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  • 651.
    Xiao, Pingnan
    et al.
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Sandhow, Lakshmi
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Heshmati, Yaser
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Kondo, Makoto
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Bouderlique, Thibault
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Dolinska, Monika
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Johansson, Anne-Sofie
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Division of Molecular Hematology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Ekblom, Marja
    Division of Molecular Hematology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Walfridsson, Julian
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Qian, Hong
    Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice2018In: Blood advances, ISSN 2473-9529, Vol. 2, no 12, p. 1480-1494Article in journal (Refereed)
    Abstract [en]

    Despite increasing evidence for the involvement of bone marrow (BM) hematopoietic stem cell niche in leukemogenesis, how BM mesenchymal stem and progenitor cells (MSPCs) contribute to leukemia niche formation and progression remains unclear. Using an MLL-AF9 acute myeloid leukemia (AML) mouse model, we demonstrate dynamic alterations of BM cellular niche components, including MSPCs and endothelial cells during AML development and its association with AML engraftment. Primary patient AML cells also induced similar niche alterations in xenografted mice. AML cell infiltration in BM causes an expansion of early B-cell factor 2+ (Ebf2+) MSPCs with reduced Cxcl12 expression and enhanced generation of more differentiated mesenchymal progenitor cells. Importantly, in vivo fate-mapping indicates that Ebf2+ MSPCs participated in AML niche formation. Ebf2+ cell deletion accelerated the AML development. These data suggest that native BM MSPCs may suppress AML. However, they can be remodeled by AML cells to form leukemic niche that might contribute to AML progression. AML induced dysregulation of hematopoietic niche factors like Angptl1, Cxcl12, Kitl, Il6, Nov, and Spp1 in AML BM MSPCs, which was associated with AML engraftment and partially appeared before the massive expansion of AML cells, indicating the possible involvement of the niche factors in AML progression. Our study demonstrates distinct dynamic features and roles of BM MSPCs during AML development.

  • 652.
    Xu, Wei
    et al.
    University of Chicago, IL USA .
    Carr, Tiffany
    University of Chicago, IL USA .
    Ramirez, Kevin
    University of Chicago, IL USA .
    McGregor, Stephanie
    University of Chicago, IL USA .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Kee, Barbara L.
    University of Chicago, IL USA .
    E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 9, p. 1534-1542Article in journal (Refereed)
    Abstract [en]

    The E2A transcription factors promote the development of thymus-seeding cells, but it remains unknown whether these proteins play a role in T lymphocyte lineage specification or commitment. Here, we showed that E2A proteins were required to promote T-lymphocyte commitment from DN2 thymocytes and to extinguish their potential for alternative fates. E2A proteins functioned in DN2 cells to limit expression of Gata3, which encodes an essential T-lymphocyte transcription factor whose ectopic expression can arrest T-cell differentiation. Genetic, or small interfering RNA-mediated, reduction of Gata3 rescued T-cell differentiation in the absence of E2A and restricted the development of alternative lineages by limiting the expanded self-renewal potential in E2A(-/-) DN2 cells. Our data support a novel paradigm in lymphocyte lineage commitment in which the E2A proteins are necessary to limit the expression of an essential lineage specification and commitment factor to restrain self-renewal and to prevent an arrest in differentiation.

  • 653. Order onlineBuy this publication >>
    Yaghmaeian Salmani, Behzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Genetic Mechanisms Regulating the Spatiotemporal Modulation of Proliferation Rate and Mode in Neural Progenitors and Daughter Cells during Embryonic CNS Development2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central nervous system (CNS) is a hallmark feature of animals with a bilateral symmetry: bilateria and can be sub-divided into the brain and nerve cord. One of the prominent properties of the CNS across bilateria is the discernible expansion of its anterior part (brain) compared with the posterior one (nerve cord). This evolutionarily conserved feature could be attributed to four major developmental agencies: First, the existence of more anterior progenitors. Second, anterior progenitors are more proliferative. Third, anterior daughter cells, generated by the progenitors, are more proliferative. Forth, fewer cells are removed by programmed cell death (PCD) anteriorly. My thesis has addressed these issues, and uncovered both biological principles and genetic regulatory networks that promote these A-P differences. I have used the Drosophila and mouse embryonic CNSs as model systems. Regarding the 1st issue, while the brain indeed contains more progenitors, my studies demonstrate that this only partly explains the anterior expansion. Indeed, with regard to the 2nd issue, my studies, on both the Drosophila and mouse CNS, demonstrate that anterior progenitors divide more extensively. Concerning the 3rd issue, in Drosophila we identified a gradient of daughter proliferation along the AP axis of the developing CNS with brain daughter cells being more proliferative. Specifically, in the brain, progenitors divide to generate a series of daughter cells that divide once (Type I), to generate two neurons or glia. In contrast, in the nerve cord, progenitors switch during later stages, from first generating dividing daughters to subsequently generating daughters that directly differentiate (Type 0). Hence, nerve cord progenitors undergo a programmed Type I->0 proliferation switch. In the Drosophila posterior CNS, this switch occurs earlier and is more prevalent, contributing to the generation of smaller lineages in the posterior regions. Similar to Drosophila, in the mouse brain we also found that progenitor and daughter cell proliferation was elevated and extended into later developmental stages, when compared to the spinal cord. DNA-labeling experiments revealed faster cycling cells in the brain when compared to the nerve cord, in both Drosophila and mouse. In both Drosophila and mouse, we found that the suppression of progenitor and daughter proliferation in the nerve cord is controlled by the Hox homeotic gene family. Hence, the absence of Hox gene expression in the brain provides a logical explanation for the extended progenitor proliferation and lack of Type I->0 switch. The repression of Hox genes in the brain is mediated by the histonemodifying Polycomb Group complex (PcG), which thereby is responsible for the anterior expansion. With respect to the 4th issue, we found no effect of PCD on anterior expansion in Drosophila, while this cannot be asserted for the mouse embryonic neurodevelopment as there are no genetic tools to abolish PCD effectively in mammals. Taken together, the studies presented in this thesis identified global and evolutionarily-conserved genetic programs that promote anterior CNS expansion, and pave the way for understanding the evolution of size along the anterior-posterior CNS axis.

    List of papers
    1. Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
    Open this publication in new window or tab >>Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
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    2014 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 30, no 2, p. 192-208Article in journal (Refereed) Published
    Abstract [en]

    During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential. Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood. We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0). This typelgreater than0 switch is triggered by activation of Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)) expression in neuroblasts. In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia. In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f. This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS.

    Place, publisher, year, edition, pages
    Elsevier (Cell Press), 2014
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-109588 (URN)10.1016/j.devcel.2014.06.021 (DOI)000339641500012 ()25073156 (PubMedID)
    Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2019-03-13
    2. Anterior-Posterior Gradient in Neural Stem and Daughter Cell Proliferation Governed by Spatial and Temporal Hox Control
    Open this publication in new window or tab >>Anterior-Posterior Gradient in Neural Stem and Daughter Cell Proliferation Governed by Spatial and Temporal Hox Control
    2017 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 27, no 8, p. 1161-1172Article in journal (Refereed) Published
    Abstract [en]

    A readily evident feature of animal central nervous systems (CNSs), apparent in all vertebrates and many invertebrates alike, is its "wedge-like appearance, with more cells generated in anterior than posterior regions. This wedge could conceivably be established by an antero-posterior (A-P) gradient in the number of neural progenitor cells, their proliferation behaviors, and/or programmed cell death (PCD). However, the contribution of each of these mechanisms, and the underlying genetic programs, are not well understood. Building upon recent progress in the Drosophila melanogaster (Drosophila) ventral nerve cord (VNC), we address these issues in a comprehensive manner. We find that, although PCD plays a role in controlling cell numbers along the A-P axis, the main driver of the wedge is a gradient of daughter proliferation, with divisions directly generating neurons (type 0) being more prevalent posteriorly and dividing daughters (type I) more prevalent anteriorly. In addition, neural progenitor (NB) cell-cycle exit occurs earlier posteriorly. The gradient of type I amp;gt; 0 daughter proliferation switch and NB exit combine to generate radically different average lineage sizes along the A-P axis, differing by more than 3-fold in cell number. We find that the Hox homeotic genes, expressed in overlapping A-P gradients and with a late temporal onset in NBs, trigger the type I amp;gt; 0 daughter proliferation switch and NB exit. Given the highly evolutionarily conserved expression of overlapping Hox homeotic genes in the CNS, our results point to a common mechanism for generating the CNS wedge.

    Place, publisher, year, edition, pages
    CELL PRESS, 2017
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-137604 (URN)10.1016/j.cub.2017.03.023 (DOI)000399986500023 ()28392108 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [621-2013-5258]; Knut and Alice Wallenberg Foundation [KAW2011.0165, KAW2012.0101]; Swedish Cancer Foundation [150663]

    Available from: 2017-05-22 Created: 2017-05-22 Last updated: 2018-05-09
    3. Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program
    Open this publication in new window or tab >>Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program
    Show others...
    2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev160747Article in journal (Refereed) Published
    Abstract [en]

    A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions.

    Place, publisher, year, edition, pages
    Cambridge, United Kingdom: The Company of Biologists Ltd., 2018
    Keywords
    Asymmetric division, Cell cycle, Combinatorial control, Evolution of the CNS, Lineage size, Nervous system development
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-147741 (URN)10.1242/dev.160747 (DOI)000438944000010 ()29530878 (PubMedID)2-s2.0-85045513794 (Scopus ID)
    Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-12-10Bibliographically approved
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    Genetic Mechanisms Regulating the Spatiotemporal Modulation of Proliferation Rate and Mode in Neural Progenitors and Daughter Cells during Embryonic CNS Development
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  • 654.
    Yaghmaeian Salmani, Behzad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Monedero Cobeta, Ignacio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bauer, Susanne
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rodriguez Curt, Jesús
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev160747Article in journal (Refereed)
    Abstract [en]

    A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions.

    Download full text (pdf)
    fulltext
  • 655.
    Ydreborg, Magdalena
    et al.
    University of Gothenburg.
    Westin, Johan
    University of Gothenburg.
    Rembeck, Karolina
    University of Gothenburg.
    Lindh, Magnus
    University of Gothenburg.
    Norgren, Hans
    University Hospital Lund .
    Holmberg, Anna
    University Hospital Lund .
    Wejstål, Rune
    University of Gothenburg.
    Norkrans, Gunnar
    University of Gothenburg.
    Cardell, Kristina
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Weiland, Ola
    KI, Karolinska University Hospital.
    Lagging, Martin
    University of Gothenburg .
    Impact of IL28B-Related Single Nucleotide Polymorphisms on Liver Transient Elastography in Chronic Hepatitis C Infection2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e80172-Article in journal (Refereed)
    Abstract [en]

    Background and Aims

    Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of hepatitis C virus (HCV) infection as well as outcome following pegylated interferon and ribavirin therapy among genotype 1 infected patients. Additionally the presence of the otherwise favorable IL28B genetic variants in the context of HCV genotype 3 infection reportedly entail more pronounced liver fibrosis and steatosis. The present study aimed to evaluate the impact of IL28B SNP variability on liver stiffness as accessed by transient elastography.

    Methods

    Seven hundred and seventy-one Swedish HCV infected patients sequentially undergoing liver stiffness measurement by means of Fibroscan® in the context of a real-life trial had samples available for IL28B genotyping (rs12979860) and HCV genotyping.

    Results

    CCrs12979860 was more common among HCV genotype 2 or 3 infected treatment-naïve patients than among those infected with genotype 1 (P<0.0001). Additionally CCrs12979860 among HCV genotype 3 infected patients was associated with higher liver stiffness values (P = 0.004), and higher AST to platelet ratio index (APRI; p = 0.02) as compared to carriers of the T allele. Among HCV genotype 1 infected patients, CCrs12979860 was significantly associated with higher viral load (P = 0.001), with a similar non-significant trend noted among HCV genotype 3 infected patients.

    Conclusion

    This study confirms previous reports that the CCrs12979860 SNP is associated with more pronounced liver pathology in patients chronically infected with HCV genotype 3 as compared to genotype 1, suggesting that IL28B genetic variants differently regulates the course of HCV infection across HCV genotypes.

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  • 656.
    Yien Tan, Hong
    et al.
    University of Malaya, Malaysia.
    Kong Yong, Yean
    University of Malaya, Malaysia.
    Shankar, Esaki M.
    University of Malaya, Malaysia; University of Malaya, Malaysia.
    Paukovics, Geza
    Macfarlane Burnet Institute Medical Research and Public Heatlh, Australia.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kamarulzaman, Adeeba
    University of Malaya, Malaysia.
    French, Martyn A.
    University of Western Australia, Australia; Royal Perth Hospital, Australia.
    Crowe, Suzanne M.
    Macfarlane Burnet Institute Medical Research and Public Heatlh, Australia; Alfred Hospital, Australia; Monash University, Australia.
    Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 10, p. 4052-4063Article in journal (Refereed)
    Abstract [en]

    Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1 beta, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18R alpha on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

  • 657.
    Yong, Yean K.
    et al.
    Xiamen Univ Malaysia, Malaysia; Univ Malaya, Malaysia; Xiamen Univ Malaysia, Malaysia.
    Saeidi, Alireza
    Univ Malaya, Malaysia.
    Tan, Hong Y.
    Xiamen Univ Malaysia, Malaysia; Univ Malaya, Malaysia; Xiamen Univ Malaysia, Malaysia; Xiamen Univ Malaysia, Malaysia.
    Rosmawati, Mohamed
    Univ Malaya, Malaysia.
    Enström, Philip F.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Al Batran, Rami
    Univ Malaya, Malaysia.
    Vasuki, V.
    Govt Thiruvarur Med Coll and Hosp, India.
    Chattopadhyay, Indranil
    Cent Univ Tamil Nadu, India.
    Murugesan, Amudhan
    Govt Theni Med Coll and Hosp, India.
    Vignesh, Ramachandran
    Univ Kuala Lumpur, Malaysia.
    Kamarulzaman, Adeeba
    Univ Malaya, Malaysia; Univ Malaya, Malaysia.
    Rajarajeswaran, Jayakumar
    Univ Malaya, Malaysia.
    Ansari, Abdul W.
    Univ Malaya, Malaysia.
    Vadivelu, Jamuna
    Univ Malaya, Malaysia.
    Ussher, James E.
    Univ Otago, New Zealand.
    Velu, Vijayakumar
    Emory Vaccine Ctr, GA USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    Univ Malaya, Malaysia; Cent Univ Tamil Nadu, India; Cent Univ Tamil Nadu, India.
    Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161(++)TCR iV alpha 7.2(+) Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 472Article in journal (Refereed)
    Abstract [en]

    Mucosal-associated invariant T (MAIT) cells, defined as CD161(++) TCR iV alpha 7.2(+) T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3(+)CD161(++)TCR iV alpha 7.2(+) MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVa7.2+ CD161(+) MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4(+) T cells and MAIT cells and with CD57 on CD8(+) T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iV alpha 7.2(+) MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.

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  • 658.
    Yong, Yean K.
    et al.
    University of Malaya, Malaysia.
    Tan, Hong Y.
    University of Malaya, Malaysia.
    Saeidi, Alireza
    University of Malaya, Malaysia.
    Rosmawati, Mohamed
    University of Malaya, Malaysia.
    Atiya, Nadia
    University of Malaya, Malaysia.
    Ansari, Abdul W.
    University of Malaya, Malaysia.
    Rajarajeswaran, Jayakumar
    University of Malaya, Malaysia.
    Vadivelu, Jamuna
    University of Malaya, Malaysia.
    Velu, Vijayakumar
    Emory Vaccine Centre, GA USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia; CUTN, India.
    Decrease of CD69 levels on TCR V7.2(+)CD4(+) innate-like lymphocytes is associated with impaired cytotoxic functions in chronic hepatitis B virus-infected patients2017In: Innate Immunity, ISSN 1753-4259, E-ISSN 1753-4267, Vol. 23, no 5, p. 459-467Article in journal (Refereed)
    Abstract [en]

    Hepatitis B virus (HBV) infection is a major cause of chronic liver disease that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses represent the key determinants of HBV clearance or persistence. Here, we investigated the role of the early activation marker, CD69 and effector cytokines, granzyme B (GrB) and IFN- in the exhaustion of innate-like TCR V7.2(+)CD4(+)T cells, in 15 individuals with chronic HBV (CHB) infection where six were HBV DNA(+) and nine were HBV DNA(-). The percentage of cytokine-producing T cells and MAIT cells were significantly perturbed in HBV patients relative to healthy controls (HCs). The intracellular expression of GrB and IFN- was significantly reduced in MAIT cells derived from HBV-infected patients as compared to HCs, and the levels correlated with the percentage and levels [mean fluorescence intensity (MFI)] of CD69 expression. The total expression of CD69 (iMFI) was lower in CHB patients as compared to HCs. The frequency of CD69(+) cells correlated with the levels of cytokine expression (MFI), particularly in CHB patients as compared to HCs. In summary, the polyfunctionality of peripheral T cells was significantly reduced among CHB patients, especially in the TCR V7.2(+)CD4(+)T cells, and the levels of cytokine expression correlated with functional cytokine levels.

  • 659.
    Yoshitake, Shimako
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Kuteeva, Eugenia
    Karolinska Institute, Stockholm, Sweden and Atlas Antibodies AB, AlbaNova University Center, Stockholm, Sweden.
    Hokfelt, Tomas
    Karolinska Institute, Stockholm, Sweden .
    Mennicken, Francoise
    AstraZeneca R&D Montréal, Quebec, Canada.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Yamaguchi, Masatoshi
    Fukuoka University, Japan .
    Kehr, Jan
    Karolinska Institute, Stockholm, Sweden and Pronexus Analytical AB, Bromma, Sweden .
    Yoshitake, Takashi
    Karolinska Institute, Stockholm, Sweden and Kagoshima University, Japan .
    Correlation between the effects of local and intracerebroventricular infusions of galanin on 5-HT release studied by microdialysis, and distribution of galanin and galanin receptors in prefrontal cortex, ventral hippocampus, amygdala, hypothalamus, and striatum of awake rats2014In: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 68, no 5, p. 179-193Article in journal (Refereed)
    Abstract [en]

    The neuropeptide galanin is implicated in regulation of affective behavior, including modulation of 5-HT signaling. Here, we investigated, by use of microdialysis in freely moving rats, the effects of intracerebral (i.c.) and intracerebroventricular (i.c.v.) infusions of galanin on basal extracellular 5-HT levels in medial prefrontal cortex (mPFC), CA1 area of ventral hippocampus (vHPC), central amygdaloid nucleus (CeA), ventromedial hypothalamic nucleus ventrolateral part (VMHvl), and ventromedial caudate putamen (CPu). These results were compared with a parallel immunohistochemical analysis of the distribution of galanin, 5-HT, and noradrenaline (NA) nerve terminals, and with data on galanin receptors. Galanin i.c.v. significantly decreased the 5-HT levels in mPFC to 79% and in vHPC to 72%. Local infusions of galanin caused a long-lasting decrease in 5-HT levels in vHPC to 88%, and a moderate decrease in CeA, whereas the 5-HT levels in mPFC significantly increased to 121%. These effects of i.c. galanin correlated well with the density of 5-HT and galanin nerve terminals and galanin receptors autoradiography in mPFC, vHPC, and CeA. No effects of i.c. or i.c.v. galanin on 5-HT levels were observed in CPu or VMHvl, in agreement with the low numbers of galanin-positive terminals and low/moderate galanin receptor density. Galanin was often found to coexist in NA, but could never be detected in 5-HT terminals. Together the results show a neuroanatomical correlation between the effects of galanin infusions on 5-HT release and distribution of galanin and its receptors, and that i.c.v. and i.c. administration can give opposite effects on 5-HT release.

  • 660.
    Younis, Shady
    et al.
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden // Department of Animal Production, Ain Shams University, Shoubra El-Kheima, 11241 Cairo, Egypt.
    Kamel, Wael
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Wang, Hao
    Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
    Yu, Di
    Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Daniels, Robert
    Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
    Essand, Magnus
    Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
    Akusjärvi, Göran
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
    Andersson, Leif
    Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden // Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden // Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77483, USA.
    Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 6, p. E3808-E3816Article in journal (Refereed)
    Abstract [en]

    The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A–cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

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  • 661.
    Yu, Xia
    et al.
    Capital Medical University, Peoples R China.
    Wang, Guirong
    Capital Medical University, Peoples R China.
    Chen, Suting
    Capital Medical University, Peoples R China.
    Wei, Guomei
    Capital Medical University, Peoples R China.
    Shang, Yuanyuan
    Capital Medical University, Peoples R China.
    Dong, Lingling
    Capital Medical University, Peoples R China.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Institute, England.
    Parkhill, Julian
    Wellcome Trust Sanger Institute, England.
    Peacock, Sharon J.
    Wellcome Trust Sanger Institute, England; University of Cambridge, England; London School Hyg and Trop Med, England.
    Koser, Claudio U.
    University of Cambridge, England.
    Huang, Hairong
    Capital Medical University, Peoples R China.
    Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin2016In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 60, no 9, p. 5232-5237Article in journal (Refereed)
    Abstract [en]

    Antofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its in vitro activity. We determined the wild-type and non-wild-type MIC ranges for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX), using the microplate alamarBlue assay, of 126 clinical Mycobacterium tuberculosis strains from Beijing, China, of which 48 were OFX resistant on the basis of drug susceptibility testing on Lowenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance-determining regions of gyrA (Rv0006) and gyrB (Rv0005). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX but higher MIC levels than LFX and MFX on the basis of the tentative epidemiological cutoff values (ECOFFs) determined in this study. All strains with non-wild-type MICs for AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration of OFX for Lowenstein-Jensen medium that was recently revised by the World Health Organization might be too high, resulting in the misclassification of phenotypically non-wildtype strains with known resistance mutations as wild type. On the basis of our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.

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  • 662.
    Zdolsek, Joachim
    et al.
    Linköping University, Department of Medical and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Vrinnevi Hospital, Sweden.
    Bergek, Christian
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hahn, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Sodertalje Hospital, Sweden.
    Colloid osmotic pressure and extravasation of plasma proteins following infusion of Ringers acetate and hydroxyethyl starch 130/0.42015In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, no 10, p. 1303-1310Article in journal (Refereed)
    Abstract [en]

    BackgroundDuring fluid infusion therapy, plasma proteins are diluted and leak from the intravascular space, which alters the colloid osmotic pressure (COP) and potentially affects coagulation. We hypothesised that acetated Ringers and starch solution, alone or in combination, influence these mechanisms differently. Materials and methodsOn different occasions, 10 male volunteers were infused with 20ml/kg acetated Ringers and 10ml/kg 6% hyroxyethyl starch 130/0.4 (Voluven((R))) alone or in combination (first with starch solution followed by Ringers solution). Blood samples were collected every 30-min for measurements of COP, blood haemoglobin, platelets, and plasma concentrations of albumin, immunoglobulins (IgG and IgM), coagulation factor VII (FVII), fibrinogen, cystatin C, activated partial thromboplastin time (APTT) and prothrombin international normalised ratio (PT-INR). Changes were compared with the haemoglobin-derived plasma dilution. ResultsThe COP increased by 8.4% (SD 3) with starch and decreased by 26.2% (7.9) with Ringers. These infusions diluted the plasma by 23.4% (5.3) and 18.7% (4.9) respectively. The COP changes in the combined experiment followed the same pattern as the individual infusions. Albumin and IgG changes in excess of the plasma dilution were very subtle. The intravascular contents of the IgM and platelets decreased, whereas FVII, fibrinogen and cystatin C increased. PT-INR increased by 1/3 of the plasma dilution, whereas changes in APTT did not correlate with the plasma dilution. ConclusionsThe starch increased COP and only minor capillary leak occurred in healthy volunteers. The fluid-induced plasma dilution correlated with mild impairment of the extrinsic coagulation pathway but not of the intrinsic pathway.

  • 663.
    Zimmerli, Dario
    et al.
    Univ Zurich, Switzerland.
    Cecconi, Virginia
    Univ Zurich, Switzerland.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Restivo, Gaetana
    Univ Hosp Zurich, Switzerland.
    Hafner, Jurg
    Univ Hosp Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    van den Broek, Maries
    Univ Zurich, Switzerland.
    WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma2018In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 27, p. 3753-3762Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/beta-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

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  • 664.
    Zook, Erin C.
    et al.
    University of Chicago, IL 60637 USA.
    Ramirez, Kevin
    University of Chicago, IL 60637 USA.
    Guo, Xiaohuan
    University of Chicago, IL 60637 USA.
    van der Voort, Grant
    University of Chicago, IL 60637 USA.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Svensson, Eric C.
    University of Chicago, IL 60637 USA.
    Fu, Yang-Xin
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    Kee, Barbara L.
    University of Chicago, IL 60637 USA; University of Chicago, IL 60637 USA.
    The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC22016In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 213, no 5, p. 687-696Article in journal (Refereed)
    Abstract [en]

    Group 2 innate lymphoid cells ( ILC2s) are a subset of ILCs that play a protective role in the response to helminth infection, but they also contribute to allergic lung inflammation. Here, we report that the deletion of the ETS1 transcription factor in lymphoid cells resulted in a loss of ILC2s in the bone marrow and lymph nodes and that ETS1 promotes the fitness of the common progenitor of all ILCs. ETS1-deficient ILC2 progenitors failed to up-regulate messenger RNA for the E protein transcription factor inhibitor ID2, a critical factor for ILCs, and these cells were unable to expand in cytokine-driven in vitro cultures. In vivo, ETS1 was required for the IL-33-induced accumulation of lung ILC2s and for the production of the T helper type 2 cytokines IL-5 and IL-13. IL-25 also failed to elicit an expansion of inflammatory ILC2s when these cells lacked ETS1. Our data reveal ETS1 as a critical regulator of ILC2 expansion and cytokine production and implicate ETS1 in the regulation of Id2 at the inception of ILC2 development.

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  • 665.
    Zsigmond, Peter
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Nord, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Kullman, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Diczfalusy, Elin
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Dizdar (Dizdar Segrell), Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease2014In: Neurology and Clinical Neuroscience, ISSN 2049-4173, Vol. 2, no 5, p. 149-155Article in journal (Refereed)
    Abstract [en]

    Background The mechanism by which deep brain stimulation of the nucleus subthalamicus improves Parkinson’s disease symptoms remains unclear. In a previous perioperative study, we showed that there might be alterations of neurotransmitter levels in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus. Aim In this study, we examined whether deep brain stimulation of the nucleus subthalamicus and levodopa infusion interact and affect the levels of neurotransmitters. Methods Five patients with advanced Parkinson’s disease took part in the study. During subthalamic nucleus surgery, microdialysis catheters were inserted bilaterally in the globus pallidum interna and unilaterally in the right putamen. A study protocol was set up and was followed for 3 days. Levodopa infusion with and without concomitant bilateral deep brain stimulation of the nucleus subthalamicus was also carried out. Results The putaminal dopamine levels increased during deep brain stimulation of the nucleus subthalamicus. In addition, an increase of gamma amino buturic acid concentrations in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus and during levodopa infusion was found. Conclusions These findings provide evidence that the subthalamic nucleus has a direct action on the substantia nigra pars compacta, and that deep brain stimulation of the nucleus subthalamicus might indirectly release putaminal dopamine. There is also evidence that deep brain stimulation of the nucleus subthalamicus interferes with levodopa therapy resulting in higher levels of levodopa in the brain, explaining why it is possible to decrease levodopa medication after deep brain stimulation surgery.

  • 666. Order onlineBuy this publication >>
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Molecular mechanisms in lymphoid restriction: securing the B lineage fate2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    With the work in this thesis I have aimed to deepen the understanding of the mechanisms behind the development of different blood cell lineages with a specific focus on B cell development.

    To understand the interplay between extracellular signaling and transcription factor networks in early lymphoid development we investigated the functional collaborations of FLT3 and IL7R. We found that signaling via FLT3 and IL7R act in powerful synergy on proliferation of common lymphoid progenitors (CLPs). In addition to a role in expansion of progenitor cells we provided evidence for that IL7R signaling play a crucial role in B-cell commitment. IL7 deficient mice display a dramatic block in development before functional lineage restriction in the Ly6D+ CLP-compartment. The few Ly6D+CLPs that do develop have reduced mRNA levels of transcription factor EBF1, a protein with crucial functions in lineage restriction and activation of the B-lymphoid program. One crucial function of EBF1 is to activate Pax5. Even though Pax5 deficient fetal liver cells upon transplantation to congenic hosts will generate an abundance of cells with an activated B-lineage transcriptional program, the pro-B cells have disrupted regulation of non-B-lineage transcripts and a propensity to develop into T- and NK-cells in vitro. Both the activation of the B-lineage program and lineage restriction was dependent on the dose of transcription factors. Mice carrying a heterozygous mutation for the transcription factor E2A had slightly reduced relative frequency of progenitor cells and an impaired B-lineage specification in CLPs. Loss of one allele of Ebf1 resulted in reduced surface expression of IL2Rα and pre-B cell receptor (BCR), reduced IL7-response in vitro, and disrupted cell cycle dynamics in pro- and pre-B cells. While heterozygous loss of Pax5 did not result in any dramatic phenotype,  the combined loss of one allele of Pax5 and one allele of Ebf1 (Pax5+/-Ebf1+/-) had a dramatic effect on lineage plasticity in B-cell progenitors compared to the single heterozygotes. Furthermore, these Pax5+/-Ebf1+/- mice developed spontaneous, transplantable pro-B cell tumors and had a significantly reduced probability to survive over time. The transformed cells show high in vitro plasticity and tumor cells with induced overexpression of intracellular Notch1 can transform into T-lineage cell in vivo.

    The data presented in this thesis add important pieces of information to the field of developmental hematopoiesis. By increasing the analytical depth of development in normal circumstances, and by understanding the consequence of genetic mutations in relation to cell type, we hope to contribute to the understanding of hematopoietic development in health and disease.

    List of papers
    1. Interleukin-7-induced Stat-5 Acts in Synergy with Flt-3 Signaling to Stimulate Expansion of Hematopoietic Progenitor Cells
    Open this publication in new window or tab >>Interleukin-7-induced Stat-5 Acts in Synergy with Flt-3 Signaling to Stimulate Expansion of Hematopoietic Progenitor Cells
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    2010 (English)In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 285, no 47, p. 36275-36284Article in journal (Refereed) Published
    Abstract [en]

    The development of lymphoid cells from bone marrow progenitors is dictated by interplay between internal cues such as transcription factors and external signals like the cytokines Flt-3 ligand and Il-7. These proteins are both of large importance for normal lymphoid development; however, it is unclear if they act in direct synergy to expand a transient Il-7R(+)Flt-3(+) population or if the collaboration is created through sequential activities. We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R(+)Flt-3(+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors. The stimulation resulted in a reduced expression of pro-apoptotic genes and also mediated survival of primary progenitor cells in vitro. However, functional analysis of single cells suggested that the anti-apoptotic effect was additive indicating that the synergy observed mainly depends on stimulation of proliferation. Analysis of downstream signaling events suggested that although Il-7 induced Stat-5 phosphorylation, Flt-3L caused activation of the ERK and AKT signaling pathways. Flt-3L could also drive proliferation in synergy with ectopically expressed constitutively active Stat-5. This synergy could be inhibited with either receptor tyrosine kinase or MAPK inhibitors suggesting that Flt-3L and Il-7 act in synergy by activation of independent signaling pathways to expand early hematopoietic progenitors.

    Place, publisher, year, edition, pages
    The American Society for Biochemistry and Molecular Biology, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-62734 (URN)10.1074/jbc.M110.155531 (DOI)000284146100037 ()20829349 (PubMedID)
    Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2015-02-16
    2. IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
    Open this publication in new window or tab >>IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
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    2011 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 5, p. 1283-1290Article in journal (Refereed) Published
    Abstract [en]

    eficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D(-) multipotent CLPs, the formation of the lineage restricted LY6D(+) CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D(+) CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D(+) cells develop in Ebf-1-deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D(+) CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-70104 (URN)10.1182/blood-2011-01-332189 (DOI)000293510000020 ()
    Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08
    3. Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo
    Open this publication in new window or tab >>Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo
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    2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 39, p. 15871-15876Article in journal (Refereed) Published
    Abstract [en]

    To better understand the process of B-lymphocyte lineage restriction, we have investigated molecular and functional properties in early B-lineage cells from Pax-5-deficient animals crossed to a B-lineage-restricted reporter mouse, allowing us to identify B-lineage-specified progenitors independently of conventional surface markers. Pax-5 deficiency resulted in a dramatic increase in the frequency of specified progenitor B-cellsmarked by expression of a lambda 5 (Igll1) promoter-controlled reporter gene. Gene expression analysis of ex vivo isolated progenitor cells revealed that Pax-5 deficiency has a minor impact on B-cell specification. However, single-cell in vitro differentiation analysis of ex vivo isolated cells revealed that specified B-lineage progenitors still displayed a high degree of plasticity for development into NK or T lineage cells. In contrast, we were unable to detect any major changes in myeloid lineage potential in specified Pax-5-deficient cells. By comparison of gene expression patterns in ex vivo isolated Pax-5-and Ebf-1-deficient progenitors, it was possible to identify a set of B-cell-restricted genes dependent on Ebf-1 but not Pax-5, supporting the idea that B-cell specification and commitment is controlled by distinct regulatory networks.

    Place, publisher, year, edition, pages
    National Academy of Sciences, 2012
    Keywords
    transcription, Notch-1, Deltex
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85090 (URN)10.1073/pnas.1210144109 (DOI)000309604500070 ()
    Note

    Funding Agencies|Swedish Cancer Society||Swedish Research Council||Swedish Childhood Cancer Foundation||faculty of Medicine at Linkoping University||

    Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2017-12-07
    4. Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner
    Open this publication in new window or tab >>Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner
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    2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, p. 33449-33461Article in journal (Refereed) Published
    Abstract [en]

    Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2R-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1(+/-) pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development.

    Place, publisher, year, edition, pages
    American Society for Biochemistry and Molecular Biology, 2013
    Keywords
    Development; Differentiation; Immunology; Lymphocyte; Transcription Factors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-103303 (URN)10.1074/jbc.M113.506261 (DOI)000328841700057 ()
    Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2019-02-11
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    Molecular mechanisms in lymphoid restriction: securing the B lineage fate
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  • 667.
    Åhsberg, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Welinder, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Stjernberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Larsson, Malin
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, p. 33449-33461Article in journal (Refereed)
    Abstract [en]

    Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2R-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1(+/-) pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development.

  • 668.
    Åhsberg, Josefine
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Xiao, Pingnan
    Karolinska Inst, Sweden.
    Okuyama, Kazuki
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Somasundaram, Rajesh
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Lund Univ, Sweden.
    Qian, Hong
    Lund Univ, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden.
    Letter: Progression of progenitor B-cell leukemia is associated with alterations of the bone marrow micro-environment in HAEMATOLOGICA, vol 105, issue 3, pp2020In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 105, no 3Article in journal (Other academic)
    Abstract [en]

    n/a

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    fulltext
  • 669.
    Åkerlund, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sundqvist, Martin
    Universitetssjukhuset, Örebro, Sweden.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Åhrén, Christina
    regionala Strama, Västra Götalandsregionen, Göteborg, Sweden.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Giske, Christian G
    Karolinska universitetssjukhuset, Solna, Sweden.
    Svarstiderna kan kortas vid mikrobiologisk diagnostik av sepsis: Bättre öppettider på laboratorier och aktiv rådgivning ger snabbare terapi2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 7, article id C73SArticle in journal (Refereed)
    Abstract [sv]

    Snabbt insatt adekvat antibiotikabehandling är livräddande vid allvarliga bakteriella infektioner. 

    Snabb mikrobiologisk diagnostik krävs i och med ökande antibiotikaresistens och kommer att ge medicinska vinster.

    En enkät till landets mikrobiologiska laboratorier visar på stora skillnader avseende tillgänglighet, snabbhet och kommunikation med svarsmottagande enhet vad gäller positiva blododlingar.

    För snabbare svar krävs att mikrobiologiska laboratorier erbjuder mer generösa öppettider, effektivare transportsystem och patientnära blododlingsinkubatorer samt tidig och aktiv rådgivning till behandlande läkare.

    n/a

  • 670. Order onlineBuy this publication >>
    Östholm Balkhed, Åse
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae: Antibiotic consumption, Detection and Resistance Epidemiology2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    ESBL-producing Enterobacteriaceae are emerging worldwide and they are frequently multi-drug resistant, thus limiting treatment options for infections caused by these pathogens.

    The overall aim of the thesis was to investigate ESBL-producing Enterobacteriaceae in a Swedish county.

    First, we developed a molecular method, a multiplex PCR assay for identification of SHV, TEM and CTX-M genes in clinical isolates of Enterobacteriaceae with an ESBL phenotype.

    From 2002 until the end of 2007 all isolates of ESBL-producing Enterobacteriaceae in Östergötland, Sweden were further investigated. The prevalence of ESBL-producing Enterobacteriaceae was low, <1%, but increasing,while the antibiotic consumption remained unchanged. CTX-M enzymes, particularly CTX-M group 1, dominate in our region as well as in the rest of Europe.

    Furthermore, we have investigated antimicrobial susceptibility by performing MIC-testing in a large, well-characterized population of CTX-M-producing E. coli. Only three oral antimicrobial agents (fosfomycin, nitrofurantoin and mecillinam) demonstrated susceptibility above 90%. High susceptibility, >90%, was also demonstrated for carbapenems, colistin, tigecycline and amikacin. Sixty-eight per cent of ESBL-producing E. coli was multi-resistant, and the most common multi-resistance pattern was the ESBL phenotype with decreased susceptibility to trimethoprim, trimethoprim-sulfamethoxazole, ciprofloxacin, gentamicin and tobramycin. Isolates belonging to CTX-M group 9 are generally more susceptible to antibiotics than the CTX-M group 1-producing E. coli.

    Finally, a prospective multicentre case-control study examined the prevalence of ESBL-producing Enterobacteriaceae in faecal samples before and after travel abroad and the risk factors of acquisition. Sixty-eight of 226 travellers (30%) had ESBL-producing Enterobacteriaceae in the faecal flora. The geographical area visited had the highest impact on acquisition, with highest the risk for travellers visiting the Indian subcontinent, followed by Asia and Africa north of the equator. Also, acquisition of ESBL-producing Enterobacteriaceae during travel is associated with abdominal symptoms such as diarrhoea. Age also seemed to affect the risk of acquiring ESBL-producing Enterobacteriaceae, the highest risks were found among travellers ≥ 65 years.

    This thesis has contributed to increased understanding of the epidemiology of ESBL-producing Enterobacteriaceae and their susceptibility to both beta-lactam and non-beta-lactam agents.

    List of papers
    1. Multiplex PCR amplification assay for the detection of blaSHV, blaTEM and blaCTX-M genes in Enterobacteriaceae
    Open this publication in new window or tab >>Multiplex PCR amplification assay for the detection of blaSHV, blaTEM and blaCTX-M genes in Enterobacteriaceae
    Show others...
    2007 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 115, no 12, p. 1400-1408Article in journal (Refereed) Published
    Abstract [en]

    Extended-spectrum β-lactamases (ESBLs) are often mediated by bla-SHV, blaTEM and blaCTX-M genes in Enterobacteriaceae and other Gram-negative bacteria. Numerous molecular typing methods, including PCR-based assays, have been developed for their identification. To reduce the number of PCR amplifications needed we have developed a multiplex PCR assay which detects and discriminates between bla-SHV, blaTEM and blaCTX-M PCR amplicons of 747, 445 and 593 bp, respectively. This multiplex PCR assay allowed the identification of bla-SHV, blaTEM and blaCTX-M genes in a series of clinical isolates of Enterobacteriaceae with previously characterised ESBL phenotype. The presence of blaSHV, blaTEM and blaCTX-M genes was confirmed by partial DNA sequence analysis. Apparently, the universal well-established CTX-M primer pair used here to reveal plasmid-encoded blaCTX-M genes would also amplify the chromosomally located K-1 enzyme gene in all Klebsiella oxytoca strains included in the study.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-41186 (URN)10.1111/j.1600-0463.2007.00722.x (DOI)55314 (Local ID)55314 (Archive number)55314 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
    2. Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae and trends in antibiotic consumption in a county of Sweden
    Open this publication in new window or tab >>Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae and trends in antibiotic consumption in a county of Sweden
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    2010 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 42, no 11-12, p. 831-838Article in journal (Refereed) Published
    Abstract [en]

    In the last decade extended-spectrum beta-lactamase (ESBL)-producing bacteria have become an increasing problem. Our aims were to investigate the prevalence of ESBL-producing Enterobacteriaceae and trends in antibiotic use in the county of Ostergotland, Sweden. From 2002 through 2007 there were 224 ESBL-producing Escherichia coli and 23 Klebsiella pneumoniae isolates with an ESBL-phenotype identified among all Enterobacteriaceae isolated at the clinical laboratory. Trends in antibiotic consumption expressed as defined daily doses (DDD) per 1000 inhabitants and day (DID) were studied. The prevalence of ESBL-producing isolates among Enterobacteriaceae in our region is still low (andlt; 1%). Patients with ESBL-producing E. coli increased significantly (p andlt; 0.001) from 5 in y 2002 to 47 in y 2007. CTX-M group 1 was the dominant enzyme group in both E. coli and K. pneumoniae. Antibiotic susceptibility testing of ciprofloxacin, gentamicin and trimethoprim-sulfamethoxazole revealed that 58% of E. coli and 50% of K. pneumoniae isolates were multi-resistant. Antibiotic use remained unchanged from 2001 through 2009, but there was a trend towards increased use of drugs with low ESBL selection potential, which was probably due to the increased prevalence of ESBL producers.

    Place, publisher, year, edition, pages
    Informa Healthcare, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-63145 (URN)10.3109/00365548.2010.498017 (DOI)000284168300006 ()
    Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2017-12-11Bibliographically approved
    3. In vitro activity of beta-lactam antibiotics against CTX-M-producing Escherichia coli
    Open this publication in new window or tab >>In vitro activity of beta-lactam antibiotics against CTX-M-producing Escherichia coli
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    2011 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 30, no 8, p. 981-987Article in journal (Refereed) Published
    Abstract [en]

    Beta-lactam antibiotics have been discussed as options for the treatment of infections caused by multiresistant extended-spectrum beta-lactamase (ESBL)-producing bacteria if the minimum inhibitory concentration (MIC) is low. The objective of this study was to investigate the in vitro activity of different beta-lactam antibiotics against CTX-M-producing Escherichia coli. A total of 198 isolates of E. coli with the ESBL phenotype were studied. Polymerase chain reaction (PCR) amplification of CTX-M genes and amplicon sequencing were performed. The MICs for amoxicillin-clavulanic acid, aztreonam, cefepime, cefotaxime, ceftazidime, ceftibuten, ertapenem, imipenem, mecillinam, meropenem, piperacillin-tazobactam, and temocillin were determined with the Etest. Susceptibility was defined according to the breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). MIC(50) and MIC(90) values were calculated. Isolates from CTX-M group 9 showed higher susceptibility to the beta-lactam antibiotics tested than isolates belonging to CTX-M group 1. More than 90% of the isolates belonging to CTX-M group 9 were susceptible to amoxicillin-clavulanic acid, ceftazidime, ceftibuten, piperacillin-tazobactam, and temocillin. The susceptibility was high to mecillinam, being 91%, regardless of the CTX-M group. All isolates were susceptible to imipenem and meropenem, and 99% to ertapenem. This study shows significant differences in susceptibility to different beta-lactam antibiotics among the CTX-M-producing E. coli isolates and a significant difference for many antibiotics tested between the CTX-M-producing groups 1 and 9. The good in vitro activity of other beta-lactam antibiotics compared to carbapenems indicate that clinical studies are warranted in order to examine the potential role of these beta-lactam antibiotics in the treatment of infections caused by multiresistant ESBL-producing E. coli.

    Place, publisher, year, edition, pages
    Springer Science Business Media, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-69787 (URN)10.1007/s10096-011-1183-4 (DOI)000292553500008 ()
    Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08Bibliographically approved
    4. High frequency of co-resistance in CTX-M-producing Escherichia coli to non-beta-lactam antibiotics, with the exception of amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin, in a county of Sweden
    Open this publication in new window or tab >>High frequency of co-resistance in CTX-M-producing Escherichia coli to non-beta-lactam antibiotics, with the exception of amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin, in a county of Sweden
    Show others...
    2013 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 4, p. 271-278Article in journal (Refereed) Published
    Abstract [en]

    Background: The objective of this study was to investigate the in vitro activity of different antibiotics against CTX-M-producing Escherichia coli in a county of Sweden, and to determine the occurrence of multi-resistance and plasmid- mediated quinolone resistance among these isolates. Methods: A total of 198 isolates of E. coli with extended-spectrum beta-lactamase (ESBL) phenotype and mainly CTX-M genotype were studied. The minimum inhibitory concentrations (MICs) for amikacin, chloramphenicol, ciprofloxacin, colistin, fosfomycin, gentamicin, nalidixic acid, nitrofurantoin, tigecycline, tobramycin, trimethoprim, and trimethoprim-sulfamethoxazole were determined with the Etest. Susceptibility was defined according to the breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). MIC(50) and MIC(90) values were calculated. Results: Ninety-five percent or more of the isolates were susceptible to amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin. CTX-M group 9 was more susceptible than CTX-M group 1 to ciprofloxacin, gentamicin, and tobramycin. Sixty-eight percent of the isolates were multi-resistant, and the most common multi-resistance pattern was ESBL phenotype with decreased susceptibility to trimethoprim, trimethoprim-sulfamethoxazole, ciprofloxacin, gentamicin, and tobramycin. Only 1 isolate carried a qnrS1 gene, but 37% carried aac(6')-Ib-cr. Conclusions: A high frequency of co-resistance between ESBL-producing E. coli and non-beta-lactam antibiotics was seen. On the other hand, very high susceptibility was seen for amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin. These data support the replacement of gentamicin and tobramycin, normally used in Sweden, with amikacin, for severe infections.

    Keywords
    Etest, minimum inhibitory concentration, extended-spectrum beta-lactamase
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-87612 (URN)10.3109/00365548.2012.734636 (DOI)000316693600005 ()23113731 (PubMedID)
    Available from: 2013-01-19 Created: 2013-01-19 Last updated: 2017-12-06
    5. Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: incidence and risk factors
    Open this publication in new window or tab >>Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: incidence and risk factors
    Show others...
    2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 9, p. 2144-2153Article in journal (Refereed) Published
    Abstract [en]

    Objectives To study the acquisition of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) among the faecal flora during travel, with a focus on risk factors, antibiotic susceptibility and ESBL-encoding genes.

    Methods An observational prospective multicentre cohort study of individuals attending vaccination clinics in south-east Sweden was performed, in which the submission of faecal samples and questionnaires before and after travelling outside Scandinavia was requested. Faecal samples were screened for ESBL-PE by culturing on ChromID ESBL and an in-house method. ESBL-PE was confirmed by phenotypic and genotypic methods. Susceptibility testing was performed with the Etest. Individuals who acquired ESBL-PE during travel (travel-associated carriers) were compared with non-carriers regarding risk factors, and unadjusted and adjusted ORs after manual stepwise elimination were calculated using logistic regression.

    Results Of 262 enrolled individuals, 2.4% were colonized before travel. Among 226 evaluable participants, ESBL-PE was detected in the post-travel samples from 68 (30%) travellers. The most important risk factor in the final model was the geographic area visited: Indian subcontinent (OR 24.8, P < 0.001), Asia (OR 8.63, P < 0.001) and Africa north of the equator (OR 4.94, P  = 0.002). Age and gastrointestinal symptoms also affected the risk significantly. Multiresistance was seen in 77 (66%) of the ESBL-PE isolates, predominantly a combination of reduced susceptibility to third-generation cephalosporins, trimethoprim/sulfamethoxazole and aminoglycosides. The most common species and ESBL-encoding gene were Escherichia coli (90%) and CTX-M (73%), respectively.

    Conclusion Acquisition of multiresistant ESBL-PE among the faecal flora during international travel is common. The geographical area visited has the highest impact on ESBL-PE acquisition.

    Place, publisher, year, edition, pages
    Oxford University Press, 2013
    Keywords
    travel medicine, CTX-M, antibiotic resistance
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-97437 (URN)10.1093/jac/dkt167 (DOI)000323424100029 ()23674762 (PubMedID)
    Note

    Funding Agencies|Medical Research Council of Southeast Sweden|FORSS-12368FORSS-36511FORSS-87551|ALF grants, Ostergotland County Council|LIO-10885LIO-16741LIO-61341LIO-127281|

    Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2017-12-06Bibliographically approved
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    Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae: Antibiotic consumption, Detection and Resistance Epidemiology
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