantly correlated with those of UA. Other parameters including insulin, HOMA-R, HOMA-B, and BMI were also differentially regulated between these groups. Conclusions. These results indicate that (1) while similar glycemic effects were observed, distinct regulations of UA and other diabetic parameters were observed with pioglitazone depending on the baseline UA levels; (2) pioglitazone downregulated hyperuricemia by possibly relieving insulin resistance; and (3) the level of UA together with other parameters might provide some diabetic characteristics of the subjects.

  8. Does Historical Coexistence with Dingoes Explain Current Avoidance of Domestic Dogs? Island Bandicoots Are Naïve to Dogs, unlike Their Mainland Counterparts

    PubMed Central

    Carthey, Alexandra J. R.; Banks, Peter B.

    2016-01-01

    Introduced predators have a global reputation for causing declines and extinctions of native species. Native prey naiveté towards novel predators is thought to be a key reason for predator impacts. However, naiveté is not necessarily forever: where coexistence establishes, it is likely that naiveté will be reduced through adaptation, and the once alien predator will eventually become recognised by prey. For example, native marsupial bandicoots in Sydney avoid backyards with domestic dogs (C. lupus familiaris), but not domestic cats (Felis catus), even though cats and dogs were both introduced about 200 years ago (Carthey and Banks 2012). The authors attributed bandicoots’ recognition of dogs to long-term exposure to a close relative of dogs, dingoes that arrived in Australia 4000 years ago. Here, we test a prediction of this hypothesis by taking the study to Tasmania, where dingoes have never been present but where domestic dogs also arrived about 200 years ago. We use a similar survey design to that of Carthey and Banks (2012): asking Hobart residents to report on pet-ownership, bandicoot sightings and scats within their backyards, as well as an array of yard characteristic control variables. We predicted that if long term experience with dingoes enabled mainland bandicoots to recognise domestic dogs, then Tasmanian bandicoots, which are inexperienced with dingoes, would not recognise domestic dogs. Our results indicate that Tasmanian bandicoots are naïve to both dogs and cats after only 200 years of coexistence, supporting our hypothesis and the notion that naiveté in native prey towards alien predators (as observed on the mainland) may eventually be overcome. PMID:27603517

  9. Drill-rig noise suppression using the Karhunen-Loéve transform for seismic-while-drilling experiment at Brukunga, South Australia

    NASA Astrophysics Data System (ADS)

    Sun, Baichun; Bóna, Andrej; Zhou, Binzhong; King, Andrew; Dupuis, Christian; Kepic, Anton

    2016-02-01

    Diamond-impregnated drill bits are known to be low energy vibration seismic sources. With the strong interference from the drill rig, it is difficult to obtain the drill-bit wavefield with a surface receiver array. To overcome the challenge of surface wave interference generated from the rig for seismic-while-drilling (SWD), we need to separate the rig- and bit-generated signals. To this end, we apply two wavefield separation methods, the Karhunen-Loéve (KL) transform and the f - k filter, and compare their performance. The applicability of these methods is based on the drill rig and drill bit having different spatial positions. While the drill-bit spatial position changes during the process of drilling, the drill rig remains stationary. This results in the source wavefields from the drill rig and the drill-bit having different characteristics, and allows us to separate and extract the drill-bit signal. We use a synthetic model to compare the KL transform and f - k filter. Both techniques are robust when the noise wavefield has consistent amplitude moveout. However, for changing amplitudes, such as the rig noise, which has an unrepeatable wavefield due to power amplitude variation, we show that the KL transform performs better in such situations. We also show the results of signal analysis of the SWD experiment data acquired from Brukunga, South Australia. We demonstrate the feasibility of the KL transform in separating the coherent noises from the stationary drill rig in a hard rock drilling environment, particularly emphasising the suppression of the surface and direct waves from the rig. The results show that drill-rig noise can be effectively suppressed in the correlation domain.

  10. Safety and Immunogenicity of Pfs25-EPA/Alhydrogel®, a Transmission Blocking Vaccine against Plasmodium falciparum: An Open Label Study in Malaria Naïve Adults

    PubMed Central

    Talaat, Kawsar R.; Ellis, Ruth D.; Hurd, Janet; Hentrich, Autumn; Gabriel, Erin; Hynes, Noreen A.; Rausch, Kelly M.; Zhu, Daming; Muratova, Olga; Herrera, Raul; Anderson, Charles; Jones, David; Aebig, Joan; Brockley, Sarah; MacDonald, Nicholas J.; Wang, Xiaowei; Fay, Michael P.; Healy, Sara A.; Durbin, Anna P.; Narum, David L.; Wu, Yimin; Duffy, Patrick E.

    2016-01-01

    Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®. Thirty malaria-naïve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 μg of conjugated Pfs25 mass, at 0, 2, 4, and 10 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint. Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases. No vaccine-related serious adverse events occurred. The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147) μg/mL two weeks after the 4th vaccination, and declined to near baseline one year later. Antibody avidity increased over successive vaccinations. Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA) also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity. These results support the further evaluation of Pfs25-EPA/Alhydrogel® in a malaria-endemic population. PMID:27749907

  11. Network-Level Dysconnectivity in Drug-Naïve First-Episode Psychosis: Dissociating Transdiagnostic and Diagnosis-Specific Alterations

    PubMed Central

    Gong, Qiyong; Hu, Xinyu; Pettersson-Yeo, William; Xu, Xin; Lui, Su; Crossley, Nicolas; Wu, Min; Zhu, Hongyan; Mechelli, Andrea

    2017-01-01

    The neuroimaging literature provides compelling evidence for functional dysconnectivity in people with psychosis. However, it is likely that at least some of the observed alterations represent secondary effects of illness chronicity and/or antipsychotic medication. In addition, the extent to which these alterations are specific to psychosis or represent a transdiagnostic feature of psychiatric illness remains unclear. The aim of this study was therefore to examine the diagnostic specificity of functional dysconnectivity in drug-naïve first-episode psychosis (FEP). We used resting-state functional magnetic resonance imaging and functional connectivity analysis to estimate network-level connectivity in 50 patients with FEP, 50 patients with major depressive disorder (MDD), 50 patients with post-traumatic stress disorder (PTSD), and 122 healthy controls (HCs). The FEP, MDD, and PTSD groups showed reductions in intranetwork connectivity of the default mode network relative to the HC group (p<0.05 corrected); therefore, intranetwork alterations were expressed across the three diagnostic groups. In addition, the FEP group showed heightened internetwork connectivity between the default mode network, particularly the anterior cingulate cortex, and the central executive network relative to the MDD, PTSD, and HC groups (p<0.05 corrected); therefore, internetwork alterations were specific to the FEP. These findings suggest that network-level alterations are present in individuals with a first episode of psychosis who have not been exposed to antipsychotic medication. In addition, they suggest a dissociation between aberrant internetwork connectivity as a distinctive feature of psychosis and aberrant intranetwork connectivity as a transdiagnostic feature of psychiatric illness. PMID:27782128

  12. Safety and Immunogenicity of Pfs25-EPA/Alhydrogel®, a Transmission Blocking Vaccine against Plasmodium falciparum: An Open Label Study in Malaria Naïve Adults.

    PubMed

    Talaat, Kawsar R; Ellis, Ruth D; Hurd, Janet; Hentrich, Autumn; Gabriel, Erin; Hynes, Noreen A; Rausch, Kelly M; Zhu, Daming; Muratova, Olga; Herrera, Raul; Anderson, Charles; Jones, David; Aebig, Joan; Brockley, Sarah; MacDonald, Nicholas J; Wang, Xiaowei; Fay, Michael P; Healy, Sara A; Durbin, Anna P; Narum, David L; Wu, Yimin; Duffy, Patrick E

    2016-01-01

    Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®. Thirty malaria-naïve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 μg of conjugated Pfs25 mass, at 0, 2, 4, and 10 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint. Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases. No vaccine-related serious adverse events occurred. The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147) μg/mL two weeks after the 4th vaccination, and declined to near baseline one year later. Antibody avidity increased over successive vaccinations. Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA) also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity. These results support the further evaluation of Pfs25-EPA/Alhydrogel® in a malaria-endemic population.

  13. Selective granulocyte and monocyte adsorptive apheresis as a first-line treatment for steroid naïve patients with active ulcerative colitis: a prospective uncontrolled study.

    PubMed

    Suzuki, Yasuo; Yoshimura, Naoki; Saniabadi, Abby R; Saito, Yasushi

    2004-04-01

    Corticosteroid therapy of ulcerative colitis (UC) is associated with frequent adverse side effects and poor quality of life. Recently, adsorptive granulocyte and monocyte/macrophage apheresis has shown efficacy in patients with severe steroid refractory UC. The objective of this study was to investigate if, instead of corticosteroids, adsorptive leukocytapheresis has efficacy as the first-line therapy for steroid-naïve patients with active UC. Twenty patients, aged 15-49 years, with a mean clinical activity index (CAI) of 8.6 were recruited. Adsorptive leukocytapheresis was done with Adacolumn, which contains cellulose acetate beads as adsorptive carriers for granulocytes and monocytes (FcgammaR and complement receptors expressing leukocytes). Each patient received 6 to 10 leukocytapheresis sessions of 60-min duration, at 2 sessions/week. Efficacy was assessed 1 week after the last session. Post treatment, the mean CAI was 3.0 (P = 0001), and 17 of 20 patients (85%) were in remission. There were significant falls in C-reactive protein (P = 0.0003), total white cell counts (P = 0.003), neutrophils (P = 0.0029), and monocytes (P = 0.0038), an increase in lymphocytes (P = 0.001), and increases in the blood levels of soluble TNF-alpha receptors I (P = 0.0007) and II (P = 0.0045) in the column outflow (blood return to the patients). Further, at 8 months, 60% of patients had maintained their remission. No severe side effects were reported. In conclusion, adsorptive leukocytapheresis should reduce corticosteroid therapy in patients with moderate UC; cases with early-stage active disease may benefit most.

  14. Phase II Clinical Trial of Gefitinib for the Treatment of Chemonaïve Patients with Advanced Non-small Cell Lung Cancer with Poor Performance Status

    PubMed Central

    Karim, Nagla Abdel; Musaad, Salma; Zarzour, Ahmad; Patil, Sadanand; Jazieh, Abdul Rahman

    2014-01-01

    BACKGROUND Patients with advanced non-small cell lung cancer (NSCLC) have no curative treatment options; therefore, improving their quality of life (QOL) is an important goal. Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, is a safe oral agent that may be of benefit to a specific population of NSCLC. PATIENTS AND METHODS A Phase II clinical trial included chemonaïve patients with advanced NSCLC and poor performance status (PS). Response rate, progression-free survival, overall survival, QOL using the Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire, and Trial Outcome Index (TOI) were evaluated. RESULTS Twelve out of 19 enrolled patients were evaluable. The median age for the evaluable patients was 68.8 years (59.7–74.6). Out of all the patients, 7 (58.3%) had adenocarcinoma and 5 (41.7%) had squamous cell carcinoma. The median duration of treatment was 62.5 days (26.5–115.0) in the evaluable patients. Grade 3/4 toxicities included fatigue, rash, diarrhea, and nausea. One patient had partial response, eight patients had stable disease (SD), and three patients progressed. The median overall survival for the evaluable population was 4.9 months (2.3–16). The median progression-free survival was 3.7 months (1.9–6.6). TOI was marginally associated with the overall survival, with a hazard ratio of 0.92 (95% confidence interval: 0.84, 1.0) (P = 0.061). FACT-L score and the TOI were highly correlated (r = 0.96, P < 0.0001). TOI scores were higher in African Americans compared to Caucasians and increased with age. CONCLUSION Our results suggest that gefitinib use in patients with