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  • 251.
    Altuvia, S.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Wagner, E.G.H.
    Switching on and off with RNA.2000Ingår i: Proc. Natl. Acad. Sci. USA, Vol. 97, nr 18, s. 9824-9826Artikel i tidskrift (Refereegranskat)
  • 252.
    Alvarez, Alberto
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Martinez-Corral, Ines
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Daubel, Nina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Betsholtz, C.
    Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Dag Hammarskjoldsvag 20, S-75185 Uppsala, Sweden;Karolinska Inst, ICMC, Dept Med Huddinge, Novum, Blickagangen 6, S-14157 Huddinge, Sweden.
    Mäkinen, Taija
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gängel, Konstantin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreER(T2) lines2019Ingår i: Transgenic research, ISSN 0962-8819, E-ISSN 1573-9368Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The CreER(T2)/loxP system is widely used to induce conditional gene deletion in mice. One of the main advantages of the system is that Cre-mediated recombination can be controlled in time through Tamoxifen administration. This has allowed researchers to study the function of embryonic lethal genes at later developmental timepoints. In addition, CreER(T2) mouse lines are commonly used in combination with reporter genes for lineage tracing and mosaic analysis. In order for these experiments to be reliable, it is crucial that the cell labeling approach only marks the desired cell population and their progeny, as unfaithful expression of reporter genes in other cell types or even unintended labeling of the correct cell population at an undesired time point could lead to wrong conclusions. Here we report that all CreER(T2) mouse lines that we have studied exhibit a certain degree of Tamoxifen-independent, basal, Cre activity. Using Ai14 and Ai3, two commonly used fluorescent reporter genes, we show that those basal Cre activity levels are sufficient to label a significant amount of cells in a variety of tissues during embryogenesis, postnatal development and adulthood. This unintended labelling of cells imposes a serious problem for lineage tracing and mosaic analysis experiments. Importantly, however, we find that reporter constructs differ greatly in their susceptibility to basal CreER(T2) activity. While Ai14 and Ai3 easily recombine under basal CreER(T2) activity levels, mTmG and R26R-EYFP rarely become activated under these conditions and are therefore better suited for cell tracking experiments.

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    FULLTEXT01
  • 253.
    Alvarez, Alberto
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Muhl, Lars
    Karolinska Inst, Stockholm, Sweden.
    Gaengel, Konstantin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function2017Ingår i: Protein Kinases In Development And Disease / [ed] Jenny, A, Elsevier, 2017, s. 433-482Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are key regulators of vascular development in vertebrates. Their activation is regulated through a family of secreted glycoproteins, the vascular endothelial growth factors (VEGFs). Expression, proteolytic processing, and diffusion range of VEGF proteins need to be tightly regulated, due to their crucial roles in development. While some VEGFs form concentration gradients across developing tissues and act as morphogenes, others function as inhibitors of receptor activation and downstream signaling. Ligand-induced receptor dimerization leads to activation of the intrinsic tyrosine kinase activity, which results in autophosphorylation of the receptors and in turn triggers the recruitment of interacting proteins as well as the initiation of downstream signaling. Although many biochemical details of VEGFR signaling have been revealed, the in vivo relevance of certain signaling aspects still remains to be demonstrated. Here, we highlight basic principles of VEGFR signaling and discuss its crucial role during development of the vascular system in mammals.

  • 254.
    Alvarsson, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ligand-based Methods for Data Management and Modelling2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Drug discovery is a complicated and expensive process in the billion dollar range. One way of making the drug development process more efficient is better information handling, modelling and visualisation. The majority of todays drugs are small molecules, which interact with drug targets to cause an effect. Since the 1980s large amounts of compounds have been systematically tested by robots in so called high-throughput screening. Ligand-based drug discovery is based on modelling drug molecules. In the field known as Quantitative Structure–Activity Relationship (QSAR) molecules are described by molecular descriptors which are used for building mathematical models. Based on these models molecular properties can be predicted and using the molecular descriptors molecules can be compared for, e.g., similarity. Bioclipse is a workbench for the life sciences which provides ligand-based tools through a point and click interface. 

    The aims of this thesis were to research, and develop new or improved ligand-based methods and open source software, and to work towards making these tools available for users through the Bioclipse workbench. To this end, a series of molecular signature studies was done and various Bioclipse plugins were developed.

    An introduction to the field is provided in the thesis summary which is followed by five research papers. Paper I describes the Bioclipse 2 software and the Bioclipse scripting language. In Paper II the laboratory information system Brunn for supporting work with dose-response studies on microtiter plates is described. In Paper III the creation of a molecular fingerprint based on the molecular signature descriptor is presented and the new fingerprints are evaluated for target prediction and found to perform on par with industrial standard commercial molecular fingerprints. In Paper IV the effect of different parameter choices when using the signature fingerprint together with support vector machines (SVM) using the radial basis function (RBF) kernel is explored and reasonable default values are found. In Paper V the performance of SVM based QSAR using large datasets with the molecular signature descriptor is studied, and a QSAR model based on 1.2 million substances is created and made available from the Bioclipse workbench.

    Delarbeten
    1. Bioclipse 2: A scriptable integration platform for the life sciences
    Öppna denna publikation i ny flik eller fönster >>Bioclipse 2: A scriptable integration platform for the life sciences
    Visa övriga...
    2009 (Engelska)Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 10, s. 397-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Contemporary biological research integrates neighboring scientific domains to answer complex ques- tions in fields such as systems biology and drug discovery. This calls for tools that are intuitive to use, yet flexible to adapt to new tasks.

    Results: Bioclipse is a free, open source workbench with advanced features for the life sciences. Version 2.0 constitutes a complete rewrite of Bioclipse, and delivers a stable, scalable integration platform for developers and an intuitive workbench for end users. All functionality is available both from the graphical user interface and from a built-in novel domain-specific language, supporting the scientist in interdisciplinary research and reproducible analyses through advanced visualization of the inputs and the results. New components for Bioclipse 2 include a rewritten editor for chemical structures, a table for multiple molecules that supports gigabyte-sized files, as well as a graphical editor for sequences and alignments.

    Conclusions: Bioclipse 2 is equipped with advanced tools required to carry out complex analysis in the fields of bio- and cheminformatics. Developed as a Rich Client based on Eclipse, Bioclipse 2 leverages on today’s powerful desktop computers for providing a responsive user interface, but also takes full advantage of the Web and networked (Web/Cloud) services for more demanding calculations or retrieval of data. That Bioclipse 2 is based on an advanced and widely used service platform ensures wide extensibility, and new algorithms, visualizations as well as scripting commands can easily be added. The intuitive tools for end users and the extensible architecture make Bioclipse 2 ideal for interdisciplinary and integrative research. Bioclipse 2 is released under the Eclipse Public License (EPL), a flexible open source license that allows additional plugins to be of any license. Bioclipse 2 is implemented in Java and supported on all major platforms; Source code and binaries are freely available at http://www.bioclipse.net.

    Nyckelord
    Bioclipse, bioinformatics, cheminformatics, scriptable, script, workbench, life science, platform
    Nationell ämneskategori
    Bioinformatik och systembiologi Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-109304 (URN)10.1186/1471-2105-10-397 (DOI)000273329400001 ()
    Tillgänglig från: 2009-12-16 Skapad: 2009-10-13 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Brunn: an open source laboratory information system for microplates with a graphical plate layout design process
    Öppna denna publikation i ny flik eller fönster >>Brunn: an open source laboratory information system for microplates with a graphical plate layout design process
    Visa övriga...
    2011 (Engelska)Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 12, nr 1, artikel-id 179Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background:

    Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data.

    Results:

    A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple-step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves.

    Conclusions:

    Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources.

    Nyckelord
    brunn, microtiter, bioclipse, screening, information system, lis, lims
    Nationell ämneskategori
    Farmakologi och toxikologi
    Forskningsämne
    Bioinformatik
    Identifikatorer
    urn:nbn:se:uu:diva-153210 (URN)10.1186/1471-2105-12-179 (DOI)000292027200001 ()21599898 (PubMedID)
    Tillgänglig från: 2011-05-09 Skapad: 2011-05-09 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Ligand-Based Target Prediction with Signature Fingerprints
    Öppna denna publikation i ny flik eller fönster >>Ligand-Based Target Prediction with Signature Fingerprints
    Visa övriga...
    2014 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, nr 10, s. 2647-2653Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    When evaluating a potential drug candidate it is desirable to predict target interactions in silico prior to synthesis in order to assess, e.g., secondary pharmacology. This can be done by looking at known target binding profiles of similar compounds using chemical similarity searching. The purpose of this study was to construct and evaluate the performance of chemical fingerprints based on the molecular signature descriptor for performing target binding predictions. For the comparison we used the area under the receiver operating characteristics curve (AUC) complemented with net reclassification improvement (NRI). We created two open source signature fingerprints, a bit and a count version, and evaluated their performance compared to a set of established fingerprints with regards to predictions of binding targets using Tanimoto-based similarity searching on publicly available data sets extracted from ChEMBL. The results showed that the count version of the signature fingerprint performed on par with well-established fingerprints such as ECFP. The count version outperformed the bit version slightly; however, the count version is more complex and takes more computing time and memory to run so its usage should probably be evaluated on a case-by-case basis. The NRI based tests complemented the AUC based ones and showed signs of higher power.

    Nationell ämneskategori
    Farmaceutiska vetenskaper Bioinformatik (beräkningsbiologi)
    Forskningsämne
    Bioinformatik
    Identifikatorer
    urn:nbn:se:uu:diva-237934 (URN)10.1021/ci500361u (DOI)000343849600004 ()25230336 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, VR-2011-6129eSSENCE - An eScience CollaborationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish National Infrastructure for Computing (SNIC)
    Tillgänglig från: 2014-12-08 Skapad: 2014-12-08 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    4. Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines
    Öppna denna publikation i ny flik eller fönster >>Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines
    Visa övriga...
    2014 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, nr 11, s. 3211-3217Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, ?, and signature height. C is a penalty parameter that limits overfitting, ? controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected.

    Nationell ämneskategori
    Medicinsk bioteknologi Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-240239 (URN)10.1021/ci500344v (DOI)000345551000017 ()25318024 (PubMedID)
    Forskningsfinansiär
    eSSENCE - An eScience CollaborationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Tillgänglig från: 2015-01-07 Skapad: 2015-01-06 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    5. Large-scale ligand-based predictive modelling using support vector machines
    Öppna denna publikation i ny flik eller fönster >>Large-scale ligand-based predictive modelling using support vector machines
    Visa övriga...
    2016 (Engelska)Ingår i: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 8, artikel-id 39Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models within a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and modelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million chemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical structures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the LIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel, but with dramatically less time for model building even on modest computer resources. Using a non-linear kernel proved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To deploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR and made our models of logD and solubility available from within Bioclipse.

    Nyckelord
    Predictive modelling; Support vector machine; Bioclipse; Molecular signatures; QSAR
    Nationell ämneskategori
    Farmaceutiska vetenskaper Bioinformatik (beräkningsbiologi)
    Forskningsämne
    Bioinformatik
    Identifikatorer
    urn:nbn:se:uu:diva-248959 (URN)10.1186/s13321-016-0151-5 (DOI)000381186100001 ()27516811 (PubMedID)
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), b2013262 b2015001Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceeSSENCE - An eScience Collaboration
    Tillgänglig från: 2015-04-09 Skapad: 2015-04-09 Senast uppdaterad: 2018-08-28Bibliografiskt granskad
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  • 255.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Andersson, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brunn: an open source laboratory information system for microplates with a graphical plate layout design process2011Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 12, nr 1, artikel-id 179Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:

    Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data.

    Results:

    A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple-step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves.

    Conclusions:

    Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources.

    Ladda ner fulltext (pdf)
    fulltext
  • 256.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Andersson, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Carlsson, Lars
    AstraZeneca R&D.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines2014Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, nr 11, s. 3211-3217Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, ?, and signature height. C is a penalty parameter that limits overfitting, ? controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected.

  • 257.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eklund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Engkvist, Ola
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Carlsson, Lars
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Noeske, Tobias
    Ligand-Based Target Prediction with Signature Fingerprints2014Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 54, nr 10, s. 2647-2653Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    When evaluating a potential drug candidate it is desirable to predict target interactions in silico prior to synthesis in order to assess, e.g., secondary pharmacology. This can be done by looking at known target binding profiles of similar compounds using chemical similarity searching. The purpose of this study was to construct and evaluate the performance of chemical fingerprints based on the molecular signature descriptor for performing target binding predictions. For the comparison we used the area under the receiver operating characteristics curve (AUC) complemented with net reclassification improvement (NRI). We created two open source signature fingerprints, a bit and a count version, and evaluated their performance compared to a set of established fingerprints with regards to predictions of binding targets using Tanimoto-based similarity searching on publicly available data sets extracted from ChEMBL. The results showed that the count version of the signature fingerprint performed on par with well-established fingerprints such as ECFP. The count version outperformed the bit version slightly; however, the count version is more complex and takes more computing time and memory to run so its usage should probably be evaluated on a case-by-case basis. The NRI based tests complemented the AUC based ones and showed signs of higher power.

  • 258.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lampa, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Andersson, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Large-scale ligand-based predictive modelling using support vector machines2016Ingår i: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 8, artikel-id 39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The increasing size of datasets in drug discovery makes it challenging to build robust and accurate predictive models within a reasonable amount of time. In order to investigate the effect of dataset sizes on predictive performance and modelling time, ligand-based regression models were trained on open datasets of varying sizes of up to 1.2 million chemical structures. For modelling, two implementations of support vector machines (SVM) were used. Chemical structures were described by the signatures molecular descriptor. Results showed that for the larger datasets, the LIBLINEAR SVM implementation performed on par with the well-established libsvm with a radial basis function kernel, but with dramatically less time for model building even on modest computer resources. Using a non-linear kernel proved to be infeasible for large data sizes, even with substantial computational resources on a computer cluster. To deploy the resulting models, we extended the Bioclipse decision support framework to support models from LIBLINEAR and made our models of logD and solubility available from within Bioclipse.

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    fulltext
  • 259.
    Alvebratt, Caroline
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Cheung, Ocean
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A Modified In Situ Method to Determine Release from a Complex Drug Carrier in Particle-Rich Suspensions2018Ingår i: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 19, nr 7, s. 2859-2865Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Effective and compound-sparing methods to evaluate promising drug delivery systems are a prerequisite for successful selection of formulations in early development stages. The aim of the study was to develop a small-scale in situ method to determine drug release and supersaturation in highly concentrated suspensions of enabling formulations. Mesoporous magnesium carbonate (MMC), which delivers the drug in an amorphous form, was selected as a drug carrier. Five model compounds were loaded into the MMC at a 1:10 ratio using a solvent evaporation technique. The μDiss Profiler was used to study the drug release from MMC in fasted-state simulated intestinal fluid. To avoid extensive light scattering previously seen in particle-rich suspensions in the μDiss Profiler, an in-house-designed protective nylon filter was placed on the in situ UV probes. Three types of release experiments were conducted for each compound: micronized crystalline drug with MMC present, drug-loaded MMC, and drug-loaded MMC with 0.01% w/w hydroxypropyl methyl cellulose. The nylon filters effectively diminished interference with the UV absorption; however, the release profiles obtained were heavily compound dependent. For one of the compounds, changes in the UV spectra were detected during the release from the MMC, and these were consistent with degradation of the compound. To conclude, the addition of protective nylon filters to the probes of the μDiss Profiler is a useful contribution to the method, making evaluations of particle-rich suspensions feasible. The method is a valuable addition to the current ones, allowing for fast and effective evaluation of advanced drug delivery systems.

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    fulltext
  • 260.
    Alvebratt, Caroline
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Keemink, Janneke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Edueng, Khadijah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Cheung, Ocean
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för materialvetenskap, Nanoteknologi och funktionella material.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för materialvetenskap, Nanoteknologi och funktionella material.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    An in vitro dissolution–digestion–permeation assay for the study of advanced drug delivery systems2020Ingår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 149, s. 21-29Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Advanced drug delivery systems (ADDS) are widely explored to overcome poor aqueous solubility of orally administered drugs. However, the prediction of their in vivo performance is challenging, as in vitro models typically do not capture the interplay between processes occurring in the gut. In additions, different models are used to evaluate the different systems. We therefore present a method that allows monitoring of luminal processing (dissolution, digestion) and its interplay with permeation to better inform on the absorption of felodipine formulated as ADDS. Experiments were performed in a µFLUX-apparatus, consisting of two chambers, representing the intestinal and serosal compartment, separated by Caco-2 monolayers. During dissolution–digestion–permeation experiments, ADDS were added to the donor compartment containing simulated intestinal fluid and immobilized lipase. Dissolution and permeation in both compartments were monitored using in situ UV-probes or, when turbidity interfered the measurements, with HPLC analysis.

    The method showed that all ADDS increased donor and receiver concentrations compared to the condition using crystalline felodipine. A poor correlation between the compartments indicated the need for an serosal compartment to evaluate drug absorption from ADDS. The method enables medium-throughput assessment of: (i) dynamic processes occurring in the small intestine, and (ii) drug concentrations in real-time.

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    fulltext
  • 261.
    Alzghoul, Ahmad
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Alhalaweh, Amjad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Experimental and Computational Prediction of Glass Transition Temperature of Drugs2014Ingår i: JOURNAL OF CHEMICAL INFORMATION AND MODELING, ISSN 1549-9596, Vol. 54, nr 12, s. 3396-3403Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glass transition temperature (T-g) is an important inherent property of an amorphous solid material which is usually determined experimentally. In this study, the relation between T-g and melting temperature (T-m) was evaluated using a data set of 71 structurally diverse druglike compounds. Further, in silico models for prediction of T-g were developed based on calculated molecular descriptors and linear (multilinear regression, partial least-squares, principal component regression) and nonlinear (neural network, support vector regression) modeling techniques. The models based on T-m predicted T-g with an RMSE of 19.5 K for the test set. Among the five computational models developed herein the support vector regression gave the best result with RMSE of 18.7 K for the test set using only four chemical descriptors. Hence, two different models that predict T-g of drug-like molecules with high accuracy were developed. If T-m is available, a simple linear regression can be used to predict T-g. However, the results also suggest that support vector regression and calculated molecular descriptors can predict T-g with equal accuracy, already before compound synthesis.

  • 262.
    Amandusson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Axelson, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Comparison between adaptive and fixed stimulus paired-pulsetranscranial magnetic stimulation (ppTMS) in normal subjects2017Ingår i: Clinical Neurophysiology Practice, ISSN 2467-981X, s. 91-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives

    Paired-pulse TMS (ppTMS) examines cortical excitability but may require lengthy test procedures and fine tuning of stimulus parameters due to the inherent variability of the elicited motor evoked potentials (MEPs) and their tendency to exhibit a ‘ceiling/floor effects’ in inhibition trials. Aiming to overcome some of these limitations, we implemented an ‘adaptive’ ppTMS protocol and compared the obtained excitability indices with those from ‘conventional’ fixed-stimulus ppTMS.

    Methods

    Short- and long interval intracortical inhibition (SICI and LICI) as well as intracortical facilitation (ICF) were examined in 20 healthy subjects by adaptive ppTMS and fixed-stimulus ppTMS. The test stimulus intensity was either adapted to produce 500 μV MEPs (by a maximum likelihood strategy in combination with parameter estimation by sequential testing) or fixed to 120% of resting motor threshold (rMT). The conditioning stimulus was 80% rMT for SICI and ICF and 120% MT for LICI in both tests.

    Results

    There were significant (p < 0.05) intraindividual correlations between the two methods for all excitability measures. There was a clustering of SICI and LICI indices near maximal inhibition (‘ceiling effect’) in fixed-stimulus ppTMS which was not observed for adaptive SICI and LICI.

    Conclusions

    Adaptive ppTMS excitability data correlates to those acquired from fixed-stimulus ppTMS.

    Significance

    Adaptive ppTMS is easy to implement and may serve as a more sensitive method to detect changes in cortical inhibition than fixed stimulus ppTMS. Whether equally confident data are produced by less stimuli with our adaptive approach (as already confirmed for motor threshold estimation) remains to be explored.

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  • 263.
    Amandusson, Åsa
    Klin o experimentell medicin, Linköpings universitet.
    Estrogen receptor expression in relation to pain modulation and transmission: experimental studies in rats2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Estrogens have a remarkably wide range of actions in the mammalian brain. They not only play a pivotal role in reproductive behavior and sexual differentiation, but also contribute to e.g. thermoregulation, feeding, memory, neuronal survival and the perception of somatosensory stimuli. A multitude of studies on both animals and human subjects has demonstrated potential effects of gonadal hormones, such as estrogens, on pain transmission. These effects most likely involve multiple neuroanatomical circuits as well as diverse neurochemical systems and therefore need to be evaluated specifically in relation to the localization and intrinsic characteristics of the neurons engaged. The overall aim of this thesis is to gain specific knowledge of the possible cellular mechanisms by which estrogens may influence the transmission of nociceptive stimuli at the level of the spinal cord.

    The estrogen receptors, by which estrogens regulate non-genomic as well as genomic mechanisms, are crucial to estrogen signaling in general and essential to the estrogen-induced effects in the brain. In Paper I, we use immunohistochemistry to label neurons containing estrogen receptor-! (ERα) in the medullary and spinal dorsal horn of female rats. Large numbers of ER!-expressing neurons were found in lamina I and lamina II, i.e. in the areas involved in the processing of primary afferent nociceptive information. This distribution in part overlaps that of enkephalin, a potent pain-inhibiting endogenous opioid. The effects of gonadal hormones on pain modulation may, to a great extent, be blocked by the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in the prosecution of hormonal pain regulation. By combining immunohistochemical labeling of ERα with in situ hybridization of preproenkephalin mRNA (Paper II), we demonstrate that the majority of enkephalinergic neurons in the superficial laminae of the spinal and medullary dorsal horn express ER!. This co-localization and the fact that the preproenkephalin gene contains a sequence that binds ERs, suggest that estrogens may potentially regulate enkephalin expression in these cells. This is further supported by the findings in Paper III in which we show that a single subcutaneous injection of estradiol induces a significant increase (on average 68%) in preproenkephalin mRNA content in the spinal cord after 4 hours. The expression of the enkephalin gene in the spinal cord is thus sensitive to fluctuating estradiol levels. In Paper IV, a noxious injection of formalin is used to induce activation of a neuronal population involved in nociceptive transmission from the face. By using a dual-labeling immunohistochemistry protocol, we were able to identify ER!-expressing cells within this neuronal population suggesting that nociceptive-responsive neurons in the medullary dorsal horn express ER!. In all, our findings provide morphological as well as biochemical evidence in support for an estrogen-dependent modulation of nociceptive processing at the level of the dorsal horn.

    Delarbeten
    1. Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat
    Öppna denna publikation i ny flik eller fönster >>Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat
    2010 (Engelska)Ingår i: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, nr 3, s. 245-248Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERalpha-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12% of ERalpha-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERalpha, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2010
    Nyckelord
    Estrogen receptor, Spinal trigeminal nucleus, Gonadal hormone, Pain, Fos
    Nationell ämneskategori
    Fysiologi
    Forskningsämne
    Klinisk neurofysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-120674 (URN)10.1016/j.ejpain.2009.05.008 (DOI)19525133 (PubMedID)
    Tillgänglig från: 2010-03-15 Skapad: 2010-03-15 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Estrogen-induced alterations of spinal cord enkephalin gene expression
    Öppna denna publikation i ny flik eller fönster >>Estrogen-induced alterations of spinal cord enkephalin gene expression
    Visa övriga...
    1999 (Engelska)Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, nr 2, s. 243-248Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Enkephalin-synthesizing neurons in the superficial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P<0.05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P<0.05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

    Nationell ämneskategori
    Cell- och molekylärbiologi
    Forskningsämne
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-125109 (URN)10.1016/S0304-3959(99)00109-8 (DOI)10534596 (PubMedID)
    Tillgänglig från: 2010-05-07 Skapad: 2010-05-07 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat
    Öppna denna publikation i ny flik eller fönster >>Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat
    1995 (Engelska)Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 196, nr 1-2, s. 25-28Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Using an immunohistochemical technique, we demonstrate that large numbers of neurons in the laminar spinal trigeminal nucleus and spinal gray matter of the female rat express estrogen receptors (ER). Densely packed ER-immunoreactive neurons were present in lamina II, but labeled neurons were also present in lamina I, the neck of the dorsal horn, and in lamina X. Labeling was present throughout the length of the spinal cord, with the exception of segments caudal to S1, which were unlabeled. The distribution of ER-containing neurons to areas that are involved in processing of primary afferent nociceptive information suggests that the pain modulatory effects of estrogen may be exerted at the spinal level.

    Nationell ämneskategori
    Fysiologi
    Forskningsämne
    Klinisk neurofysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-125104 (URN)7501248 (PubMedID)
    Tillgänglig från: 2010-05-07 Skapad: 2010-05-07 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    4. Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression fo neurons in the superficial laminae of the spinal and medullary dorsal horn of rats
    Öppna denna publikation i ny flik eller fönster >>Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression fo neurons in the superficial laminae of the spinal and medullary dorsal horn of rats
    1996 (Engelska)Ingår i: Eur J Neurosci, Vol. 8, nr 11, s. 2240-2245Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A double-labelling procedure combining immunohistochemical staining with in situ hybridization using a radiolabelled cRNA probe was employed to demonstrate oestrogen receptor-like immunoreactivity and preproenkephalin-A mRNA in the medullary and spinal dorsal horn of female rats. Both markers labelled large numbers of neurons in the substantia gelatinosa and its trigeminal homologue. Many of these neurons were double-labelled, displaying both oestrogen receptor-like-immunoreactivity and preproenkephalin-A mRNA; cell counts showed that 40-60% of the of the oestrogen receptor-like-immunoreactive cells in the superficial laminae also were labelled for preproenkephalin-A mRNA, and that 60-70% of the preproenkephalin-A mRNA-labelled neurons in the same laminae displayed oestrogen receptor-like immunoreactivity. Previous studies have shown that oestrogen receptors can bind to the promoter region of the preproenkephalin-A gene, and studies on the hypothalamus have demonstrated that oestrogen regulates enkephalin expression in select neuronal populations. The present results demonstrate that enkephalinergic neurons in the superficial dorsal horn contain oestrogen receptors and suggest that oestrogen may play an important role in the modulation of sensory and nociceptive processing in the lower medulla and spinal cord.

    Nationell ämneskategori
    Cell- och molekylärbiologi
    Forskningsämne
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-125106 (URN)8950107 (PubMedID)
    Tillgänglig från: 2010-05-07 Skapad: 2010-05-07 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
  • 264.
    Amandusson, Åsa
    et al.
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University.
    Blomqvist, Anders
    Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat2010Ingår i: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, nr 3, s. 245-248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERalpha-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12% of ERalpha-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERalpha, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

  • 265.
    Amandusson, Åsa
    et al.
    Klin o experimentell medicin.
    Hallbeck, M
    Hallbeck, AL
    Hermansson, O
    Blomqvist, A
    Estrogen-induced alterations of spinal cord enkephalin gene expression1999Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, nr 2, s. 243-248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Enkephalin-synthesizing neurons in the superficial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P<0.05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P<0.05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

  • 266.
    Amandusson, Åsa
    et al.
    Klin o experimentell medicin.
    Hermansson, O
    Blomqvist, A
    Colocalization of oestrogen receptor immunoreactivity and preproenkephalin mRNA expression fo neurons in the superficial laminae of the spinal and medullary dorsal horn of rats1996Ingår i: Eur J Neurosci, Vol. 8, nr 11, s. 2240-2245Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A double-labelling procedure combining immunohistochemical staining with in situ hybridization using a radiolabelled cRNA probe was employed to demonstrate oestrogen receptor-like immunoreactivity and preproenkephalin-A mRNA in the medullary and spinal dorsal horn of female rats. Both markers labelled large numbers of neurons in the substantia gelatinosa and its trigeminal homologue. Many of these neurons were double-labelled, displaying both oestrogen receptor-like-immunoreactivity and preproenkephalin-A mRNA; cell counts showed that 40-60% of the of the oestrogen receptor-like-immunoreactive cells in the superficial laminae also were labelled for preproenkephalin-A mRNA, and that 60-70% of the preproenkephalin-A mRNA-labelled neurons in the same laminae displayed oestrogen receptor-like immunoreactivity. Previous studies have shown that oestrogen receptors can bind to the promoter region of the preproenkephalin-A gene, and studies on the hypothalamus have demonstrated that oestrogen regulates enkephalin expression in select neuronal populations. The present results demonstrate that enkephalinergic neurons in the superficial dorsal horn contain oestrogen receptors and suggest that oestrogen may play an important role in the modulation of sensory and nociceptive processing in the lower medulla and spinal cord.

  • 267.
    Amandusson, Åsa
    et al.
    Linköpings Universitet.
    Hermansson, O
    Blomqvist, A
    Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat1995Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 196, nr 1-2, s. 25-28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Using an immunohistochemical technique, we demonstrate that large numbers of neurons in the laminar spinal trigeminal nucleus and spinal gray matter of the female rat express estrogen receptors (ER). Densely packed ER-immunoreactive neurons were present in lamina II, but labeled neurons were also present in lamina I, the neck of the dorsal horn, and in lamina X. Labeling was present throughout the length of the spinal cord, with the exception of segments caudal to S1, which were unlabeled. The distribution of ER-containing neurons to areas that are involved in processing of primary afferent nociceptive information suggests that the pain modulatory effects of estrogen may be exerted at the spinal level.

  • 268. Amaral, A F S
    et al.
    Minelli, C
    Guerra, S
    Wjst, M
    Probst-Hensch, N
    Pin, I
    Svanes, C
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Heinrich, J
    Jarvis, D L
    The locus C11orf30 increases susceptibility to poly-sensitization2015Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 70, nr 3, s. 328-333Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A number of genetic variants have been associated with allergic sensitization, but whether these are allergen specific or increase susceptibility to poly-sensitization is unknown. Using data from the large multicentre population-based European Community Respiratory Health Survey, we assessed the association between 10 loci and specific IgE and skin prick tests to individual allergens and poly-sensitization. We found that the 10 loci associate with sensitization to different allergens in a nonspecific manner and that one in particular, C11orf30-rs2155219, doubles the risk of poly-sensitization (specific IgE/4 allergens: OR = 1.81, 95% CI 0.80-4.24; skin prick test/4+ allergens: OR = 2.27, 95% CI 1.34-3.95). The association of rs2155219 with higher levels of expression of C11orf30, which may be involved in transcription repression of interferon-stimulated genes, and its association with sensitization to multiple allergens suggest that this locus is highly relevant for atopy.

  • 269.
    Amaral, Andre F. S.
    et al.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Newson, Roger B.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England.;Univ London Imperial Coll Sci Technol & Med, Dept Primary Care & Publ Hlth, Sch Publ Hlth, London, England..
    Abramson, Michael J.
    Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia..
    Anto, Josep M.
    Ctr Res Environm Epidemiol CREAL, Barcelona, Spain.;IMIM Hosp del Mar, Med Res Inst, Barcelona, Spain.;UPF, Barcelona, Spain.;CIBERESP, Madrid, Spain..
    Bono, Roberto
    Univ Turin, Dept Publ Hlth & Pediat, Turin, Italy..
    Corsico, Angelo G.
    Univ Pavia, Div Resp Dis, IRCCS Policlin San Matteo Fdn, Via Palestro 3, I-27100 Pavia, Italy..
    de Marco, Roberto
    Univ Verona, Unit Epidemiol & Med Stat, Dept Publ Hlth & Community Med, I-37100 Verona, Italy..
    Demoly, Pascal
    CHU Montpellier, Dept Pulmonol, Div Allergy, Arnaud de Villeneuve Hosp, Paris, France.;INSERM, EPAR Team, UMR S 1136, Paris, France..
    Forsberg, Bertil
    Umea Univ, Div Occupat & Environm Med, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gislason, Thorarinn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Natl Univ Hosp Iceland, Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland..
    Heinrich, Joachim
    Helmholtz Zentrum, Inst Epidemiol 1, Munich, Germany.;Univ Munich, Inst & Outpatient Clin Occupat Social & Environm, Inner City Clin, Univ Hosp Munich, Munich, Germany..
    Huerta, Ismael
    Dept Hlth Asturias, Directorate Gen Publ Hlth, Epidemiol Surveillance Sect, Oviedo, Spain..
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Jogi, Rain
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning. Tartu Univ Hosp, Lung Clin, Tartu, Estonia..
    Kim, Jeong-Lim
    Univ Gothenburg, Dept Publich Hlth & Community Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Maldonado, Jose
    Univ Hosp Huelva, Unit Clin Management Pneumol & Allergy, Huelva, Spain..
    Rovira, Jesus Martinez-Moratalla
    Univ Hosp Albacete, Unit Pneumol, Albacete, Spain..
    Neukirch, Catherine
    INSERM, UMR1152, Paris, France.;Univ Paris 07, UMR1152, Paris, France..
    Nowak, Dennis
    Univ Munich, Inst & Outpatient Clin Occupat Social & Environm, Inner City Clin, Univ Hosp Munich, Munich, Germany.;German Ctr Lung Res, Munich, Germany..
    Pin, Isabelle
    CHU Grenoble, Pole Couple Enfants, Pediat, F-38043 Grenoble, France.;Inst Albert Bonniot, INSERM, U823, Grenoble, France.;Univ Grenoble 1, Grenoble, France..
    Probst-Hensch, Nicole
    Swiss Trop & Publ Hlth Inst, Basel, Switzerland.;Univ Basel, Basel, Switzerland..
    Raherison-Semjen, Chantal
    Bordeaux Univ, Inst Publ Hlth & Epidemiol, INSERM, U897, Bordeaux, France..
    Svanes, Cecilie
    Univ Bergen, Ctr Int Hlth, Bergen, Norway.;Haukeland Hosp, Dept Occupat Med, N-5021 Bergen, Norway..
    Landa, Isabel Urrutia
    Galdakao Hosp, Dept Pneumol, Bizkaia, Spain..
    van Ree, Ronald
    Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Versteeg, Serge A.
    Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Weyler, Joost
    Univ Antwerp, Epidemiol & Social Med, B-2020 Antwerp, Belgium.;Univ Antwerp, StatUA Stat Ctr, B-2020 Antwerp, Belgium..
    Zock, Jan-Paul
    Ctr Res Environm Epidemiol CREAL, Barcelona, Spain.;UPF, Barcelona, Spain.;CIBERESP, Madrid, Spain..
    Burney, Peter G. J.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Jarvis, Deborah L.
    Univ London Imperial Coll Sci Technol & Med, Resp Epidemiol Occupat Med & Publ Hlth, Natl Heart & Lung Inst, Emmanuel Kaye Bldg,1B Manresa Rd, London SW3 6LR, England..
    Changes in IgE sensitization and total IgE levels over 20 years of follow-up2016Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 137, nr 6, s. 1788-1795Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect. Objective: We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period. Methods: Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse. Results: Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to -0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts. Conclusion: Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years.

  • 270.
    Amelin, Kristin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Team- och distansläkemedelsgenomgångar inom särskilda boenden: Ger val av arbetsmetod upphov till skillnader i utfall avseende kvalitativa och kvantitativa effektmått på läkemedelsbehandlingen?2018Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Team- och distansläkemedelsgenomgångar inom särskilda boenden

     – Ger val av arbetsmetod upphov till skillnader i utfall avseende kvalitativa och kvantitativa effektmått på läkemedelsbehandlingen?

    Introduktion: Läkemedelsgenomgångar (LMG:ar) delas in i enkla respektive fördjupade genomgångar och ska erbjudas patienter ≥ 75 år med polyfarmaci. I Region Uppsala används två arbetsmetoder för apotekarmedverkan, team och distans, där apotekaren deltar i teamrond respektive skickar synpunkter och förslag skriftligt. Studier och forskare har visat på varierande resultat och åsikter om arbetsmetoderna skiljer sig i utfall och vilken som ska föredras. 

    Syfte: Syftet med rapporten var att jämföra utfallet av distans- och teambaserade LMG:ar inom särskilt boende (SÄBO) i Region Uppsala med avseende på både kvalitativa samt kvantitativa mått.

    Metod: Arbetsmetoderna jämfördes med hjälp av verktygen MAI och SoS Indikatorer i kombination med Janusmed Interaktioner. Även skillnader i antal läkemedel (stående och vid behov) granskades. Alla LMG:ar utfördes under 2017 av kliniska apotekare anställda av Region Uppsala och genomfördes för patienter på SÄBO i Uppsala kommun.

    Resultat: Inga statiskt signifikanta skillnader observerades vid jämförelse av arbetsmetoderna (p>0,05).

    Slutsats: Arbetsmetoderna ger inte upphov till skillnader i utfall för de värderade parametrarna. Flera faktorer kan ha påverkat resultaten och faktorer som geografiska avstånd, tidsbrist eller behov kommer troligen alltid spela en stor roll vid valet av metod. Ytterligare studier krävs då studier där arbetsmetoderna jämförs saknas.

  • 271.
    Amer Abdullah, Saba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kvarstår indikationen för långvarig behandling med antidepressiva läkemdedel (SSRI, SNRI, och mirtazapin) respektive syrasekretionshämmare hos äldre patienter?2018Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Inledning: Användning av läkemedel till äldre har ökat under de senaste åren på grund av den ökade livslängden samt utvecklingen av behandlingsmöjligheter. Depression och syrarelaterade sjukdomar är vanligt förekommande bland äldre och därför behandlas många med antidepressiva och protonpumpshämmare (PPI). Det finns studier och rapporter som visar ett samband mellan långvarig behandling med dessa preparat och förekomsten av flera olika allvarliga sjukdomstillstånd.

     

    Syfte: Syftet med studien är att undersöka i vilken omfattning läkarna dokumenterar att indikationen kvarstår för långvarig behandling med antidepressiva läkemedel (SSRI, SNRI och mirtazapin) och PPI hos äldre patienter.

     

    Material och metod: En deskriptiv journalgranskningsstudie. Patienter som är ≥ 75 år och är inlagda på en akutgeriatrisk avdelning vid Västerås sjukhus inkluderades. Behandling med antidepressiva i mer än ett år räknades som långvarig. För PPI var motsvarande gräns sex månader.

     

    Resultat: Totalt screenades 176 patienter varav 161 uppfyllde inklusionskriterier. Tjugonio (18%) patienter behandlades med antidepressiva och 52 (32%) med PPI. Vid långvarig behandling med antidepressiva fanns dokumentation om att indikationen kvarstår ett år efter behandlingsstarten hos 7 patienter (24%). För PPI fanns dokumentation hos 12 patienter (23%).

     

    Slutsats: Dokumentation vid långvarig behandling med antidepressiva och PPI hos den undersökta gruppen multisjuka äldre var bristfällig. Huruvida en utvärdering av behandlingsindikationen är gjord utan att läkarna har dokumenterat den går inte att uttala sig om utifrån resultaten av denna studie.

  • 272.
    Ameur, Adam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bunikis, Ignas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    CanvasDB: a local database infrastructure for analysis of targeted- and whole genome re-sequencing projects2014Ingår i: Database: The Journal of Biological Databases and Curation, ISSN 1758-0463, E-ISSN 1758-0463, s. bau098-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CanvasDB is an infrastructure for management and analysis of genetic variants from massively parallel sequencing (MPS) projects. The system stores SNP and indel calls in a local database, designed to handle very large datasets, to allow for rapid analysis using simple commands in R. Functional annotations are included in the system, making it suitable for direct identification of disease-causing mutations in human exome-(WES) or whole-genome sequencing (WGS) projects. The system has a built-in filtering function implemented to simultaneously take into account variant calls from all individual samples. This enables advanced comparative analysis of variant distribution between groups of samples, including detection of candidate causative mutations within family structures and genome-wide association by sequencing. In most cases, these analyses are executed within just a matter of seconds, even when there are several hundreds of samples and millions of variants in the database. We demonstrate the scalability of canvasDB by importing the individual variant calls from all 1092 individuals present in the 1000 Genomes Project into the system, over 4.4 billion SNPs and indels in total. Our results show that canvasDB makes it possible to perform advanced analyses of large-scale WGS projects on a local server.

  • 273.
    Amidon, Gregory E.
    et al.
    Univ Michigan, Ann Arbor, MI USA.
    Anderson, Bradley D.
    Univ Kentucky, Lexington, KY 40506 USA.
    Balthasar, Joseph P.
    SUNY Buffalo, Univ Buffalo, Buffalo, NY USA.
    Bergström, Christel A.S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Huang, Shiew-Mei
    US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Kasting, Gerald
    Univ Cincinnati, Cincinnati, OH USA.
    Kesisoglou, Filippos
    Merck & Co Inc, Kenilworth, NJ USA.
    Khinast, Johannes G.
    Graz Univ Technol, Inst Proc & Particle Engn, Graz, Austria.
    Mager, Donald E.
    SUNY Buffalo, Univ Buffalo, Buffalo, NY USA.
    Roberts, Christopher J.
    Univ Delaware, Newark, DE USA.
    Yu, Lian
    Univ Wisconsin, Madison, WI USA.
    Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling2019Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, nr 1, s. 2-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    With this issue of the Journal of Pharmaceutical Sciences, we celebrate the nearly 6 decades of contributions to mechanistic-based modeling and computational pharmaceutical sciences. Along with its predecessor, The Journal of the American Pharmaceutical Association: Scientific Edition first published in 1911, JPharmSci has been a leader in the advancement of pharmaceutical sciences beginning with its inaugural edition in 1961. As one of the first scientific journals focusing on pharmaceutical sciences, JPharmSci has established a reputation for publishing high-quality research articles using computational methods and mechanism-based modeling. The journal’s publication record is remarkable. With over 15,000 articles, 3000 notes, and more than 650 reviews from industry, academia, and regulatory agencies around the world, JPharmSci has truly been the leader in advancing pharmaceutical sciences.

  • 274.
    Amin, Kawa
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The relationship between inflammation and structural changes in the airways of the lower and upper respiratory tract: Studies in patients with asthma, Sjögren's syndrome, rhinitis and children with otitis media with effusion2000Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The pathophysiology of asthma, Sjögrens syndrome (SS), rhinitis, and otitis media with effusion (OME) in children has been extensively investigated in upper and lower respiratory tract, respectively, and shown to comprise structural changes in the airways and involvement of inflammatory cells. By comparing diseases that have bronchial hyperresponsivenses or mucosal inflammation as a common denominator, it may be possible to learn more about the mechanisms underlying inflammation in the upper and lower respiratory tract.

    With immunohistochemical techniques and a panel of monoclonal antibodies, inflammatory cells were identified and structural changes of the airway were quantitatively studied in the bronchial, nasal and middle ear mucosa and submucosa.

    The highest number of eosinophils and mast ceils in bronchial, nasal or middle ear biopsies was found in patients with atopic asthma (AA), perennial non-allergic rhinitis (PNAR) and children with OME. The number of the neutrophils was highest in SS, non-atopic asthma (NAA) and children with OME. The number of T lymphocytes in SS and AA was significantly higher than in NAA and healthy controls (HC). The degree of epithelial damage was higher in the AA group andin patients with perennial allergic rhinitis where the biopsy was taken within the pollen season (PARSEASON) group compared to the other patient groups. The tenascin- and Iaminin-positive layers in AA and SS were thicker than other groups. In AA, and PARSEASON a significant negative correlation was found between epithelial integrity and the count for eosinophils or neutrophils. The most pronounced epithelial damage was observed in patients with allergic rhinitis in areas characterized by an increased number of inflammatory cells. Eosinophils in asthmatic and PARSEASON patients and neutrophils in SS were found in the area of epithelial damage.

    This work has demonstrated a quantitatively different inflammatory profile in AA, NAA and SS, different profiles in perennial allergic and non-allergic rhinitis and a specific inflammatory profile in the middle ear of children with OME suggesting differences in the pathogenesis of respiratory tract diseases.

  • 275.
    Amin, Kawa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    H Rasool, Aram
    Hattem, Ali
    AM Al-Karboly, Taha
    E Taher, Taher
    Bystrom, Jonas
    Autoantibody profiles in autoimmune hepatitis and chronic hepatitis C identifies similarities in patients with severe disease2017Ingår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 23, nr 8, s. 1345-1352Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM: To determine how the auto-antibodies (Abs) profilesoverlap in chronic hepatitis C infection (CHC) andautoimmune hepatitis (AIH) and correlate to liverdisease.METHODS: Levels of antinuclear Ab, smooth muscle antibody (SMA)and liver/kidney microsomal-1 (LKM-1) Ab and markersof liver damage were determined in the sera of 50 patients with CHC infection, 20 AIH patients and 20healthy controls using enzyme linked immunosorbentassay and other immune assays. RESULTS: We found that AIH patients had more severe liverdisease as determined by elevation of total IgG,alkaline phosphatase, total serum bilirubin and serumtransaminases and significantly higher prevalence ofthe three non-organ-specific autoantibodies (auto-Abs)than CHC patients. Antinuclear Ab, SMA and LKM-1 Abwere also present in 36% of CHC patients and relatedto disease severity. CHC cases positive for auto-Abswere directly comparable to AIH in respect of mostmarkers of liver damage and total IgG. These caseshad longer disease duration compared with auto-Abnegative cases, but there was no difference in gender,age or viral load. KLM-1+ Ab CHC cases showed bestoverlap with AIH. CONCLUSION: Auto-Ab levels in CHC may be important markers ofdisease severity and positive cases have a diseasesimilar to AIH. Auto-Abs might have a pathogenic roleas indicated by elevated markers of liver damage.Future studies will unravel any novel associationsbetween these two diseases, whether genetic or other.

  • 276.
    Amin, Kawa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi. Clin Chem & Asthma Res Ctr, Uppsala, Sweden.;Univ Hosp, Uppsala, Sweden..
    Janson, C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Byström, J.
    Queen Mary Univ London, Barts & London, Harvey Res Inst, Expt Med & Rheumatol William, London, England..
    Role of Eosinophil Granulocytes in Allergic Airway Inflammation Endotypes2016Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 84, nr 2, s. 75-85Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Eosinophil granulocytes are intriguing members of the innate immunity system that have been considered important defenders during parasitic diseases as well as culprits during allergy-associated inflammatory diseases. Novel studies have, however, found new homoeostasis-maintaining roles for the cell. Recent clinical trials blocking different Th2 cytokines have uncovered that asthma is heterogeneous entity and forms different characteristic endotypes. Although eosinophils are present in allergic asthma with early onset, the cells may not be essential for the pathology. The cells are, however, likely disease causing in asthma with a late onset, which is often associated with chronic rhinosinusitis. Assessment of eosinophilia, fraction exhaled nitric oxide (FeNO) and periostin are markers that have emerged useful in assessing and monitoring asthma severity and endotype. Current scientific knowledge suggests that eosinophils are recruited by the inflammatory environment, activated by the innate interleukin (IL)-33 and prevented from apoptosis by both lymphocytes and innate immune cells such as type two innate immune cells. Eosinophils contain four specific granule proteins that exhibit an array of toxic and immune-modulatory activates. The granule proteins can be released by different mechanisms. Additionally, eosinophils contain a number of inflammatory cytokines and lipid mediators as well as radical oxygen species that might contribute to the disease both by the recruitment of other cells and the direct damage to supporting cells, leading to exacerbations and tissue fibrosis. This review aimed to outline current knowledge how eosinophils are recruited, activated and mediate damage to tissues and therapies used to control the cells.

  • 277.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Analysis of Caffeine in Dietary Products by Multiple Injection Capillary Electrophoresis2012Ingår i: Caffeine: Chemistry, Analysis, Function and Effects / [ed] Victor R Preedy, London: Royal Society of Chemistry, 2012, s. 154-178Kapitel i bok, del av antologi (Refereegranskat)
  • 278.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Analysis of somatropin by double-injection capillary-zone electrophoresis in polybrene/chondroitin sulfate a double-coated capillaries2016Ingår i: Capillary Electrophoresis of Proteins and Peptides: Methods and Protocols / [ed] Nguyet Thuy Tran, Myriam Taverna, New York: Springer-Verlag New York, 2016, s. 93-105Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Purity determination of somatropin as a recombinant protein is important to ensure its safety and quality. This is carried out by capillary zone electrophoresis in double-injection mode using polybrene/chondroitin sulfate A double-coated capillaries. Modification of the capillary wall eliminates protein-wall interactions which results in improved accuracy and precision of the determinations. In the double-injection mode two somatropin samples are analyzed within a single electrophoretic run. Prior to the second injection, the first injected plug is electrophoresed for a predetermined time period in order to adjust the inter- plug distance. Here, the principle for the separation of somatropin charge variants is described.

  • 279.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Double-injection capillary electrophoresis for the identification of analytes2014Ingår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 35, nr 20, s. 2915-2921Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This paper presents a new approach for identifying analytes by CE. The compound to be identified is analyzed together with the corresponding reference standard during a double injection capillary electrophoretic run. The inter-plug distance is regulated by applying an electrical field over the capillary for a predetermined time period (tPE). The migration time of an analyte being exposed to the partial electrophoresis was calculated from the partial migration time (tmig(p)) as described in this paper. The identification is based on the closeness of agreement between the calculated migration time (tmig(c)) and observed migration time (tmig) of the reference standard. The validity of the derived equations was checked by analyzing several substances such as caffeine, melamine, acetyl salicylic acid, paracetamol, ibuprofen, metoprolol, naproxen, somatropin, several insulin analogs, as well as different pharmaceutical and natural products. The migration time ratios for the identified solutes varied between 0.996 and 1.006 (i.e., 1.001 ± 0.005), indicating good agreement between the observed and calculated migration times.

  • 280.
    Amini, Ahmad
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk kemi.
    Enantiomeric separation by capillary electrophoresis: With special emphasis on the partial filling technique1998Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Capillary electrophoresis as a powerful separation technique was employed for resolution of racemic drugs. Taurodeoxycholate (TDC), different cyclodextrins and α1- acid glycoprotein (AGP) were dissolved in the background electrolyte at low pH (3.0 to 4.0 ) as chiral selectors.

    Enantioresolutions were based on the principle of micellar electrokinetic chromatography, inclusion complexation and affinity interactions between the enantiomers and TDC, cyclodextrins and AGP, respectively.

    The influence of chiral selector concentration and type, temperature and addition of organic modifiers on enantioselectivity were studied. The temperature was found to be an important factor for regulation of the enantioresolution.

    In order to avoid UV-absorbance interferences between AGP as a UV-absorbing chiral selector as well as to reduce consumption of chiral selector solution, the partial filling technique (PFT) was employed. The technique was developed and equations describing the feature of the technique as an efficient separation mode in CE was presented. Parameters such as applied plug length (PLapp) and effective plug length (PLeff) were determined. Equations expressing the relation between the PLeff and selectivity and resolution factors were developed.

    The PFT was used for determination of association constants between AGP as chiral selector and the enantiomers of disopyramide and remoxipride. The association was strongly temperature dependent, and a maximum in binding was observed at 25°C. The PFT was found to be a very convenient approach for measurement of association constants.

    To verity the above mentioned technique for evaluation of binding constants, the association constants between methyl-β-cyclodextrin and the enantiomers of orciprenaline at different chiral selector concentrations were measured and compared with the data obtained by the conventional technique. The results illustrate the reliability of the system based on the PFT.

  • 281.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Identification of Ɛ-Caprolactam and Melamine in Polyvinyl- Pyrrolidone Powder by Double Injection Micellar Elektrokinetic Chromatography2015Ingår i: Pharmaceutica analytica acta, ISSN 2153-2435, Vol. 6, nr 11, artikel-id 1000442Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A double-injection micellar electrokinetic chromatography (DIMEKC) method for the identification of Ɛ- caprolactam andmelamine deliberately added to povidone (polyvinylpyrrolidone) products has been developed. The separations were performedin 89 mM phosphate buffer (pH 7.4) containing 52 mM sodium dodecyl sulfate (SDS) in fused silica capillaries with UV absorptiondetection at 200 nm. The identification relied on the agreement between the calculated migration time (t mig(c) ) of the analytes andthe migration time (t mig ) of their corresponding reference standards being analysed simultaneously within a double injection run.The migration time of the analytes was calculated from the partial migration times (t mig(p) ) as described in this paper. The migrationtime ratios (t mig(c) / t mig ) varied

  • 282.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Identification of ε-caprolactam, melamine and urea in polyvinylpyrrolidone powders by micellar electrokinetic chromatography2014Ingår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 91, s. 12-16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A sodium dodecyl sulfate micellar electrokinetic chromatography (SDS-MEKC) method for the simultaneous separation and identification of ɛ-caprolactam, melamine and urea deliberately added to polyvinylpyrrolidone (povidone) products has been developed. All samples to be analyzed contained paracetamol as an internal marker (IM). The optimized separations were performed in 50 mM phosphate buffer (pH 7.0) containing 2% (w/v) sodium dodecyl sulfate (SDS) in fused silica capillaries with UV absorption detection at 200 nm. The method was validated with respect to repeatability and intermediate precision, selectivity and robustness with satisfactory results. The relative migration times (RMT) were found to be between 0.03% and 0.13% for intra-day precision and between 0.50% and 0.60% for inter-day precision in four days. The detection limits were determined to be 1.3 (11.5 μM), 0.4 (3.5 μM) and 41 μg/ml (0.4 mM) for ɛ-caprolactam, melamine and urea, respectively.

  • 283.
    Amini, Ahmad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Lodén, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Arvidsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Principles for different modes of multiple-injection CZE2008Ingår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, nr 19, s. 3952-3958Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This paper introduces four different modes of multiple-injection CZE (MICZE). The validity of these MICZE models was evaluated by the experimental data. Prior to the application of MICZE, the electrophoretic conditions are developed in the single-injection mode by adjusting different experimental parameters such as pH, type and concentration of buffer additives and temperature. Based on the migration time difference (tmig) between the analyte and the internal standard or injection marker, one or more MICZE modes can be employed. The injection marker is added to the sample to compensate for injection-volume fluctuations. The inter-plug distance is regulated by applying an electrical field over the capillary for a short period of time between each injection. After the final injection, the separation is completed by electrophoresis for a time period corresponding to that in the single-injection mode

  • 284.
    Amini, Ahmad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Nilsson, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Quantitative analysis of polypeptide pharmaceuticals by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry2008Ingår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 46, nr 3, s. 411-417Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An accurate method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been developed for quantitative analysis of calcitonin and insulin in different commercially available pharmaceutical products. Tryptic peptides derived from these polypeptides were chemically modified at their C-terminal lysine-residues with 2-methoxy-4,5-dihydro-imidazole (light tagging) as standard and deuterated 2-methoxy-4,5-dihydro-imidazole (heavy tagging) as internal standard (IS). The heavy modified tryptic peptides (4D-Lys tag), differed by four atomic mass units from the corresponding light labelled counterparts (4H-Lys tag). The normalized peak areas (the ratio between the light and heavy tagged peptides) were used to construct a standard curve to determine the concentration of the analytes. The concentrations of calcitonin and insulin content of the analyzed pharmaceutical products were accurately determined, and less than 5% error was obtained between the present method and the manufacturer specified values. It was also found that the cysteine residues in CSNLSTCVLGK from tryptic calcitonin were converted to lanthionine by the loss of one sulfhydryl group during the labelling procedure.

  • 285.
    Amini, Ahmad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Rundlöf, Torgny
    Rönnquist, Kerstin
    Tydén, Monica
    Turunen, Taina
    Korhola, Paula
    Anette, Perolari
    A protocol for the quality assessment of illegally distributed human growth hormones with respect to identity, purity, endotoxin level and microorganism content2015Ingår i: Analytical Methods, ISSN 1759-9660, E-ISSN 1759-9679, Vol. 7, nr 20, s. 8857-8864Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Different methods based on MALDI-TOF-MS and double injection capillary zone electrophoresis (DICZE) were used for the identification and purity determination of somatropin in illegally distributed products. During the past few years, more than 200 products suspected to contain somatropin have been analysed. Some of the samples were also subjected to control microorganisms and endotoxins. The identification of somatropin was carried out by peptide mapping using trypsin as the proteolytic enzyme. A double chain peptide cross-linked via a disulfide bond was used as the signature peptide. Capillary electrophoresis in double injection mode was applied to both identification and purity determination of the samples. The identification was based on the comparison between the observed migration time of the reference standard and the calculated migration time of the analyte, being present in the second injection plug. The DICZE provides electrophoretic fingerprints of intact somatropin and the related proteins which facilitate the identification. In addition, some of these samples revealed the presence of microorganisms as well as a high level of endotoxins. Taken together, the doubtful quality of the analysed samples and the microbiological findings represent a serious threat for the consumers and public health.

  • 286.
    Amini, Farahnaz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Development and evaluation of gene expressions in Bufo bufo- tadpoles as biomarkers for exposure of chemical pollutants2019Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Introduction: Occurrence and emission of chemical pollutants such as organic compounds, heavy metals and pharmaceuticals are high in the aquatic environment and a concern worldwide due to the risk of affecting organisms negatively. Biomarkers can indicate the magnitude of organism response to environmental pollutants and provide the causal link between the presence of a chemical and ecological effect. These pollution indicators can be used in effect-based environmental monitoring. Cytochrome p450 1A (CYP1A), metallothionein (MT) and cytochrome p450 3A (CYP3A) are examples which can be used as biomarkers for identification of exposure of pollutants.

    The aims of this project were to find functioning primers for MT, CYP1A and CYP3A, and examine whether mRNA levels of these genes are relevant to use as biomarkers to demonstrate exposure of metals, dioxin-like chemicals and ethinyl estradiol (EE2).

    Methods: The tadpoles were exposed to Cadmium chloride (CdCl2), β-naphthoflavone (BNF) and EE2. RNA of the liver tissue samples was isolated, and concentration and integrity were measured. The primers were designed based on different strategies, A, existing gene mRNA sequences, B, Short Read Archive (SRA) database of NBCI and C, extended RNA-sequencing. qRTPCR was used for RNA-primer-testing and mRNA expression level measurement.

    The results show significantly differences between sites and individuals, expression level of CYP1A was significantly induced but no induction of CYP3A and MT was achieved.

    Conclusions: Applying CYP1A gene as biomarker on wild tadpoles looks promising. For the use of CYP3A and MT as biomarkers, further efforts are needed.

  • 287. Amirian, E Susan
    et al.
    Armstrong, Georgina N
    Zhou, Renke
    Lau, Ching C
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill S
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Lachance, Daniel
    Olson, Sara H
    Bernstein, Jonine L
    Merrell, Ryan T
    Wrensch, Margaret R
    Davis, Faith G
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I
    Scheurer, Michael E
    Aldape, Kenneth
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Brännström, Thomas
    Broholm, Helle
    Collins, Peter
    Giannini, Caterina
    Rosenblum, Marc
    Tihan, Tarik
    Melin, Beatrice S
    Bondy, Melissa L
    The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium2016Ingår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 183, nr 2, s. 85-91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

  • 288.
    Amlinger, Lina
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Hoekzema, Mirthe
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Wagner, Gerhart E. H.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Koskiniemi, Sanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Lundgren, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Fluorescent CRISPR Adaptation Reporter for rapid quantification of spacer acquisition2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 10392Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CRISPR-Cas systems are adaptive prokaryotic immune systems protecting against horizontally transferred DNA or RNA such as viruses and other mobile genetic elements. Memory of past invaders is stored as spacers in CRISPR loci in a process called adaptation. Here we developed a novel assay where spacer integration results in fluorescence, enabling detection of memory formation in single cells and quantification of as few as 0.05% cells with expanded CRISPR arrays in a bacterial population. Using this fluorescent CRISPR Adaptation Reporter (f-CAR), we quantified adaptation of the two CRISPR arrays of the type I-E CRISPR-Cas system in Escherichia coli, and confirmed that more integration events are targeted to CRISPR-II than to CRISPR-I. The f-CAR conveniently analyzes and compares many samples, allowing new insights into adaptation. For instance, we show that in an E. coli culture the majority of acquisition events occur in late exponential phase.

    Ladda ner fulltext (pdf)
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  • 289.
    Ammar, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Immunohistochemical studies on small arteries from women with polycystic ovary syndrome: Focus on makers for endothelial dysfunction2012Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Women with polycystic ovary syndrome (PCOS) have an increased risk of developing cardiovascular disease (CVD). Metabolic syndrome predominate which may lead to impaired insulin sensitivity and development of type II diabetes and hypertension. Endothelial dysfunction together with pro-inflammatory, pro-thrombotic and pro-oxidant environment serves as initial phase for CVD complications. The research group performs functional studies on isolated arteries with focus on endothelium dependent relaxation from PCOS women and age matched controls and the aim of the presented project was to compare markers for endothelial dysfunction using immunohistochemistry (IHC). Small arteries were isolated from subcutaneous fat biopsies from patients and controls and fixed in O.C.T. compound (-70C dry ice). The biopsies were sectioned in 8µm thin slices for further staining with primary antibodies, DAB as a chromogen and Mayer´s Hematoxylin. The primary antibody was selected for endothelial cell adhesion molecules PECAM-1, P-selectin, vWF and VCAM-1.    There was a tendency for stronger expression of P-selectin in arteries from PCOS women compared with controls, while in the controls a tendency was seen towards stronger expression of VCAM-1 and a weaker staining for vWF if compared with PCOS. There was no obvious difference for other stained markers between the groups. There were differences between tested markers in control groups and the PCOS women whit IHC staining as well as earlier functional tests. Tested markers reflected that endothelial dysfunction were expressed in the endothelium of isolated arteries from PCOS and control women, however further functional studies and IHC studies were warranted to quantify their contribution.

  • 290.
    Amrullah Zaman, Zohra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Uppföljning och utvärdering av farmaceuter som jobbar på pediatrisk vårdavdelning2018Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Uppföljning & utvärdering av farmaceuter som jobbar på pediatrisk vårdavdelning

    Introduktion

    År 2014 inledde barnläkemedelsgruppen på Astrid Lindgrens barnsjukhus (ALB) implementering av en funktion för vårdenhetsfarmaceut (VEF). Projektet resulterade i anställande av två apotekare som placerades på Barnonkologen respektive Neonatalverksamheten. Därefter har antalet VEF ökat.

    Syfte

    Deskriptiv uppföljningsstudie för att erhålla vetskap om hur projektet från 2014 fallit ut. Hur ser det ut idag sedan införandet av permanenta farmaceuttjänster inom pediatriska vårdavdelningar? Framförallt på Barnonkologen respektive Neonatalverksamhet, men även övriga vårdavdelningar.

    Material och metod

    En tidsstudie utfördes på de sju avdelningar på ALB som har VEF för att studera tiden för olika aktiviteter i läkemedelsrummet under givna tidpunkter. En enkätstudie genomfördes med syfte att följa upp hur sjuksköterskor upplevde läkemedelsarbetet med VEF på avdelningen. På de avdelningar med journalsystemet TakeCare utfördes läkemedelsförrådsstudie för kassationsberäkning av ett bestämt antal läkemedel. Vårdproduktionsstudie genomfördes för att ta reda på antalet läkemedelsdoser som enheterna exponeras för, därav läkemedelsbelastningen. Slutligen studerades databas för barnläkemedel (ePed) för att se hur stor andel av beställningarna på enheterna som har läkemedelsinstruktioner.

    Resultat

    För farmaceuter var mediantiden för faktiskt iordningställandetid (ställtid ej inkluderad) 53 min och för övrig aktivitet (ex; rådgivning, annat läkemedelsarbete) 47 min under tidsperiod om fyra timmar i läkemedelsrummet. Enkätstudien visade stor uppskattning bland sjuksköterskor och att VEF bidrar med mycket mer än bara iordningställande. Jämfört med 2014 fanns ökad positiv inställning på Neo Solna, dock utan signifikant skillnad. Läkemedelsförrådsstudien visade att en betydande kassation förekommer på barnavdelningar, därav ett viktigt mått vid framtida uppföljningar. Läkemedelsbelastningen på enheterna var likvärdig 2014 och kring 80% av beställningarna på enheterna har läkemedelsinstruktioner i ePed.

    Slutsats

    Farmaceuter uppfyller en avlastande och kvalitetshöjande funktion på ALB, samt fungerar som stöd vid läkemedelsrelaterade frågor. Farmaceuterna är mycket uppskattade bland sjuksköterskor, dels för iordningställande hjälpen (ca två timmar under arbetsdag om åtta timmar, ställtid ej inkluderad) men även för att de bidrar med annan nödvändig kompetens. Det finns gott om läkemedelsjobb samt annat typ av arbete för farmaceuter på ALB.

  • 291. An, Xiaojin
    et al.
    Jin, Yi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Guo, Hongnian
    Foo, Shi-Yin
    Cully, Brittany L
    Wu, Jiaping
    Zeng, Huiyan
    Rosenzweig, Anthony
    Li, Jian
    Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor.2009Ingår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 120, nr 7, s. 617-27Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Response gene to complement 32 (RGC-32) is induced by activation of complement and regulates cell proliferation. To determine the mechanism of RGC-32 in angiogenesis, we examined the role of RGC-32 in hypoxia-related endothelial cell function.

    METHODS AND RESULTS: Hypoxia/ischemia is able to stimulate both angiogenesis and apoptosis. Hypoxia-inducible factor-1/vascular endothelial growth factor is a key transcriptional regulatory pathway for angiogenesis during hypoxia. We demonstrated that the increased RGC-32 expression by hypoxia was via hypoxia-inducible factor-1/vascular endothelial growth factor induction in cultured endothelial cells. However, overexpression of RGC-32 reduced the proliferation and migration and destabilized vascular structure formation in vitro and inhibited angiogenesis in Matrigel assays in vivo. Silencing RGC-32 had an opposing, stimulatory effect. RGC-32 also stimulated apoptosis as shown by the increased apoptotic cells and caspase-3 cleavage. Mechanistic studies revealed that the effect of RGC-32 on the antiangiogenic response was via attenuating fibroblast growth factor 2 expression and further inhibiting expression of cyclin E without affecting vascular endothelial growth factor and fibroblast growth factor 2 signaling in endothelial cells. In the mouse hind-limb ischemia model, RGC-32 inhibited capillary density with a significant attenuation in blood flow. Additionally, treatment with RGC-32 in the xenograft tumor model resulted in reduced growth of blood vessels that is consistent with reduced colon tumor size.

    CONCLUSIONS: We provide the first direct evidence for RGC-32 as a hypoxia-inducible gene and antiangiogenic factor in endothelial cells. These data suggest that RGC-32 plays an important homeostatic role in that it contributes to differentiating the pathways for vascular endothelial growth factor and fibroblast growth factor 2 in angiogenesis and provides a new target for ischemic disorder and tumor therapies.

  • 292. An, Xiaojin
    et al.
    Jin, Yi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Philbrick, Melissa J
    Wu, Jiaping
    Messmer-Blust, Angela
    Song, Xiaoxiao
    Cully, Brittany L
    He, Ping
    Xu, Ming
    Duffy, Heather S
    Li, Jian
    Endothelial cells require related transcription enhancer factor-1 for cell-cell connections through the induction of gap junction proteins.2012Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 32, nr 8, s. 1951-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Capillary network formation represents a specialized endothelial cell function and is a prerequisite to establish a continuous vessel lumen. Formation of endothelial cell connections that form the vascular structure is regulated, at least in part, at the transcriptional level. We report here that related transcription enhancer factor-1 (RTEF-1) plays an important role in vascular structure formation.

    METHODS AND RESULTS: Knockdown of RTEF-1 by small interfering RNA or blockage of RTEF-1 function by the transcription enhancer activators domain decreased endothelial connections in a Matrigel assay, whereas overexpression of RTEF-1 in endothelial cells resulted in a significant increase in cell connections and aggregation. In a model of oxygen-induced retinopathy, endothelial-specific RTEF-1 overexpressing mice had enhanced angiogenic sprouting and vascular structure remodeling, resulting in the formation of a denser and more highly interconnected superficial capillary plexus. Mechanistic studies revealed that RTEF-1 induced the expression of functional gap junction proteins including connexin 43, connexin 40, and connexin 37. Blocking connexin 43 function inhibited RTEF-1-induced endothelial cell connections and aggregation.

    CONCLUSIONS: These findings provide novel insights into the transcriptional control of endothelial function in the coordination of cell-cell connections.

  • 293.
    Anagandula, Mahesh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Studies of Enterovirus Infection and Induction of Innate Immunity in Human Pancreatic Cells2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Several epidemiological and clinical studies have indicated a possible role of Enterovirus (EV) infection in type 1 diabetes (T1D) development. However, the exact casual mechanism of these viruses in T1D development is not known. The aim of this thesis is to study various EVs that have been shown to differ in their immune phenotype, lytic ability, association with induction of islet autoantibodies, ability to replicate, cause islet disintegration and induce innate antiviral pathways in infected pancreatic cells in vitro. Furthermore, EV presence and pathogenic process in pancreatic tissue and isolated islets of T1D patients was also studied.

    Studies in this thesis for first time show the detection of EV RNA and protein in recent onset live T1D patients supporting the EV hypothesis in T1D development. Further all EV serotypes studied were able to replicate in islets, causing variable amount of islet disintegration ranging from extensive islet disintegration to not affecting islet morphology at all. However, one of the EV serotype replicated in only two out of seven donors infected, highlighting the importance of individual variation between donors. Further, this serotype impaired the insulin response to glucose stimulation without causing any visible islet disintegration, suggesting that this serotype might impaired the insulin response by inducing a functional block. Infection of human islets with the EV serotypes that are differentially associated with the development of islet autoantibodies showed the islet cell disintegration that is comparable with their degree of islet autoantibody seroconversion. Suggesting that the extent of the epidemic-associated islet autoantibody induction may depend on the ability of the viral serotypes to damage islet cells. Furthermore, one of the EV strains showed unique ability to infect and replicate both in endo and exocrine cells of the pancreas. EV replication in both endo and exocrine cells affected the genes involved in innate and antiviral pathways and induction of certain genes with important antiviral activity significantly varied between different donors. Suggesting that the same EV infection could result in different outcome in different individuals. Finally, we compared the results obtained by lytic and non lytic EV strains in vitro with the findings reported in fulminant and slowly progressing autoimmune T1D and found some similarities. In conclusion the results presented in this thesis further support the role of EV in T1D development and provide more insights regarding viral and host variation.  This will improve our understanding of the possible causative mechanism by EV in T1D development.

    Delarbeten
    1. Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes
    Öppna denna publikation i ny flik eller fönster >>Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes
    Visa övriga...
    2015 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 5, s. 1682-1687Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in 6 adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh frozen whole pancreatic tissue using PCR and sequencing. Non-diabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetes patients (2 of 9 controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (1 of 9 controls). Enterovirus specific RNA sequences were detected in 4 of 6 cases (0 of 6 controls). The results were confirmed in different laboratories. Only 1.7 % of the islets contained VP1 positive cells and the amount of enterovirus RNA was low. The results provides evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, being consistent with the possibility that a low grade enteroviral infection in the pancreatic islets contribute to disease progression in humans.

    Nationell ämneskategori
    Endokrinologi och diabetes Mikrobiologi
    Identifikatorer
    urn:nbn:se:uu:diva-239513 (URN)10.2337/db14-1370 (DOI)000353431200023 ()25422108 (PubMedID)
    Tillgänglig från: 2014-12-29 Skapad: 2014-12-29 Senast uppdaterad: 2017-12-05
    2. Infection of Human Islets of Langerhans With Two Strains of Coxsackie B Virus Serotype 1: Assessment of Virus Replication, Degree of Cell Death and Induction of Genes Involved in the Innate Immunity Pathway
    Öppna denna publikation i ny flik eller fönster >>Infection of Human Islets of Langerhans With Two Strains of Coxsackie B Virus Serotype 1: Assessment of Virus Replication, Degree of Cell Death and Induction of Genes Involved in the Innate Immunity Pathway
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    2014 (Engelska)Ingår i: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, nr 8, s. 1402-1411Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1. Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFN beta, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFN beta, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential beta-cell tropism of the virus.

    Nyckelord
    enterovirus, type 1 diabetes, innate immunity, human pancreatic islets, RNA sensors
    Nationell ämneskategori
    Infektionsmedicin Mikrobiologi
    Identifikatorer
    urn:nbn:se:uu:diva-231113 (URN)10.1002/jmv.23835 (DOI)000339486200015 ()24249667 (PubMedID)
    Tillgänglig från: 2014-09-05 Skapad: 2014-09-04 Senast uppdaterad: 2017-12-05
    3. Expression of Innate Immunity Genes and Damage of Primary Human Pancreatic Islets by Epidemic Strains of Echovirus: Implication for Post-Virus Islet Autoimmunity
    Öppna denna publikation i ny flik eller fönster >>Expression of Innate Immunity Genes and Damage of Primary Human Pancreatic Islets by Epidemic Strains of Echovirus: Implication for Post-Virus Islet Autoimmunity
    Visa övriga...
    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 11, s. e77850-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Three large-scale Echovirus (E) epidemics (E4, E16, E30), each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7) were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS) were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05); however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively). In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-212334 (URN)10.1371/journal.pone.0077850 (DOI)000326499300010 ()
    Tillgänglig från: 2013-12-10 Skapad: 2013-12-09 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    4. Field strains of Echovirus 6 infect human endocrine and exocrine pancreatic cells and induce pro-inflammatory innate immune responses.
    Öppna denna publikation i ny flik eller fönster >>Field strains of Echovirus 6 infect human endocrine and exocrine pancreatic cells and induce pro-inflammatory innate immune responses.
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    (Engelska)Artikel i tidskrift (Refereegranskat) In press
    Abstract [en]

    Increasing evidence suggests that type 1 diabetes (T1D) is a combined endocrine-exocrine disease. Human enteroviruses (HEV) have been suggested to induce T1D, but so far evidence on HEV infection in human pancreas has been reported only in islets and ductal cells. Aim of this study was to investigate the capability of HEV strains to infect primary human endocrine and exocrine pancreatic cells and to induce the expression of innate immunity genes in both cell types. Isolated human pancreatic islets and exocrine cells were either mock-infected or inoculated with seven field isolates of Echovirus 6 (E6). Beta-cell tropic strains of E4, E16 and E30 were assayed in primary exocrine cells. Viral infection, replication, virus-induced cytopathic effect (CPE) and expression of innate immunity genes were measured. All the seven strains of E6 replicated in both pancreatic endocrine and exocrine cells with infectious progeny production and appearance of CPE. By contrast, no virus titer increase or CPE were observed in exocrine cells exposed to E4, E16 and E30. Virus particles were found in E6-infected acinar cells, both free in cytoplasm and enclosed in vacuoles. Insulin granules accumulation in proximity to virus particles and beta cells functional impairment were demonstrated in E6-infected islets. Endocrine and exocrine cells responded to E6 infection by upregulating the transcription of genes involved in viral recognition (IF1H1), antiviral defense (OAS1, IFN-β) and inflammation (CXCL10, CCL5). Our results indicate that islets and exocrine pancreatic cells productively support the E6 infection and suggest that HEV-associated T1D may involve both endocrine and exocrine pancreas.

    Nationell ämneskategori
    Klinisk medicin Mikrobiologi
    Identifikatorer
    urn:nbn:se:uu:diva-283276 (URN)
    Tillgänglig från: 2016-04-12 Skapad: 2016-04-12 Senast uppdaterad: 2016-06-01
    5. Gene expression analysis of human islets in a subject at onset of type 1 diabetes
    Öppna denna publikation i ny flik eller fönster >>Gene expression analysis of human islets in a subject at onset of type 1 diabetes
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    2014 (Engelska)Ingår i: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 51, nr 2, s. 199-204Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Swollen islet cells have been repeatedly described at onset of type 1 diabetes, but the underlying mechanism of this observation, termed hydropic degeneration, awaits characterization. In this study, laser capture microdissection was applied to extract the islets from an organ donor that died at onset of type 1 diabetes and from an organ donor without pancreatic disease. Morphologic analysis revealed extensive hydropic degeneration in 73 % of the islets from the donor with type 1 diabetes. Expression levels of genes involved in apoptosis, ER stress, beta cell function, and inflammation were analyzed in isolated and laser-captured islets by qPCR. The chemokine MCP-1 was expressed in islets from the donor with type 1 diabetes while undetectable in the control donor. No other signs of inflammation were detected. There were no signs of apoptosis on the gene expression level, which was also confirmed by negative immunostaining for cleaved caspase-8. There was an increased expression of the transcription factor ATF4, involved in transcription of ER stress genes, in the diabetic islets, but no further signs of ER stress were identified. In summary, on the transcription level, islets at onset of type 1 diabetes in which many beta cells display hydropic degeneration show no obvious signs of apoptosis, ER stress, or inflammation, supporting the notion that these cells are responding normally to high glucose and eventually succumbing to beta cell exhaustion. Also, this study validates the feasibility of performing qPCR analysis of RNA extracted from islets from subjects with recent onset of T1D and healthy controls by laser capture microdissection.

    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-202844 (URN)10.1007/s00592-013-0479-5 (DOI)000334054200004 ()23624551 (PubMedID)
    Tillgänglig från: 2013-06-28 Skapad: 2013-06-28 Senast uppdaterad: 2018-08-30Bibliografiskt granskad
    6. Enterovirus-induced changes in explanted human islet of Langerhans resemble findings in islets of fulminant and conventional type 1 diabetes
    Öppna denna publikation i ny flik eller fönster >>Enterovirus-induced changes in explanted human islet of Langerhans resemble findings in islets of fulminant and conventional type 1 diabetes
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Hypothesis: Fulminant Type 1 diabetes is a unique subtype of T1D, mostly reported in the Japanese population, which is characterized by extensive beta cell death already at onset, often without any insulitis. Enterovirus (EV) infections are associated with the etiology of both fulminant and conventional T1D. However the causative mechanism is not known for any of these diseases. EVs capability to cause lytic vs non-lytic infection in explanted human islets may have implications on the pathogenesis of these two types of T1D.

    Aim: To study the effect of infection of explanted human pancreatic islets with lytic (CBV-1) and non-lytic (CBV-4) Coxsackie B virus strains on cytopathic effect/islet disintegration and to what extent genes involved in viral sensing, antiviral defense and encoding of islet auto-antigens are affected by the viral replication. Also, to compare these findings with the findings reported in fulminant and conventional T1D.

    Methods: Degree of cytopathic effect/islet disintegration was studied and viral replication was measured. Genes involved in viral sensing (NOD2, TLR7 and TLR4), antiviral pathways (OAS2, MX1, PKR, and IRF7), genes coding for known islet auto antigens (GAD65, ZNT8) and the islet hormones, insulin and glucagon, were studied. Mock-infected explanted islet served as controls.

    Results: All CBV strains replicated in the explanted islets but only the CBV-1 strains caused cytopathic effect/islet cell disintegration. Infection with all CBV strains resulted in the induction of genes encoding OAS2 and MX1. In contrast, mRNA expression levels of the gene encoding insulin was reduced. The gene encoding PKR was induced by one of the lytic strains (CBV-1-11) and also by the non-lytic CBV4 strain, while the mRNA expression levels of genes encoding glucagon, NOD2, TLR7, TLR4, MCL1, GAD65 and ZNT8 were not significantly affected.

    Nationell ämneskategori
    Endokrinologi och diabetes Mikrobiologi
    Identifikatorer
    urn:nbn:se:uu:diva-283281 (URN)
    Tillgänglig från: 2016-04-12 Skapad: 2016-04-12 Senast uppdaterad: 2016-06-01
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  • 294.
    Andaloussi, Mounir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Henriksson, Lena M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Wieckowska, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindh, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Björkelid, Christofer
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Larsson, Anna M.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Suresh, Surisetti
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Iyer, Harini
    Srinivasa, Bachally R.
    Bergfors, Terese
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Mowbray, Sherry L.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Jones, T. Alwyn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase2011Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, nr 14, s. 4964-4976Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

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  • 295.
    Andaloussi, Mounir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Moreau, Emmanuel
    Chavignon, Olivier
    Teulade, Jean C.
    A convenient synthesis of linear pyridinoimidazo[1,2-a] pyridine and pyrroloimidazo[1,2-a] pyridine cores2007Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 48, nr 47, s. 8392-8395Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two new imidazo[1,2-a] pyridine derivatives, pyridinoimidazo[1,2-a] pyridine (10) and pyrroloimidazo[1,2-a] pyridine (16), were synthesised from 2-amino-4-methyl-5-nitropyridine (1) by linear cyclisation, making use of dimethylformamide dimethylacetal (DMFDMA) as an agent of vinylamine functionalisation. This report describes first the formation of pyridine and pyrroloimidazopyridine from (1), and then the formation of pyridine-fused and pyrrolo-fused pyridine by the Friedlander method and reductive cyclisation followed by treatment of the resulting adduct with chloroacetaldehyde.

  • 296.
    Anderberg, Eva Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Studies on the dissolution of fine particulate practically insoluble drugs and on the effect of surface active enhancers on gastrointestinal absorption of hydrophilic drugs 1992Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 297.
    Andersen, G N
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hägglund, M
    Nagaeva, O
    Frängsmyr, L
    Petrovska, R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Mincheva-Nilsson, L
    Wikberg, J E S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Quantitative measurement of the levels of melanocortin receptor subtype 1, 2, 3 and 5 and pro-opio-melanocortin peptide gene expression in subsets of human peripheral blood leucocytes2005Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, nr 3, s. 279-284Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Levels of the melanocortin receptor (MCR) 1, 2, 3 and 5 subtypes and pro-opio-melanocortin (POMC) protein mRNA were measured by the real-time quantitative reverse transcriptase polymerase chain reaction method in CD4+ T helper (Th) cells, CD8+ T cytotoxic cells, CD19+ B cells, CD56+ natural killer (NK) cells, CD14+ monocytes and CD15+ granulocytes from healthy donors. We found high levels of all of the MC1, 2, 3 and 5R subtype mRNA in Th cells and moderate levels in NK cells, monocytes and granulocytes. POMC peptide mRNA was found in all examined leucocyte subsets, but only low levels were present in granulocytes. Our findings suggest a co-ordinating role for MCR subtypes and their naturally occurring ligands in the co-operation between innate and adaptive immunity. Moreover, our findings are compatible with earlier finding of MCR-mediated tolerance induction in Th cells.

  • 298.
    Andersen, M.
    et al.
    North Denmark Reg Hosp, Dept Rheumatol, Bispensgade 37, DK-9800 Hjorring, Denmark.;Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark..
    Nagaev, I.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Meyer, M. K.
    Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark.;North Denmark Reg Hosp, Ctr Clin Sci, Hjorring, Denmark..
    Nagaeva, O.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Wikberg, Jarl E. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mincheva-Nilsson, L.
    Umea Univ, Dept Clin Microbiol, Div Clin Immunol, Umea, Sweden..
    Andersen, G. N.
    North Denmark Reg Hosp, Dept Rheumatol, Bispensgade 37, DK-9800 Hjorring, Denmark.;Aalborg Univ, Dept Clin Med, Aalborg, Denmark..
    Melanocortin 2, 3 and 4 Receptor Gene Expressions are Downregulated in CD8(+) T Cytotoxic Lymphocytes and CD19(+) B Lymphocytes in Rheumatoid Arthritis Responding to TNF-alfa Inhibition2017Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 1, s. 31-39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF- inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4(+) T helper (h) lymphocytes (ly), CD8(+) T cytotoxic (c) ly, CD19(+) B ly and CD14(+) monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8(+) Tc and CD19(+) B ly was significant. Fold change in MC1-5R and IFN gene expressions correlated significantly in CD8(+) Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1 gene expressions correlated significantly in CD4(+) Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8(+) Tc ly and CD19(+) B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8(+) Tc ly and CD4(+) Th ly point at a central immune modulating function of the melanocortin system in RA.

  • 299.
    Andersen, Maria Goul
    et al.
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark.
    Thorsted, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Storgaard, Merete
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark.
    Kristoffersson, Anders N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Friberg, Lena E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Öbrink-Hansen, Kristina
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark.
    Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?2018Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, nr 5, artikel-id e02306Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% fTMIC) and 0.125 mg/liter (100% fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

  • 300.
    Andersen, Søren S. L.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Real time large scale in vivo observations reveal intrinsic synchrony, plasticity and growth cone dynamics of midline crossing axons at the ventral floor plate of the zebrafish spinal cord2019Ingår i: Journal of Integrative Neuroscience, ISSN 0219-6352, E-ISSN 1757-448X, Vol. 18, nr 4, s. 351-368Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    How axons are wiring the vertebrate spinal cord has in particular been studied at the ventral floor plate using fixed samples or looking at single growing axons with various microscopy techniques. Thereby may remain hidden important live organismal scale information concerning dynamics and concurrent timing of the many axons simultaneously crossing the floor plate. Here then, applying light-sheet microscopy, axonal growth and guidance at the floor plate are followed in vivo in real time at high resolution along several hundred micrometers of the zebrafish spinal cord by using an interneuron expressing GFP as a model axon. The commissural axons are observed crossing the ventral floor plate midline perpendicularly at about 20 microns/h and in a manner dependent on the Robo3 receptor. Commissural growth rate reaches a minimum at the midline, confirming previous observations. Ipsilateral axons extend concurrently, at three to six times higher growth rates. At guidance points, commissural axons are seen to decrease their growth rate and growth cones increase in size. Commissural filopodia appear to interact with the nascent neural network, and thereby trigger immediate plastic and reversible sinusoidal-shaped bending movements of neighboring commissural shafts. A simple protocol isolating single neuronal cells from the spinal cord is developed to facilitate further molecular characterization. The recordings show the strikingly stereotyped spatio-temporal control that governs midline crossing. The live observations give renewed perspective on the mechanisms of axonal guidance in the spinal cord that provide for a discussion of the current distinction between diffusible long-range versus substrate-bound short-range guidance cues.

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