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  • 151.
    Patcha Brodin, Veronika
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Wigren, Jane
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Winberg, Martin E.
    Rasmusson, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Li, Jianxun
    Department of Oral Biology, College of Dentistry, University of Illinois, Chicago, USA.
    Särndahl, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Differential inside-out activation of β2 integrins by leukotriene B4 and fMLP in human neutrophils2004In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 300, no 2, p. 308-319Article in journal (Refereed)
    Abstract [en]

    We have investigated how LTB4, an endogenous chemoattractant encountered early in the inflammatory process, and fMLP, a bacteria-derived chemotactic peptide emanating from the site of infection, mediate inside-out regulation of the β2-integrin. The role of the two chemoattractants on β2-integrin avidity was investigated by measuring their effect on β2-integrin clustering and surface mobility, whereas their effect on β2-integrin affinity was measured by the expression of a high affinity epitope, a ligand-binding domain on β2-integrins, and by integrin binding to s-ICAM. We find that the two chemoattractants modulate the β2-integrin differently. LTB4 induces an increase in integrin clustering and surface mobility, but only a modest increase in integrin affinity. fMLP evokes a large increase in β2-integrin affinity as well as in clustering and mobility. Lipoxin, which acts as a stop signal for the functions mediated by pro-inflammatory agents, was used as a tool for further examining the inside-out mechanisms. While LTB4-induced integrin clustering and mobility were inhibited by lipoxin, only a minor inhibition of fMLP-induced β2-integrin avidity and no inhibition of integrin affinity were detected. The different modes of the inside-out regulation of β2-integrins suggest that distinct mechanisms are involved in the β2-integrin modulation induced by various chemoattractants.

  • 152.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Edston, Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Differential accumulation of pulmonary and cardiac mast cell-subsets and eosinophils between fatal anaphylaxis and asthma death - A postmortem comparative study2007In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 169, no 1, p. 43-49Article in journal (Refereed)
    Abstract [en]

    The distribution profile of infiltrated mast cell-subpopulations and eosinophils in the lung and heart sections of the patients who died of severe allergic hyperresponsiveness, was investigated. Four study groups were designed comprising 9 cases who died in systemic anaphylaxis (Group I), 10 asthmatic individuals whose death were assigned to acute and severe bronchial asthma (Group II), 10 asthmatic cases who died from non-immunological diseases (Group III). Twenty consecutive autopsies of non-allergic subjects who died of unnatural causes (Group IV) served as control group in this study. Utilizing antibodies against human tryptase and chymase and a double immunohistochemical staining method, we distinguished successfully all three subsets of mast cells (MC), MC-TC (containing both tryptase and chymase), MC-T (containing only tryptase) and MC-C (containing only chymase) types, subdivided on the basis of the protease compositions of their secretory granules. In order to immunostaining eosinophils, we used antibody to major basic protein as a marker. We also measured postmortem blood tryptase, specific and total serum IgE. The intriguing finding of this study was the marked differences of cellular composition in the lung between fatal anaphylaxis and asthma death Significant augmentation of MCs infiltrated in lung and heart sections of anaphylaxis patients and drastic infiltration of bronchial eosinophils in asthmatic death and consequent release of their related inflammatory mediators might explain the differential expression of the associated symptoms in these two groups. The anaphylactic deaths did show neither emphysema nor significant mucous bronchial secretions whereas all asthmatic deaths did. The degree of pulmonary congestion and edema was also more severe in anaphylaxis. This corresponded with the histological findings and the location and number of mast cell-subsets and eosinophils in the different compartments of the lungs. We have demonstrated that the third type of mast cell MC-C is only found in the lungs in anaphylactic deaths. The practical consequence of our study will be that it is now possible to confirm a suspicion of anaphylaxis death not only by measurements of serum mast cell tryptase, but also by immunohistochemical methods.

  • 153.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Mycobacterium tuberculosis induce rapid apoptosis in human neutrophils through oxygen-dependent pathway2000Conference paper (Other academic)
  • 154.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Activation of Human Neutrophils by Mycobacterium tuberculosis H37Ra Involves Phospholipase Cγ2, Shc Adapter Protein, and p38 Mitogen-Activated Protein Kinase2000In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 164, no 2, p. 959-965Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that human neutrophils play a significant protective role in mycobacteria infection. When encountered with mycobacteria, neutrophils exhibit the typical early bactericidal responses including phagocytosis and generation of reactive oxygen intermediates (ROI), but the underlying mechanisms are largely unknown. The present study shows that stimulation of neutrophils with an attenuated strain of Mycobacterium tuberculosis H37Ra (Mtb) led to a tyrosine kinase-dependent ROI production in these cells. Stimulation with Mtb induces a rapid and transient tyrosine phosphorylation of several proteins, one of which was identified as phospholipase Cγ2 (PLCγ2). Several tyrosine-phosphorylated proteins were associated with the PLCγ2 precipitates from Mtb-stimulated neutrophils, of which pp46 was characterized as the Shc adapter protein. A role for PLCγ2-Shc association in the generation of ROI is supported by the observations that stimulation with Mtb causes the activation of p38 mitogen-activated protein kinase (MAPK), a downstream target of the Shc/Ras signaling cascade, and that the effect of genistein on ROI production coincided with its ability to inhibit both PLCγ2-Shc association and p38 MAPK activation. Moreover, pretreatment of neutrophils with a PLC inhibitor markedly suppresses the Mtb-stimulated ROI production as well as p38 MAPK activation in these cells. Taken together, these results indicate that stimulation of neutrophils with Mtb triggers the tyrosine phosphorylation of PLCγ2 and its association with Shc, and that such association is critical for the Mtb-stimulated ROI production through activating p38 MAPK.

  • 155. Order onlineBuy this publication >>
    Persson, Alexander
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Apoptotic neutrophils enhance the immune response against Mycobacterium tuberculosis2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease that for years was considered to belong of the past, but tuberculosis is back causing over 2 million deaths per year. The infection can be dormant for decades and an active immune response can prevent the infection from progressing into active disease. However, the HIV/AIDS epidemic has caused an alarming rise in tuberculosis cases.

    The main infectious route for Mtb is through the airways into the lungs, where they encounter alveolar macrophages. Mtb are phagocytosed by these macrophages, but instead of being killing within the phagosome, Mtb modulates the cell to become a host in which the bacteria thrive. The lack of capacity to eradicate the infection stimulate cells of the immune system to gather around infected macrophages and form a granuloma that walls off the infection. Within this granuloma, Mtb can wait silently and later progress into active disease. However, only a fraction of exposed individuals develop disease, indicating that initial eradication of Mtb infections is possible. Such immediate response must be directed by the innate immunity comprised of phagocytes such as neutrophils (PMNs) and non-activated macrophages. Upon Mtb infection, macrophages become anergic and PMNs enter apoptosis. PMNs have a short lifespan and are cleared by neighbouring phagocytes, a mechanism described to resolve the inflammation and modulate tissue regeneration.

    We found that Mtb-induced apoptosis in PMNs was not dependent on phagocytosis of the bacteria, indicating that Mtb have the capacity to induce apoptosis in multiple PMNs. Complement-mediated phagocytosis induce survival signals such as Akt in PMNs, but despite this, complement-opsonized Mtb was able to override the anti-apoptotic activation in the cells. Since phagocytes clear apoptotic cells, we investigated how clearance of Mtb-induced apoptotic PMNs affected macrophages. We found that Mtb-induced apoptotic PMNs inflicted pro-inflammatory activation of the macrophages that cleared them. In addition, this activation was mediated by Hsp72 released from the Mtb-induced apoptotic PMNs. Furthermore, apoptotic PMNs can work in synergy with phagocytosed Mtb to activate macrophages and enhance intracellular killing of Mtb.

    Since dendritic cells are important for the regulation of immunity, we investigated whether Mtb-induced apoptotic PMNs affected the inflammatory response and maturation of dendritic cells. We found that Mtb-induced apoptotic PMNs trigger dendritic cells to enter a mature state able to activate naïve T-cell proliferation.

    We propose that infected apoptotic PMNs is a potent activator of the inflammatory response during infections. Taken together, PMNs not only kill their share of pathogens but also modulate other immune cells, thereby forming a link between the early innate and the adaptive immune response during microbial challenge with Mtb.

    List of papers
    1. Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins
    Open this publication in new window or tab >>Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins
    Show others...
    2009 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 47, no 3, p. 143-150Article in journal (Refereed) Published
    Abstract [en]

    Modulation of immune cell apoptosis is a key evasion strategy utilized by Mycobacterium tuberculosis (Mtb). To be able to multiply within macrophages, the bacterium delays apoptosis and down-regulates pro-inflammatory activation in these cells, whereas apoptosis is rapidly induced in the potently bactericidal neutrophils. Initial host-pathogen interactions between neutrophils and Mtb, subsequently leading to apoptosis, need to be investigated to understand the early features during Mtb infections. Opsonized Mtb were readily phagocytosed, and the immuno-mediated phagocytosis triggered early activation of anti-apoptotic Akt in the neutrophils but the bacteria still induced apoptosis to the same extent as non-phagocytosed Mtb. Mtb-induced apoptosis was strictly dependent on NADPH oxidase-generated reactive oxygen species, compounds shown to damage lysosomal granules. Despite this, we found no involvement of damaged azurophilic granules in Mtb-induced apoptosis in human neutrophils. Instead, the Mtb-induced apoptosis was p38 MAPK dependent and induced through the mitochondrial pathway. Moreover, Mtb deficient of mature lipoproteins lacked the determinants required for induction of neutrophil apoptosis. These results show that Mtb exert a strong intrinsic capacity to induce apoptosis in neutrophils that is capable of overcoming the anti-apoptotic signaling in the cell.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20401 (URN)10.1016/j.micpath.2009.05.006 (DOI)
    Note
    Original Publication: Alexander Persson, Robert Blomgran, Daniel Eklund, Charlotte Lundstrom and Olle Stendahl, Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins, 2009, MICROBIAL PATHOGENESIS, (47), 3, 143-150. http://dx.doi.org/10.1016/j.micpath.2009.05.006 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2009-09-08 Created: 2009-09-07 Last updated: 2017-12-13Bibliographically approved
    2. Mycobacterium tuberculosis-induced apoptotic neutrophils trigger a pro-inflammatory response in macrophages through release of heat shock protein 72, acting in synergy with the bacteria
    Open this publication in new window or tab >>Mycobacterium tuberculosis-induced apoptotic neutrophils trigger a pro-inflammatory response in macrophages through release of heat shock protein 72, acting in synergy with the bacteria
    Show others...
    2008 (English)In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 3, p. 233-240Article in journal (Refereed) Published
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) survive inside macrophages by manipulating microbicidal functions such as phago-lysosome fusion, production of reactive oxygen species and nitric oxide, and by rendering macrophages non-responsive to IFN-γ. Mtb-infected lung tissue does however not only contain macrophages, but also significant numbers of infiltrating polymorphonuclear neutrophils (PMN). These are able to phagocytose and kill ingested Mtb, but are short-lived cells that constantly need to be removed from tissues to avoid tissue damage. Phagocytosis of aged or UV-induced apoptotic PMN by macrophages induce an anti-inflammatory response in macrophages. However, in the present study, we show that engulfment of Mtb-induced apoptotic PMN by macrophages initiates secretion of TNF-α from the macrophages, reflecting a pro-inflammatory response. Moreover, Mtb-induced apoptotic PMN up-regulate heat shock proteins 60 and 72 (Hsp60, Hsp72) intracellularly and also release Hsp72 extracellularly.

    We found that both recombinant Hsp72 and released Hsp72 enhanced the pro-inflammatory response to both Mtb-induced apoptotic PMN and Mtb. This stimulatory effect of the supernatant was abrogated by depleting the Hsp72 with immunoprecipitation. These findings indicate that released Hsp72 from Mtb-infected PMN can trigger macrophage activation during the early stage of Mtb infections, thereby creating a link between innate and adaptive immunity.

    Place, publisher, year, edition, pages
    elsevier, 2008
    Keywords
    innate immunity; phagocytes; micobiology
    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-20835 (URN)10.1016/j.micinf.2007.11.007 (DOI)
    Available from: 2009-10-06 Created: 2009-09-23 Last updated: 2018-01-13Bibliographically approved
    3. Dendritic cell activation by sensing Mycobacterium tuberculosis-induced apoptotic neutrophils via DC-SIGN
    Open this publication in new window or tab >>Dendritic cell activation by sensing Mycobacterium tuberculosis-induced apoptotic neutrophils via DC-SIGN
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In Mycobacterium tuberculosis (Mtb)-infected individuals cells of the innate immune system accumulate in the spleen and in granulomas, but how this relates to the protection against Mtb or in the pathogenesis is unknown. Mtb is internalized in the lung by phagocytic cells, such as neutrophils (PMNs), dendritic cells (DCs) and macrophages. PMNs undergo accelerated apoptosis after internalization of the bacterium and are subsequently sequestered by neighbouring phagocytes. Removal of aged apoptotic cells is an immunologically silent process and the aim of this study was to clarify the interaction between Mtb-induced apoptotic PMNs and DCs, and evaluate if this interaction induced functional maturation of the DCs. In fact,  Mtb-induced apoptotic PMNs induced DC maturation, whereas exposure to spontaneous apoptotic PMNs had no effect on DCs maturation status. We found that the cell fraction contained almost all stimulatory capacity, suggesting that the cell-cell interaction is crucial for DC activation. Inhibitory studies showed that this cell contact-dependent activation required binding of the PMN Mac-1 (CD11b/CD18) to the DC via DC-SIGN and endocytic activity. Taken together, this study proves that the DCs can distinguish between normal and infected apoptotic PMNs via cellular cross talk, where the DCs can sense the presence of danger on the Mtb-infected PMNs and modulate their response accordingly.

    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-20836 (URN)
    Available from: 2009-10-06 Created: 2009-09-23 Last updated: 2018-01-13Bibliographically approved
    4. Apoptotic neutrophils activates the inflammatory response in macrophages –increased capacity to handle intracellular infection
    Open this publication in new window or tab >>Apoptotic neutrophils activates the inflammatory response in macrophages –increased capacity to handle intracellular infection
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Inflammation is essential to eradicate invading pathogens but an uncontrolled inflammation may develop into chronic inflammation and extensive tissue destruction unable of effectively controlling infections. At the site of infection, macrophages are the major regulators of the inflammatory response through balanced release of pro- or anti-inflammatory cytokines and therefore a key cell in the resolution of inflammation. Neutrophils effectively phagocytose and kill pathogens but they are short-lived and removal of these dead cells by macrophages is a key event in the resolution of inflammation and tissue repair.

    However, down-regulation of the immune response by apoptotic cells would in the presence of pathogens be detrimental to the host. In contrast to resolution of inflammation, we show that in the presence of microbial stimuli, apoptotic neutrophils in fact exert a potent pro-inflammatory activation of macrophages. This augmentation of the pro-inflammatory response is dependent on uptake of the apoptotic cells by the macrophage. In addition to secretion of TNF-α, presence of apoptotic neutrophils enhanced the capacity of the stimulated macrophages to kill intracellular Mycobacterium tuberculosis. This presents a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response, and control of intracellular infections.

    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-20837 (URN)
    Available from: 2009-10-06 Created: 2009-09-23 Last updated: 2018-01-13Bibliographically approved
    Download full text (pdf)
    Apoptotic neutrophils enhance the immune response against Mycobacterium tuberculosis
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  • 156.
    Persson, Alexander
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lundstrom, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins2009In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 47, no 3, p. 143-150Article in journal (Refereed)
    Abstract [en]

    Modulation of immune cell apoptosis is a key evasion strategy utilized by Mycobacterium tuberculosis (Mtb). To be able to multiply within macrophages, the bacterium delays apoptosis and down-regulates pro-inflammatory activation in these cells, whereas apoptosis is rapidly induced in the potently bactericidal neutrophils. Initial host-pathogen interactions between neutrophils and Mtb, subsequently leading to apoptosis, need to be investigated to understand the early features during Mtb infections. Opsonized Mtb were readily phagocytosed, and the immuno-mediated phagocytosis triggered early activation of anti-apoptotic Akt in the neutrophils but the bacteria still induced apoptosis to the same extent as non-phagocytosed Mtb. Mtb-induced apoptosis was strictly dependent on NADPH oxidase-generated reactive oxygen species, compounds shown to damage lysosomal granules. Despite this, we found no involvement of damaged azurophilic granules in Mtb-induced apoptosis in human neutrophils. Instead, the Mtb-induced apoptosis was p38 MAPK dependent and induced through the mitochondrial pathway. Moreover, Mtb deficient of mature lipoproteins lacked the determinants required for induction of neutrophil apoptosis. These results show that Mtb exert a strong intrinsic capacity to induce apoptosis in neutrophils that is capable of overcoming the anti-apoptotic signaling in the cell.

    Download full text (pdf)
    FULLTEXT01
  • 157.
    Persson, Alexander
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Blomgran-Julinder, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Rahman, Sayma
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Sun Yansen (Zhongshan) University.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Mycobacterium tuberculosis-induced apoptotic neutrophils trigger a pro-inflammatory response in macrophages through release of heat shock protein 72, acting in synergy with the bacteria2008In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 3, p. 233-240Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) survive inside macrophages by manipulating microbicidal functions such as phago-lysosome fusion, production of reactive oxygen species and nitric oxide, and by rendering macrophages non-responsive to IFN-γ. Mtb-infected lung tissue does however not only contain macrophages, but also significant numbers of infiltrating polymorphonuclear neutrophils (PMN). These are able to phagocytose and kill ingested Mtb, but are short-lived cells that constantly need to be removed from tissues to avoid tissue damage. Phagocytosis of aged or UV-induced apoptotic PMN by macrophages induce an anti-inflammatory response in macrophages. However, in the present study, we show that engulfment of Mtb-induced apoptotic PMN by macrophages initiates secretion of TNF-α from the macrophages, reflecting a pro-inflammatory response. Moreover, Mtb-induced apoptotic PMN up-regulate heat shock proteins 60 and 72 (Hsp60, Hsp72) intracellularly and also release Hsp72 extracellularly.

    We found that both recombinant Hsp72 and released Hsp72 enhanced the pro-inflammatory response to both Mtb-induced apoptotic PMN and Mtb. This stimulatory effect of the supernatant was abrogated by depleting the Hsp72 with immunoprecipitation. These findings indicate that released Hsp72 from Mtb-infected PMN can trigger macrophage activation during the early stage of Mtb infections, thereby creating a link between innate and adaptive immunity.

  • 158.
    Persson, Alexander
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Hedlund, Sebastian
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Vujic, Ana
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Larsson, Marie
    Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Dendritic cell activation by sensing Mycobacterium tuberculosis-induced apoptotic neutrophils via DC-SIGNManuscript (preprint) (Other academic)
    Abstract [en]

    In Mycobacterium tuberculosis (Mtb)-infected individuals cells of the innate immune system accumulate in the spleen and in granulomas, but how this relates to the protection against Mtb or in the pathogenesis is unknown. Mtb is internalized in the lung by phagocytic cells, such as neutrophils (PMNs), dendritic cells (DCs) and macrophages. PMNs undergo accelerated apoptosis after internalization of the bacterium and are subsequently sequestered by neighbouring phagocytes. Removal of aged apoptotic cells is an immunologically silent process and the aim of this study was to clarify the interaction between Mtb-induced apoptotic PMNs and DCs, and evaluate if this interaction induced functional maturation of the DCs. In fact,  Mtb-induced apoptotic PMNs induced DC maturation, whereas exposure to spontaneous apoptotic PMNs had no effect on DCs maturation status. We found that the cell fraction contained almost all stimulatory capacity, suggesting that the cell-cell interaction is crucial for DC activation. Inhibitory studies showed that this cell contact-dependent activation required binding of the PMN Mac-1 (CD11b/CD18) to the DC via DC-SIGN and endocytic activity. Taken together, this study proves that the DCs can distinguish between normal and infected apoptotic PMNs via cellular cross talk, where the DCs can sense the presence of danger on the Mtb-infected PMNs and modulate their response accordingly.

  • 159.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Welin, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Fransson, Sven-Göran
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Alveolar macrophages from patients with tuberculosis exhibit reduced capacity of restricting growth of Mycobacterium tuberculosis: a pilot study of vitamin D stimulation in vitro2013In: HOAJ Biology, ISSN 2050-0874Article in journal (Refereed)
    Abstract [en]

    Background: The role of vitamin D supplementation as adjuvant treatment of tuberculosis (TB) has lately attracted increasing interest. Our aim was to investigate the capacity of alveolar macrophages (AMs) from patients with or without exposure to TB to control intracellular growth of virulent Mycobacterium tuberculosis (Mtb).

    Methods: AMs were freshly harvested from the bronchoalveolar lavage fluid of 7 patients with a history of TB (4 patients with previous TB and 3 patients with current TB) and 4 non-TB subjects. The H37Rv strain, genetically modified to express Vibrio harveyi luciferase, was used to determine the growth of Mtb by luminometry in the AMs from study subjects. Cytokine levels in culture supernatants were determined using a flow cytometry-based bead array technique.

    Results: AMs from patients with a TB history were less efficient in restricting Mtb growth. Stimulation with 100 nM1, 25-dihydroxyvitamin D (1,25D3) did not significantly influence the capacity of AMs from any study subjects to control the infection. Out of the cytokines evaluated (TNF-α, IL-1β, IL-10 and IL-12p40) only TNF-α demonstrated detectable levels in culture supernatants, but did not respond to stimulation with 1,25D3.

    Conclusions: We conclude that AMs of TB-patients show reduced ability to control mycobacterial growth in vitro, and, that AMs in this pilot study do no respond to 1, 25D3-stimulation. The former observation supports the concept that innate immunity is crucial for the control of TB infection.

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  • 160.
    Persson, Hans Lennart
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Jacobson, Petra
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Larsson, Marie C.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Welin, Amanda
    Göteborgs universitet.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Fransson, Sven-Göran
    Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Schon, Thomas
    Kalmar länssjukhus.
    Alveolar macrophages from patients with tuberculosis display a reduced capacity to inhibit growth of Mycomacterium tuberculosis2012Conference paper (Other academic)
  • 161.
    Pivoriunas, A.
    et al.
    Department of Experimental Research, Institute of Experimental and Clinical Medicine, Žygimantu 9, 01102 Vilnius, Lithuania.
    Savickiene, J.
    Department of Experimental Research, Institute of Experimental and Clinical Medicine, Žygimantu 9, 01102 Vilnius, Lithuania.
    Treigyte, G.
    Department of Developmental Biology, Institute of Biochemistry, Mokslininku 12, 08662 Vilnius, Lithuania.
    Tunaitis, V.
    Department of Experimental Research, Institute of Experimental and Clinical Medicine, Žygimantu 9, 01102 Vilnius, Lithuania.
    Navakauskiene, R.
    Department of Developmental Biology, Institute of Biochemistry, Mokslininku 12, 08662 Vilnius, Lithuania.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/ Cip1 in human leukemia cells2007In: Molecular and Cellular Biochemistry, ISSN 0300-8177, E-ISSN 1573-4919, Vol. 302, no 1-2Article in journal (Refereed)
    Abstract [en]

    Despite the understanding of the importance of phosphoinositide 3-kinase (PI 3-K) signaling pathway in the regulation of cellular proliferation, little is known about its role during phorbol 12-myristate 13-acetate (PMA)-induced differentiation in human leukemia cells. Here, we report a novel finding that PI 3-K inhibition by LY294002 significantly increases p21WAF1/Cip1 expression in PMA-stimulated human leukemia cells NB4 and THP1. LY294002 potentiated expression of p21WAF1/Cip1 via a p53-independent mechanism and did not affect mitogen activated protein kinase (MAPK) activation. Electrophoretic mobility shift (EMSA) experiments revealed that blocking of PI 3-K was associated with increased binding of transcription factor Sp1 to the PMA-responsive sites on the p21WAF1/Cip1 promoter. Pretreatment with rapamycin, an inhibitor of mTOR kinase, decreased the expression of p21WAF1/Cip1 protein in PMA-stimulated NB4 cells. The level of PMA-induced p21WAF1/ Cip1 protein expression was lower in NB4 cells overexpressing wild type protein kinase C ? (PKC ?) compared to those transfected with empty vector or with kinase inactive PKC ?. Sp1 binding to the p21WAF1/Cip1 promoter was completely lost in a wild type PKC ? overexpressing and PMA-stimulated NB4 cells. We demonstrate that PI 3-K signaling pathway suppresses PMA-induced expression of p21WAF1/Cip1 in human leukemia cells, and that this effect is partly mediated by PKC ?. © Springer Science+Business Media, LLC 2007.

  • 162.
    Pivoriunas, Augustas
    et al.
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Surovas, Andrejus
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Borutinskaite, Veronika
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Matuzevicius, Dalius
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Treigyte, Grazina
    Lithuania Academy of Science.
    Savickiene, Jurate
    Lithuania Academy of Science.
    Tunaitis, Virginijus
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Aldonyte, Ruta
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Jarmalaviciute, Akvile
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Suriakaite, Kristina
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Liutkevicius, Evaldas
    JSC Imunolita, Vilnius.
    Venalis, Algirdas
    Institute for Experimentat and Clinical Medicine, Vilnius.
    Navakauskas, Dalius
    Vilnius Gediminas Technical University.
    Navakauskiene, Ruta
    Lithuania Academy of Science.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Proteomic Analysis of Stromal Cells Derived from the Dental Pulp of Human Exfoliated Deciduous Teeth2010In: STEM CELLS AND DEVELOPMENT, ISSN 1547-3287, Vol. 19, no 7, p. 1081-1093Article in journal (Refereed)
    Abstract [en]

    Human dental pulp derived from exfoliated deciduous teeth has been described as a promising alternative source of multipotent stem cells. While these cells share certain similarities with mesenchymal stem-like cells (MSC) isolated from other tissues, basically they are still poorly characterized. In this study, for the first time, a proteomic map of abundantly expressed proteins in stromal cells derived from the dental pulp of human exfoliated deciduous teeth (SHED) was established. We also analyzed proteomic signatures of 2 clonal strains derived from SHEDs by single-cell cloning. The SHEDs were established from enzyme-disaggregated deciduous dental pulp from 6-year-old children. They had typical fibroblastoid morphology and high colony-forming efficiency index (16.4%). Cloning was performed at the second passage using limiting dilution in a 96-well plate (0.3 cell/well). Differentiation assessment revealed strong osteogenic but no adipogenic potential of the SHEDs in either clonal strain. The cells expressed characteristic antigens of MSC-like cells, including CD73, CD90, CD105, CD146, and did not express hematopoietic markers CD14, CD34, and CD45, as assessed with FACS analysis. For proteomic studies, cytosolic and nuclear proteins were analyzed with 2-dimensional gel electrophoresis (2-DE) and identified using matrix-assisted laser desorption/ionization (MALDI)-time of flight (TOF)-mass spectrometry (MS). All proteins were identified with high level of confidence (the lowest sequence coverage was 27%). Identification of highly expressed proteins in SHEDs revealed proteomic profiles very similar to that of MSC-like cells derived from other tissues. We also found a high degree of similarity between proteomic signatures of primary SHEDs and clonal cell strains. Thus, our data confirm a close resemblance between SHEDs and MSC-like cells from other tissues and may serve as starting point for creating-comprehensive proteomic maps.

  • 163.
    Ragnarsson, Eva Ge
    et al.
    Uppsala University.
    Schoultz, Ida
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Gullberg, Elisabet
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Carlsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Tafazoli, Farideh
    Linköping University, Department of health and environment. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Artursson, Per
    Uppsala University.
    Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis2008In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, p. 1215-1226Article in journal (Refereed)
    Abstract [en]

    Crohns disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta 1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv + Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P < 0.01) and ileal mucosa (268 +/- 47% of control; P < 0.01), whereas inv-bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size-and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta 1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta 1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.

  • 164.
    Rastad, AA
    et al.
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Andersson, J
    Beermann, B
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Bohlin, AB
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Brandt, C
    Eriksson, M
    Ewald, U
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Gothberg, S
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Lind, A
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Lindroth, Margaretha
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Ljungman, P
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Naver, L
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Norrby, SR
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Pauksen, K
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Ransjo, U
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Rebbel, H
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Ostlund, MR
    Sigurs, N
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Stahle, L
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Sawe, J
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Sonnerborg, A
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Uhnoo, I
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Stopner, BA
    Univ Lund, Dept Infect Dis & Med Microbiol, Div Infect Dis, SE-22185 Lund, Sweden Dept Microbiol, Linkoping, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Clin Virol, Huddinge, Sweden Karolinska Inst, Dept Clin Pharmacol, Huddinge, Sweden Dept Paediat, Boras, Sweden Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Staten Legmiddelskontroll, Oslo, Norway Univ Uppsala Hosp, Dept Infect Dis, S-75185 Uppsala, Sweden Univ Lund, Dept Infect Dis, Lund, Sweden Karolinska Inst, Dept Paediat, Huddinge, Sweden Karolinska Inst, Dept Haematol, Huddinge, Sweden Dept Paediat, Lund, Sweden Swedish Inst Infect Dis Control, Solna, Sweden Gothenburg Univ, Dept Paediat, Gothenburg, Sweden Univ Uppsala Hosp, Dept Paediat, S-75185 Uppsala, Sweden Med Prod Agcy, Uppsala, Sweden Karolinska Inst, Dept Paediat, Stockholm, Sweden Karolinska Inst, Dept Infect Dis, Huddinge, Sweden.
    Management of infections caused by respiratory syncytial virus2001In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 33, no 5, p. 323-328Article in journal (Refereed)
    Abstract [en]

    This is a consensus document compiled by the Medical Products Agency in Sweden and the Swedish Reference Group for Antiviral Therapy on management of respiratory syncytial virus (RSV) infections. Prophylaxis against RSV infections using palivizumab, a commercially available humanized monoclonal IgG, antibody preparation, is recommended for children <2 y of age with chronic respiratory diseases requiring continuous treatment (oxygen and/or inhalations and/or steroids) during the previous 6 months and children 6 months old who were born before gestational week 26. Ribavirin inhalation treatment may be considered in high-risk infants with clinical symptoms indicating a serious course of an RSV infection. Treatment with ribavirin in combination with intravenous polyclonal immunoglobulin should be considered in patients who have received an allogenic stem cell transplantation or organ transplantation with >1 episode of rejection treatment and who have mild or moderate RSV pneumonia. Evidence-based documentation for treatment of other groups of patients is lacking.

  • 165.
    Ravald, Nils
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Carin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Tooth loss in periodontally treated patients. A long-term study of periodontal disease and root caries2012In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 39, no 1, p. 73-79Article in journal (Refereed)
    Abstract [en]

    Aim: To study periodontal conditions, root caries, number of lost teeth and causes for tooth loss during 11-14 years after active periodontal treatment. less thanbrgreater than less thanbrgreater thanMaterial and Methods: Sixty-four patients participated in the follow-up study. Reasons for tooth loss were identified through previous case books, radiographs and clinical photos. To identify factors contributing to tooth loss, a logistic multi-level regression analysis was used. less thanbrgreater than less thanbrgreater thanResults: The number of lost teeth was 211. The main reason was periodontal disease (n = 153). Due to root caries and endodontic complications, 28 and 17 teeth, respectively, were lost. Thirteen teeth were lost for other reasons. The number of teeth (p = 0.05) and prevalence of probing pocket depths, 4-6 mm (p = 0.01) at baseline, smoking (p = 0.01) and the number of visits at dental hygienists (p = 0.03) during maintenance, significantly contributed to explain the variation in tooth loss. less thanbrgreater than less thanbrgreater thanConclusion: Previously treated patients at a specialist clinic for periodontology continued to lose teeth in spite of maintenance treatments at general practitioners and dental hygienists. The main reason for tooth loss was periodontal disease. Tooth loss was significantly more prevalent among smokers than non-smokers. Tooth-related risk factors were smoking, low numbers of teeth and prevalence of periodontal pockets, 4-6 mm.

  • 166.
    Rudolf, Frauke
    et al.
    INDEPTH Network, Guinea Bissau .
    Lemvik, Grethe
    INDEPTH Network, Guinea Bissau .
    Abate, Ebba
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. University of Gondar, Ethiopia .
    Verkuilen, Jay
    CUNY, NY USA .
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Francisco Gomes, Victor
    INDEPTH Network, Guinea Bissau .
    Eugen-Olsen, Jesper
    INDEPTH Network, Guinea Bissau .
    Ostergaard, Lars
    Aarhus University Hospital, Denmark .
    Wejse, Christian
    INDEPTH Network, Guinea Bissau .
    TBscore II: Refining and validating a simple clinical score for treatment monitoring of patients with pulmonary tuberculosis2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 11, p. 825-836Article in journal (Refereed)
    Abstract [en]

    Background: The TBscore, based on simple signs and symptoms, was introduced to predict unsuccessful outcome in tuberculosis patients on treatment. A recent inter-observer variation study showed profound variation in some variables. Further, some variables depend on a physician assessing them, making the score less applicable. The aim of the present study was to simplify the TBscore. Methods: Inter-observer variation assessment and exploratory factor analysis were combined to develop a simplified score, the TBscore II. To validate TBscore II we assessed the association between start score and failure (i.e. death or treatment failure), responsiveness using Cohens effect size, and the relationship between severity class at treatment start and a decrease andlt; 25% in score from the start until the end of the second treatment month and subsequent mortality. Results: We analyzed data from 1070 Guinean (2003-2012) and 432 Ethiopian (2007-2012) pulmonary tuberculosis patients. For the refined score, items with less than substantial agreement (kappa andlt;= 0.6) and/or not associated with the underlying constructs were excluded. Items kept were: cough, dyspnea, chest pain, anemia, body mass index (BMI) andlt; 18 kg/m(2), BMI andlt; 16 kg/m(2), mid upper arm circumference (MUAC) andlt; 220 mm, and MUAC andlt; 200 mm. The effect sizes for the change between the start of treatment and the 2-month follow-up were 0.51 in Guinea-Bissau and 0.68 in Ethiopia, and for the change between the start of treatment and the end of treatment were 0.68 in Guinea-Bissau and 0.74 in Ethiopia. Severity class placement at treatment start predicted failure (p andlt; 0.001 Guinea-Bissau, p = 0.208 Ethiopia). Inability to decrease at least 25% in score was associated with a higher failure rate during the remaining 4 months of treatment (p = 0.063 Guinea-Bissau, p = 0.008 Ethiopia). Conclusion: The TBscore II could be a useful monitoring tool, aiding triage at the beginning of treatment and during treatment.

  • 167.
    Ryberg, Anna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Monstein, Hans-Jürg
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Microbiology.
    Expression of multiple forms of 3'-end variant CCK2 receptor mRNAs in human pancreatic adenocarcinoma2011In: BMC research notes, ISSN 1756-0500, Vol. 4, p. 131-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Two main types of receptors for gastrin and cholecystokinin (CCK) have been cloned and identified. CCK1 (CCK-A) receptors are expressed in the pancreas, the gallbladder, and parts of the brain, while CCK2 (CCK-B/gastrin) receptors (CCK2R) are expressed in gastric glands and in most of the brain. A splice variant of the CCK2R designated CCKRi4sv (CCK-C), which is constitutively expressed in human pancreatic cancer cells, has also been described. The purpose of the present investigation was to study CCK2R, CCK2i4svR, and gastrin mRNA expression in human pancreatic adenocarcinoma on the assumption that co-expression of CCK2R and gastrin or constitutive CCK2i4svR mRNA expression plays a pivotal role in the progression of pancreatic cancer.

    FINDINGS: PCR amplification using CCK2R specific primer-pairs, followed by ethidium-bromide stained agarose gel electrophoresis revealed the expression of wild-type CCK2R mRNA in 12 of 17 biopsy specimens. A CCK2R intron 4 specific nested PCR assay revealed that CCK2i4svR mRNA was expressed in only one of the biopsy specimen. The authenticity of PCR amplicons was confirmed by cloning of selected amplicons and DNA sequence analysis. Moreover, we found that hitherto undescribed multiple forms of 3'-end variant CCK2R mRNAs with various deletions in the retained intron 4 and exon 5, tentatively generating truncated proteins, were expressed in the pancreatic adenocarcinomas.

    CONCLUSION: Cloning and DNA sequencing of selected amplicons revealed that CCK2R and multiple CCK2i4svR-like mRNAs are expressed in human pancreatic adenocarcinoma. The originally described CCK2i4svR mRNA was only expressed in one of 17 tumours and appears to be rarely expressed in pancreatic adenocarcinoma. We report that CCK2R- and gastrin mRNA co-expression may play a role in a portion, but not in all of these tumours, and that aberrant splicing takes places in these tissues generating multiple forms of 3'-end variant CCK2R mRNAs.

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  • 168.
    Ryberg, Anna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Olsson, Crister
    Malmö University Hospital.
    Ahrné, Siv
    Lund University.
    Monstein, Hans-Jürg
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Comparison of (GTG)5-oligonucleotide and ribosomal intergenic transcribed spacer (ITS)-PCR for molecular typing of Klebsiella isolates2011In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 84, no 2, p. 183-188Article in journal (Refereed)
    Abstract [en]

    Molecular typing of Klebsiella species has become important for monitoring dissemination of β-lactamase-producers in hospital environments. The present study was designed to evaluate poly-trinucleotide (GTG)5- and rDNA intergenic transcribed spacer (ITS)-PCR fingerprint analysis for typing of Klebsiella pneumoniae and Klebsiella oxytoca isolates. Multiple displacement amplified DNA derived from 19 K. pneumoniae (some with an ESBL-phenotype), 35 K. oxytoca isolates, five K. pneumoniae, two K. oxytoca, three Raoultella, and one Enterobacter aerogenes type and reference strains underwent (GTG)5 and ITS-PCR analysis. Dendrograms were constructed using cosine coefficient and the Neighbour joining method. (GTG)5 and ITS-PCR analysis revealed that K. pneumoniae and K. oxytoca isolates, reference and type strains formed distinct cluster groups, and tentative subclusters could be established. We conclude that (GTG)5 and ITS-PCR analysis combined with automated capillary electrophoresis provides promising tools for molecular typing of Klebsiella isolates.

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  • 169.
    Salim, Sa'ad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Silva, Manuel A
    McMaster University.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Andersson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Perdue, Mary H
    McMaster University.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 1, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Recurrent Crohns disease originates with small erosions in the follicle-associated epithelium overlying the Peyers patches. Animal studies have illustrated mucosal immune regulation by dendritic cells located in the subepithelial dome. The aim of this study was to characterize the dendritic cells at this specific site in patients with Crohns disease. Heal tissues were obtained after surgery performed on Crohns patients; ileal samples from noninflammatory bowel disease and ulcerative colitis served as standard and inflammatory controls, respectively. Flow cytometry of isolated intestinal mononuclear cells showed a larger subset of dendritic cells in Crohns samples compared with controls. This finding was corroborated by confocal microscopy, showing enhanced infiltrates of cells positive for the dendritic cell markers, DC-SIGN(+) and CD83(+), in the subepithelial dome. Moreover, the CD83(+) cells in Crohns tissues showed reduced expression of the lymph node migratory receptor, CCR7, possibly contributing to the high numbers of dendritic cells. After exposure to nonpathogenic Escherichia coli in Ussing chambers, dendritic cells in the subepithelial dome of Crohns disease demonstrated increased co-localization with translocated bacteria. Immunohistochemical results revealed that DC-SIGN(+) cells in Crohns tissues were found to express toll-like receptor 4 and produce tumor necrosis factor-a. In conclusion, nonmigrating dendritic cells that accumulate in the subepithelial dome and internalize nonpathogenic bacteria may be important for the onset and perpetuation of mucosal inflammation in Crohns disease.

  • 170.
    Samuelsson, Kristina
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Berglund, J.
    Marine Ecology, Department of Ecology and Environmental Science, Umeå University, SE-901 87 Umeå, Sweden, Umeå Marine Science Centre, SE-910 20 Hörnefors, Sweden.
    Andersson, A.
    Marine Ecology, Department of Ecology and Environmental Science, Umeå University, SE-901 87 Umeå, Sweden, Umeå Marine Science Centre, SE-910 20 Hörnefors, Sweden.
    Factors structuring the heterotrophic flagellate and ciliate community along a brackish water primary production gradient2006In: Journal of Plankton Research, ISSN 0142-7873, E-ISSN 1464-3774, Vol. 28, no 4, p. 345-349Article in journal (Refereed)
    Abstract [en]

    A seasonal study of dominant protozoa, heterotrophic flagellates and ciliates, was performed along a primary production gradient in the northern Baltic Sea. The abundances of protozoa increased with increasing primary production from north to south. Small cells dominated in the law productive north, while larger cells became more dominant in the south. The highest biovolume concentration of protozoa was observed in summer in the north and during spring in the south. The seasonal succession of protozoa followed a general pattern: choanoflagellates, large flagellates and ciliates showed peaks during spring and autumn, while small bacterivorous nanoflagellates peaked during the summer. An in situ experiment indicated that the inverse relationship between loricated choanoflagellates and other small flagellates may be explained by a seasonal change in the predator community and a seasonal change in the access to surface-attachment sites. Principal component regression analyses including all data showed that 46% of the variation of small flagellates and 20% of the variation of large flagellates could be explained by temperature and bacterial biomass. Ciliates showed a significant relationship to latitude and salinity, explaining 12-24% of the variation. In conclusion, the field data indicated that the protozoan community in general was resource controlled. © The Author 2006. Published by Oxford University Press. All rights reserved.

  • 171.
    Sandström, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Gasslander, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    von Dobeln, U.
    Department of Laboratory Medicine Karolinska University Hospital Huddinge, Stockholm.
    Svanvik, Joar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Serum amino acid profile in patients with acute pancreatitis2008In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 35, no 1, p. 225-231Article in journal (Refereed)
    Abstract [en]

    Patients in the early phase of acute pancreatitis (AP) have reduced serum levels of arginine and citrulline. This may be of patho-biological importance, since arginine is the substrate for nitric oxide, which in turn is involved in normal pancreatic physiology and in the inflammatory process. Serum amino acid spectrum was measured daily for five days and after recovery six weeks later in 19 patients admitted to the hospital for acute pancreatitis. These patients had abnormal levels of most amino acids including arginine, citrulline, glutamine and glutamate. Phenylalanine and glutamate were increased, while arginine, citrulline, ornithine and glutamine were decreased compared to levels after recovery. NO2/NO3 concentration in the urine, but not serum arginase activity, was significantly increased day 1 compared to day 5 after admission. Acute pancreatitis causes a disturbance of the serum amino acid spectrum, with possible implications for the inflammatory process and organ function both in the pancreas and the gut. Supplementation of selected amino acids could possibly be of value in this severe condition. © 2007 Springer-Verlag.

  • 172.
    Savickiene, Jurate
    et al.
    Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania.
    Borutinskaite, Veronika-Viktorija
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Treigyte, Grazina
    Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Navakauskiene, Ruta
    Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania.
    The novel histone deacetylase inhibitor BML-210 exerts growth inhibitory, proapoptotic and differentiation stimulating effects on the human leukemia cell lines2006In: European Journal of Pharmacology, ISSN 0014-2999, Vol. 549, no 1-3, p. 9-18Article in journal (Refereed)
    Abstract [en]

    Histone deacetylase inhibitors have a potent role in the strategy for the treatment of leukemias. BML-210 (N-(2-Aminophenyl)-N′ phenyloctanol diamine) is the novel histone deacetylase inhibitor, and its mechanism of action has not been characterized. In this study, we examined the in vitro effects of BML-210 on the human leukemia cell lines (NB4, HL-60, THP-1, and K562). We found that BML-210 inhibits the growth of all cell lines and promotes apoptosis in a dose- and time-dependent manner. BML-210 alone induces HL-60 and K562 cell differentiation (up to 30%) to granulocytes and erythrocytes, respectively, and in combination with differentiation agents — all-trans retinoic acid and hemin, markedly potentates it. Those treatments cause G1 arrest and histone H4 acetylation, affects transcription factor NF-κB and Sp1 binding activity to their consensus sequences, the p21 or the FasL promoters, and influences expression of Sp1, NF-κB, p21 and FasL. These findings suggest that BML-210 could be a promising antileukemic agent to induce apoptosis and to modulate differentiation through the modulation of histone acetylation and gene expression.

  • 173.
    Savickiene, Jurate
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Treigyte, G
    Pivoriunas, A
    Navakauskiene, Ruta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Sp1 and NF-kappa B transcription factor activity in the regulation of the p21 and FasL promoters during promyelocytic leukemia cell monocytic differentiation and its associated apoptosis2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 569-577Article in journal (Refereed)
    Abstract [en]

    Treatment of human acute promyelocytic leukemia cells with phorbol 12-myristate 13-acetate (PMA) results in growth arrest and differentiation toward monocytes, which subsequently die by apoptosis. However, the relationship between terminal differentiation and apoptosis remains unclear. Here we have studied Sp1 and nuclear factor B-K (NF-B-K) transcription factor activity in controlling promoters of cell cycle-regulating (p21/WAF1/CIP1) and cell death (FasL) genes during monocytic differentiation and apoptosis of the human acute promyelocytic leukemia cell lines NB4 and HL-60. Using the electrophoretic mobility shift assay, we observed that PMA treatment of NB4 cells caused an early response in Sp1 binding to the p21 and FasL promoters at 8 h. The firmly adherent cell phenotype, characteristic of differentiated cells, retained Sp1-binding activity to either promoter, but it was often lost completely in detached, apoptotic cells. The association of Sp1 with the p21 promoter during monocytic differentiation correlated with the levels of expressed p21 in the cytoplasmic fraction, as detected by immunoblotting. In HL-60 cells, very weak or no Sp1 binding to either promoter was observed. Low NF-B-K affinity for its consensus sites and to the FasL promoter was characteristic of apoptotic cells. The results of this study suggest a positive role of Sp1 and NF-B-K, as regulators of p21 and FasL genes, in leukemic cell survival and monocytic differentiation and a negative role in apoptotic cell death.

  • 174.
    Savickiene, Jurate
    et al.
    Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania.
    Treigyte, Grazina
    Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania.
    Borutinskaite, Veronika
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Navakauskiene, Ruta
    Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    The histone deacetylase inhibitor FK228 distinctly sensitizes the human leukemia cells to retinoic acid-induced differentiation2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, Vol. 1091, p. 368-384Article in journal (Refereed)
    Abstract [en]

    FK228 (depsipeptide) is a novel histone deacetylase inhibitor (HDACI) that has shown therapeutical efficacy in clinical trials for malignant lymphoma. In this article, we examined in vitro effects of FK228 on human leukemia cell lines, NB4 and HL-60. FK228 alone (0.2–1 ng/mL) inhibited leukemia cell growth in a dose-dependent manner and induced death by apoptosis. FK228 had selective differentiating effects on two cell lines when used for 6 h before induction of granulocytic differentiation by retinoic acid (RA) or in combination with RA. These effects were accompanied by a time- and dose-dependent histone H4 hyper-acetylation or histone H3 dephosphorylation and alterations in DNA binding of NF-κB in association with cell death and differentiation. Pifithrin-α (PFT), an inhibitor of p53 transcriptional activity, protected only NB4 cells with functional p53 from FK228-induced apoptosis and did not interfere with antiproliferative activity in p53-negative HL-60 cells. In NB4 cells, PFT inhibited p53 binding to the p21 (Waf1/Cip1) promotor and induced DNA binding of NF-κB leading to enhanced cell survival. Thus, beneficial effects of FK228 on human promyelocytic leukemia may be exerted through the induction of differentiation or apoptosis via histone modification and selective involvement of transcription factors, such as NF-κB and p53.

  • 175.
    Savickiene, Jurate
    et al.
    Institute of Biochemistry, Vilnius.
    Treigyte, Grazina
    Institute of Biochemistry, Vilnius.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Navakauskiene, Ruta
    Institute of Biochemistry, Vilnius.
    Response of Retinoic Acid-Resistant KG1 Cells to Combination of Retinoic Acid with Diverse Histone Deacetylase Inhibitors2009In: NATURAL COMPOUNDS AND THEIR ROLE IN APOPTOTIC CELL SIGNALING PATHWAYS, ISSN 0077-8923, Vol. 1171, p. 321-333Article in journal (Refereed)
    Abstract [en]

    Acute promyelocytic leukemia KG1 cells with t(11;17) PLZF-RAR alpha respond poorly to the differentiation inducer all-trans retinoic acid (RA), and the reason for the RA resistance is the recruitment of histone deacetylase by PLZF-RAR alpha. Here, we demonstrate that histone deacetylase inhibitors (HDACIs), FK228, BML-210, phenyl butyrate, and vitamin B3, in different combinations with RA, act as KG1 cell growth inhibitors. Partial differentiation to granulocytes was induced by 3 mu mol/L RA, and its combination with HDAC inhibitors did not enhance RA-induced but potentiated apoptosis. HDACIs induced accumulation of hyperacetylated histone H4. Chromatin immunoprecipitation analysis has revealed phenyl butyrate and its combinations with RA and vitamin B3 cause histone H4 acetylation in the p21 promoter regions corresponding to p53 and/or Sp1 sites. This was coincident with the activation of the transcription factor p53-binding activity to the p21 promoter in electrophoretic mobility shift assay. The results indicate the possibility of using the combination of agents for therapeutic strategy in RA-resistant acute myeloid leukemia to produce both differentiation and apoptosis.

  • 176.
    Savickiene, Jurate
    et al.
    Institute for Biochemistry, Vilnius, Lithuania .
    Treigyte, Grazina
    Institute for Biochemistry, Vilnius, Lithuania .
    Vistartaite, Giedre
    Institute for Biochemistry, Vilnius, Lithuania .
    Tunaitis, Virginijus
    State Research Institute Centre Innovat Med, Vilnius, Lithuania .
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Navakauskiene, Ruta
    Institute for Biochemistry, Vilnius, Lithuania .
    C/EBP alpha and PU.1 are involved in distinct differentiation responses of acute promyelocytic leukemia HL-60 and NB4 cells via chromatin remodeling2011In: DIFFERENTIATION, ISSN 0301-4681, Vol. 81, no 1, p. 57-67Article in journal (Refereed)
    Abstract [en]

    C/EBP alpha and PU.1 are the basic transcription factors that control differentiation-related genes, including granulocyte- colony-stimulating factor (G-CSFR) and human neutrophil elastase (HNE). Here, we analyzed a role of C/EBP alpha and PU.1 in human acute leukemia cell lines, HL-60 and NB4, in association with a modified chromatin structure by histone deacetylase inhibitors, FK228, sodium phenyl butyrate and vitamin B3. We found that sodium phenyl butyrate alone and 6 h-pretreatment with phenyl butyrate or FK228 before the induction of differentiation with all-trans-retinoic acid in the presence of vitamin B3 effectively accelerated and enhanced differentiation to granulocytes in HL-60 but not in NB4 cells as detected by NBT test and the expression of CD11b and CD114 (G-CSFR) using flow cytometric analysis. HDACIs induced a time- and dose-dependent accumulation of hyper-acetylated histone H4 in both cell lines with the delay in NB4 cells. Time-dependent different induction of HL-60 and NB4 cell differentiation was paralleled by the activation of C/EBP alpha and PU.1 binding to the G-CSFR and the HNE promoters in electrophoretic mobility shift assay. Chromatin immunoprecipitation analysis revealed histone H4 acetylation in the G-CSF receptor promoter at the C/EBP alpha binding site in HL-60 but not in NB4 cells under the combined treatment. The results indicate that epigenetic events, such as histone acetylation, are involved in the activity modulation of the key transcription factors responsible for the induction of granulocytic differentiation in promyelocytic leukemia cells.

  • 177.
    Schon, T
    et al.
    Kalmar County Hospital, Sweden .
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Shortening the short-course therapy-insights into host immunity may contribute to new treatment strategies for tuberculosis2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 4, p. 368-382Article, review/survey (Refereed)
    Abstract [en]

    Schon T, Lerm M, Stendahl O (Kalmar County Hospital, Kalmar; and Linkoping University, Linkoping; Sweden). Shortening the short-course therapy: insights into host immunity may contribute to newtreatment strategies for tuberculosis (Review). J Intern Med 2013; 273: 368-382. Achieving global control of tuberculosis (TB) is a great challenge considering the current increase in multidrug resistance and mortality rate. Considerable efforts are therefore being made to develop new effective vaccines, more effective and rapid diagnostic tools as well as new drugs. Shortening the duration of TB treatment with revised regimens and modes of delivery of existing drugs, as well as development of new antimicrobial agents and optimization of the host response with adjuvant immunotherapy could have a profound impact on TB cure rates. Recent data show that chronic worm infection and deficiencies in micronutrients such as vitamin D and arginine are potential areas of intervention to optimize host immunity. Nutritional supplementation to enhance nitric oxide production and vitamin D-mediated effector functions as well as the treatment of worm infection to reduce immunosuppressive effects of regulatory T (Treg) lymphocytes may be more suitable and accessible strategies for highly endemic areas than adjuvant cytokine therapy. In this review, we focus mainly on immune control of human TB, and discuss how current treatment strategies, including immunotherapy and nutritional supplementation, could be optimized to enhance the host response leading to more effective treatment.

  • 178.
    Schon, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences. Kalmar County Hospital, Sweden .
    Jureen, P
    Swedish Institute Communicable Disease Control SMI, Sweden .
    Chryssanthou, E
    Karolinska University Hospital, Sweden .
    Giske, C G.
    Karolinska University Hospital, Sweden .
    Kahlmeter, G
    Vaxjo Hospital, Sweden .
    Hoffner, S
    Swedish Institute Communicable Disease Control SMI, Sweden .
    Angeby, K
    Karolinska University Hospital, Sweden .
    Rifampicin-resistant and rifabutin-susceptible Mycobacterium tuberculosis strains: a breakpoint artefact?2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 9, p. 2074-2077Article in journal (Refereed)
    Abstract [en]

    It has long been assumed that some rifampicin-resistant Mycobacterium tuberculosis strains are susceptible to, and thus treatable with, rifabutin. However, clinical breakpoints for susceptibility testing of rifabutin as well as the evidence for a clinical effect of rifabutin in rifampicin-resistant strains remains poorly defined. The objective of this study was to re-evaluate the breakpoint for rifabutin in relation to its MIC wild-type distribution and the presence of mutations in rpoB. less thanbrgreater than less thanbrgreater thanThe MIC in 7H10 Middlebrook medium was determined for clinical isolates of M. tuberculosis (n95), where a majority were multidrug resistant. Additionally, all strains were screened for rpoB mutations by sequencing and the GenoType MTBDRplus assay. less thanbrgreater than less thanbrgreater thanRifampicin resistance was confirmed by genotypical and/or phenotypical tests in 73 isolates (76.8). Nineteen isolates, defined as rifampicin resistant and rifabutin susceptible according to the present breakpoint, exhibited significantly higher MICs of rifabutin (0.0640.5 mg/L) than rifabutin-susceptible isolates without any detectable mutations in rpoB (P0.001). These 19 isolates were clearly resistant to rifampicin (MIC 2256 mg/L) and all but one had mutations in rpoB, with 9 (47.4) specifically in Asp516Val. less thanbrgreater than less thanbrgreater thanOur results indicate that rifampicin-resistant but rifabutin-susceptible isolates according to the present breakpoints harbour rpoB mutations and have a rifabutin MIC significantly higher than strains without any detectable mutations in rpoB. So far there are no clinical, pharmacological or microbiological data to confirm that such isolates can be treated with rifabutin and we suggest a revision of the current breakpoints.

  • 179.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Gullberg, Elisabet
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    McKay, Derek M.
    Department of Physiology and Biophysics, University of Calgary, Calgary, Canada.
    Rhodes, Jonathan M.
    Department of Medicine, Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, University of Liverpool, Liverpool, United Kingdom.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Infliximab reduces bacterial uptake in mucosal biopsies of Crohn’s colitis viamicrotubule-dependent pathwayManuscript (preprint) (Other academic)
    Abstract [en]

    Background: A defective intestinal barrier, shown by increased paracellular permeability is an importantpathogenic factor in Crohn’s disease (CD). TNFα is a key mediator in the regulation of the intestinal barrierfunction. Treatment with antibodies directed against TNFα, such as infliximab, has been established as animportant part of the therapeutic arsenal in severe Crohn’s disease, but the mechanisms of action have yet tobe elucidated. Part of infliximab’s effect has been suggested to be reduced apoptosis of epithelial cells andthereby reduced paracellular permeability. Our aim was to study how infliximab affects uptake of adherent E.coli across the colonic mucosa in CD.

    Method: Seven patients with active CD colitis were examined before and after a four week treatment withinfliximab. Control biopsies were taken from healthy volunteers (4) and patients undergoing controlexamination for colonic polyps (4), aged 36 (range 25-81), coloscopy. Biopsies were taken from macroscopicallynon-inflamed descending colon and were mounted in Ussing chambers to study barrier function. Transmucosalpassage of green fluorescent protein (GFP) incorporated E. coli HM427, an adherent bacteria isolated from thecolon of a CD patient, was studied by quantifying the translocated fluorescent bacteria using flow cytometry.

    Results: Bacterial passage across the colonic mucosa was increased in CD (2500 ± 300 arb. units) comparedwith controls (960 ± 280; p<0.05), and was reduced to 500 ± 200 units after the infliximab treatment (p<0.05).In biopsies treated with colchicine (a microtubuline inhibitor) uptake of E. coli HM427 was reduced by 2/3compared to non-treated biopsies.

    Conclusion: Patients with active Crohn’s disease showed a defect in the barrier to adherent E. coli, which waspartly mediated through a microtubule dependent uptake. The four week treatment with infliximab improvedthe intestinal barrier to these bacteria. This may constitute an important part of infliximab’s mechanisms ofaction in active colitis.

  • 180.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Kufer, Thomas
    Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Germany.
    Jiang, Tieshan
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Jandu, Narveen
    University of Toronto, Toronto, Canada.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Ubiquitination and degradation of the Crohn’s Disease associated protein Nod2involves the E2 enzyme UBE2G2Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Mutations predisposing to Crohn’s disease (CD) have been mapped to the CARD15/Nod2 locus,which encodes a cytoplasmic receptor hereafter referred to as Nod2, a member of the NACHT-LRR (NLR) familyof pattern recognition receptors. The binding of bacterial muramyl dipeptide (MDP) to Nod2 triggers theactivation of the nuclear factor-κB (NFκB) pathway, thereby inducing a number of pro-inflammatory genes. Themost common variant of Nod2 associated with CD is the frame shift mutation L1007fs, which results in atruncated form of the protein unable to respond to MDP. Despite active research, little is known about howNod2 is regulated. The aim of this study was to investigate if the cellular Nod2 protein level is regulated by theubiquitin-proteasome pathway.

    Material and Methods/Results: Nod2 was shown to be subjected to rapid turnover in the colorectal cancer cellline SW480 as measured by immunoprecipitation following inhibition of protein synthesis with cyklohexamide.Immunoprecipitation of Nod2 also revealed co-precipitation of ubiquitin, suggesting that Nod2 wasubiquitinated. In line with this observation, inhibition of the proteasome using MG-132 or lactacystin, resultedin increased levels of Nod2 in the cells. UBE2G2, an E2 enzyme, thus conferring specificity of ubiquitin binding,was identified to have affinity for the CARD domain of Nod2. Activation of Nod2 with MDP enhanced itsubiquitination, and increasing amounts of UBE2G2 in the cells abrogated NFB-activation, suggesting thatubiquitination of Nod2 may be important for the resolution of the inflammatory signal.

    Conclusion: Taken together, our results show that the cellular level of Nod2 protein is regulated via theubiquitin-proteasome pathway, suggesting that Nod2-driven inflammation may be resolved through rapiddegradation of Nod2. Consequently, not only polymorphisms in Nod2 directly, but also in genes regulatingNod2 protein levels may contribute to the susceptibility to Crohn’s disease.

  • 181.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Halfvarsson, Jonas
    Örebro University Hospital.
    Torkvist, Leif
    Karolinska University Hospital.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
    Sjoqvist, Urban
    Karolinska University Hospital.
    Lordal, Mikael
    Karolinska University Hospital.
    Tysk, Curt
    Örebro University Hospital.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Combined Polymorphisms in Genes Encoding the Inflammasome Components NALP3 and CARD8 Confer Susceptibility to Crohns Disease in Swedish Men2009In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 5, p. 1180-1188Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES : Crohns disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1 beta. Production of mature IL-1 beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1 beta secretion. The combination of the polymorphisms CARD8 (C10X) and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis. Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD.

    METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping.

    RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74).

    CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

  • 182.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Elias, D.
    Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm, Sweden and Armauer Hansen Research Institute (AHRI), Addis Ababa.
    Moges, F.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Melese, E.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Tessema, T.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Britton, Sven
    Dept of Infectious Diseases, Karolinska Hospital, Stockholm.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis2003In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 21, no 3, p. 483-488Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is involved in the host defence against tuberculosis (TB). Patients with TB exhibit increased catabolism and reduced energy intake. Thus the hypothesis for this study was that restoring a relative deficiency in the amino acid arginine, the substrate for mycobactericidal NO production, would improve the clinical outcome of TB by increasing NO production.

    In a randomised double-blind study, patients with smear-positive TB (n=120) were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. Primary outcomes were sputum conversion, weight gain, and clinical symptoms after week 8. Secondary outcomes were sedimentation rate and levels of NO metabolites, arginine, citrulline, and tumour necrosis factor‐α.

    Compared with the human immunodeficiency virus (HIV)−/TB+ placebo group, the HIV−/TB+ patients in the arginine group showed significant improvement, defined as increased weight gain, higher sputum conversion rate and faster reduction of symptoms, such as cough. The arginine level increased after week 2 in the HIV−/TB+ arginine group (100.2 µM (range 90.5–109.9) versus 142.1 µM (range 114.1–170.1)) compared with the HIV−/TB+ placebo group (105.5 µM (range 93.7–117.3) versus 95.7 µM (range 82.4–108.9)). HIV seroprevalence was 52.5%. No clinical improvement or increase in serum arginine was detected in arginine supplemented HIV+/TB+ patients compared with placebo.

    Arginine is beneficial as an adjuvant treatment in human immunodeficiency virus-negative patients with active tuberculosis, most likely mediated by increased production of nitric oxide.

  • 183.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Westman, A
    Karolinska Hospital.
    Elias, D
    Armauer Hansen Research Institute.
    Abate, E
    Armauer Hansen Res Instititute.
    Diro, E
    Gondar University.
    Moges, F
    Gondar University.
    Kassu, A
    Gondar University.
    Ayele, B
    Gondar University.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Getachew, A
    Gondar University.
    Britton, S
    Karolinska Hospital.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial2011In: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 91, no 5, p. 370-377Article in journal (Refereed)
    Abstract [en]

    In tuberculosis (TB), the production of nitric oxide (NO) is confirmed but its importance in host defense is debated. Our aim was to investigate whether a food supplement rich in arginine could enhance clinical improvement in TB patients by increased NO production. Smear positive TB patients from Gondar, Ethiopia (n = 180) were randomized to a food supplementation rich in arginine (peanuts, equivalent to 1 g of arginine/day) or with a low arginine content (wheat crackers, locally called daboqolo) during four weeks. The primary outcome was cure rate according to the WHO classification and secondary outcomes were sputum smear conversion, weight gain, sedimentation rate, reduction of cough and chest X-ray improvement as well as levels of NO in urine (uNO) or exhaled air (eNO) at two months. There was no effect of the intervention on the primary outcome (OR 1.44, 95% CI: 0.69-3.0, p = 0.39) or secondary outcomes. In the subgroup analysis according to HIV status, peanut supplemented HIV+/TB patients showed increased cure rate (83.8% (31/37) vs 53.1% (17/32), p andlt; 0.01). A low baseline eNO (andlt; 10 ppb) in HIV+/TB patients was associated with a decreased cure rate. We conclude that nutritional supplementation with a food supplement rich in arginine did not have any overall clinical effect. In the subgroup of HIV positive TB patients, it significantly increased the cure rate and as an additional finding in this subgroup, low initial levels of NO in exhaled air were associated with a poor clinical outcome but this needs to be confirmed in further studies.

  • 184.
    Serrander, Lena
    et al.
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Jerström Skarman, Petra
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Rasmusson, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Witke, Walter
    European Molecular Biology Laboratory Mouse Biology Program, Monterotondo, Italy.
    Lew, Daniel P.
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Krause, Karl-Heinz
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nüße, Oliver
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Selective Inhibition of IgG-Mediated Phagocytosis in Gelsolin-Deficient Murine Neutrophils2000In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 165, no 5, p. 2451-2457Article in journal (Refereed)
    Abstract [en]

    Phagocytosis and the microbicidal functions of neutrophils require dynamic changes of the actin cytoskeleton. We have investigated the role of gelsolin, a calcium-dependent actin severing and capping protein, in peripheral blood neutrophils from gelsolin-null (Gsn) mice. The phagocytosis of complement opsonized yeast was only minimally affected. In contrast, phagocytosis of IgG-opsonized yeast was reduced close to background level in Gsn neutrophils. Thus, gelsolin is essential for efficient IgG- but not complement-mediated phagocytosis. Furthermore, attachment of IgG-opsonized yeast to Gsn neutrophils was reduced (∼50%) but not to the same extent as ingestion (∼73%). This was not due to reduced surface expression of the Fcγ-receptor or its lateral mobility. This suggests that attachment and ingestion of IgG-opsonized yeast by murine neutrophils are actin-dependent and gelsolin is important for both steps in phagocytosis. We also investigated granule exocytosis and several steps in phagosome processing, namely the formation of actin around the phagosome, translocation of granules, and activation of the NADPH-oxidase. All these functions were normal in Gsn neutrophils. Thus, the role of gelsolin is specific for IgG-mediated phagocytosis. Our data suggest that gelsolin is part of the molecular machinery that distinguishes complement and IgG-mediated phagocytosis. The latter requires a more dynamic reorganization of the cytoskeleton.

  • 185.
    Shleev, Sergey
    et al.
    Malmö University.
    Wetterö, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Rheumatology . Linköping University, Faculty of Health Sciences.
    Magnusson , Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Ruzgas, Tautgirdas
    Malmö University.
    Simultaneous use of electrochemistry and chemiluminescence to detect reactive oxygen species produced by human neutrophils2008In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 32, no 12, p. 1486-1496Article in journal (Refereed)
    Abstract [en]

    A novel approach for the simultaneous optical and electrochemical detection of biologically produced reactive oxygen species has been developed and applied. The set-up consists of a luminol-dependent chemiluminescence assay combined with two amperometric biosensors sensitive to superoxide anion radicals (O-2(center dot-))and hydrogen peroxide (H2O2), respectively. The method permits direct, real-time in vitro determination of both extra-and intracellular O-2(center dot-) and H2O2 produced by human neutrophil granulocytes. The rate of O-2(center dot-) production by stimulated neutrophils was calculated to about 10(-17) mol s(-1) per single cell. With inhibited NADPH oxidase, a distinct extracellular release of H2O2 instead of O-2(center dot-) was obtained from stimulated neutrophils with the rate of about 3 . 10(-18) mol s(-1) per single cell. When the H2O2 release was discontinued, fast H2O2 utilisation was observed. Direct interaction with and possibly attachment of neutrophils to redox protein-modified gold electrodes, resulted in a spontaneous respiratory burst in the population of cells closely associated to the electrode surface. Hence, further stimulation of human neutrophils with a potent receptor agonist (fMLF) did not significantly increase the O-2(center dot-) sensitive amperometric response. By contrast, the H2O2 sensitive biosensor, based on an HRP-modified graphite electrode, was able to reflect the bulk concentration of H2O2, produced by stimulated neutrophils and would be very useful in modestly equipped biomedical research laboratories. In summary, the system would also be appropriate for assessment of several other metabolites in different cell types, and tissues of varying complexity, with only minor electrode modifications.

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  • 186.
    Sjö, Anita
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Holmgren Peterson, Kajsa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Association of a-dystrobrevin with reorganizing tight junctions2005In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 203, no 1, p. 21-30Article in journal (Refereed)
    Abstract [en]

    Alpha-dystrobrevin (a-DB) has been described primarily as a cytoplasmic component of the dystrophin-glycoprotein complex in skeletal muscle cells. Isoforms of a-DB show different localization in cells and tissues, at basolateral membranes in epithelial cells, dystrobrevins mediate contact with the extracellular matrix, peripheral and transmembrane proteins and the filamentous actin cytoskeleton. Beside their structural role, a-DBs are assumed to be important in cell signalling and cell differentiation. We have primarily assessed the role of a-DB in two epithelial cell lines (MDCK I, HT 29), which represent different developmental stages and exhibit distinct permeability characteristics. Using a polyclonal anti-a-DB antibody, we have investigated its expression, localization and association with tight junction (TJ)- associated proteins (ZO-1, occludin) before and after protein kinase C (PKC) activation with phorbol myristate acetate. Distinct subsets of a-DB isoforms were detected in the two cell lines by immunoblotting. In both cell lines there was submembranous localization of a-DB both apically and basolaterally, shown with confocal imaging. PKC activation caused a reorganization of TJ, which was parallel to increased localization of a-DB to TJ areas, most pronounced in MDCK I cells. Moreover, actin and ZO-1 co-immunoprecipitated with a-DB, as displayed with immunoblotting. Our findings suggest that a-dystrobrevin specifically is associated with the tight junctions during their reorganization. © Springer Science+Business Media, Inc. 2005.

  • 187.
    Sjö, Anita
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Holmgren Peterson, Kajsa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Protein kinase C activation has distinct effects on the localization, phosphorylation and detergent solubility of the claudin protein family in tight and leaky epithelial cells2010In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 236, no 2, p. 181-189Article in journal (Refereed)
    Abstract [en]

    We have previously shown that protein kinase C (PKC) activation has distinct effects on the structure and barrier properties of cultured epithelial cells (HT29 and MDCK I). Since the claudin family of tight junction (TJ)-associated proteins is considered to be crucial for the function of mature TJ, we assessed their expression patterns and cellular destination, detergent solubility and phosphorylation upon PKC stimulation for 2 or 18 h with phorbol myristate acetate (PMA). In HT29 cells, claudins 1, 3, 4 and 5 and possibly claudin 2 were redistributed to apical cell-cell contacts after PKC activation and the amounts of claudins 1, 3 and 5, but not of claudin 2, were increased in cell lysates. By contrast, in MDCK I cells, PMA treatment resulted in redistribution of claudins 1, 3, 4 and 5 from the TJ and in reorganization of the proteins into more insoluble complexes. Claudins 1 and 4 were phosphorylated in both MDCK I and HT29 cells, but PKC-induced changes in claudin phosphorylation state were detected only in MDCK I cells. A major difference between HT29 and MDCK I cells, which have low and high basal transepithelial electrical resistance, respectively, was the absence of claudin 2 in the latter. Our findings show that PKC activation targets in characteristic ways the expression patterns, destination, detergent solubility and phosphorylation state of claudins in epithelial cells with different capacities to form an epithelial barrier.

  • 188.
    Sjö, Anita
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Peterson, KH
    Protein kinase C activation improves the barrier of HT 29 epithelial cells and regulates translocation and phosphorylation of tight junction proteins2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, p. 2788-Conference paper (Other academic)
  • 189.
    Skogmar, Sten
    et al.
    Lund University, Sweden .
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Tolera Balcha, Taye
    Lund University, Sweden Minist Heatlh, Ethiopia .
    Habtamu Jemal, Zelalem
    Oromia Regional Health Bur, Ethiopia .
    Tibesso, Gudeta
    Columbia University, Ethiopia .
    Bjork, Jonas
    Skåne University Hospital, Sweden .
    Bjorkman, Per
    Lund University, Sweden .
    CD4 Cell Levels during Treatment for Tuberculosis (TB) in Ethiopian Adults and Clinical Markers Associated with CD4 Lymphocytopenia2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 83270-Article in journal (Refereed)
    Abstract [en]

    Background: The clinical correlations and significance of subnormal CD4 levels in HIV-negative patients with TB are unclear. We have determined CD4 cell levels longitudinally during anti-tuberculosis treatment (ATT) in patients, with and without HIV co-infection, and their associations with clinical variables. Method: Adults diagnosed with TB (maximum duration of ATT for 2 weeks, and with no history of antiretroviral therapy (ART) in HIV-positive subjects) were included consecutively in eight out-patient clinics in Ethiopia. Healthy individuals were recruited for comparison at one of the study health centers. Data on patient characteristics and physical findings were collected by trained nurses following a structured questionnaire at inclusion and on follow-up visits at 2 and 6 months. In parallel, peripheral blood CD4 cell levels were determined. The evolution of CD4 cell levels during ATT was assessed, and the association between clinical characteristics and low CD4 cell levels at baseline was investigated using regression analysis. Results: In total, 1116 TB patients were included (307 HIV-infected). Among 809 HIV-negative patients, 200 (25%) had subnormal CD4 cell counts (less than500 cells/mm(3)), with less than350 cells/mm(3) in 82 (10%) individuals. CD4 cell levels increased significantly during the course of ATT in both HIV+ and HIV-TB-patients, but did not reach the levels in healthy subjects (median 896 cells/mm(3)). Sputum smear status, signs of wasting (low mid upper arm circumference (MUAC)), and bedridden state were significantly associated with low CD4 cell counts. Conclusion: A high proportion of Ethiopian TB patients have subnormal CD4 cell counts before starting treatment. Low CD4 cell levels are associated with smear positive disease and signs of wasting. The continuous increase of CD4 cell counts during the course of ATT suggest a reversible impact of active TB on CD4 cell homeostasis, which may be considered in interpretation of CD4 cell counts in HIV/TB co-infected subjects.

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  • 190.
    Stark, Lisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Matussek, Andreas
    County Hospital Ryhov.
    Strindhall, Jan
    School of Health Science, Jönköping.
    Geffers, Robert
    Helmholtz Centre for Infectious Research.
    Buer, Jan
    University Hospital Essen.
    Kihlström, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Monnecke, Stefan
    Technical University of Dresden.
    Lofgren, Sture
    County Hospital Ryhov.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Staphylococcus aureus isolates from blood and anterior nares induce similar innate immune responses in endothelial cells2009In: APMIS, ISSN 0903-4641, Vol. 117, no 11, p. 814-824Article in journal (Refereed)
    Abstract [en]

    To evaluate the possibility to distinguish virulent from non-virulent isolates, gene expression in human umbilical vein endothelial cells (HUVEC) induced by invasive and colonizing isolates of Staphylococcus aureus was compared. Gene expression in HUVEC was analyzed by microarray analysis after 4 h of infection with Staphylococcus aureus, isolated from healthy nasal carriers (n = 5) and from blood of septic patients (n = 5), to explore possible differences between the groups of bacteria in interaction with HUVEC. All isolates were spa-typed to disclose strain relatedness. Moreover, the isolates were characterized with DNA microarray to determine the presence of virulence genes and to investigate the potential genes of importance in HUVEC interaction. The expression of 41 genes was up-regulated, and four were down-regulated in HUVEC by all isolates. Most of the up-regulated genes encode cytokines, chemokines, interferon-induced proteins, proteins regulating apoptosis and cell proliferation. There was no difference in the gene expression pattern between HUVEC infected with invasive or colonizing isolates. Furthermore, there was no difference in the presence of bacterial virulence genes between the two groups. In conclusion, our data indicate that S. aureus isolates induce comparable expression patterns in HUVEC, irrespective of invasiveness or presence of virulence genes.

  • 191.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stimulation of macrophage innate immunity to prevent human mycobacterial disease in INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, vol 16, issue , pp E60-E602012In: INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, Elsevier , 2012, Vol. 16, p. E60-E60Conference paper (Refereed)
    Abstract [en]

    n/a

  • 192. Order onlineBuy this publication >>
    Sundberg, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nitrifyers in constructed wetlands treating landfill leachates2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Landfill leachate is produced many years after a landfill site closes. Hence, treatment by “natural methods”, as e.g. constructed wetlands, with low management requirements is attractive. Constructed wetlands usually provide both shallow and deep areas with aerobic and anaerobic zones, which is suitable for nitrification followed by denitrification of the ammonium-rich leachates. Full-scale treatment systems are influenced by climatic variables that affect the microbial community. Also, the operational strategy can have a considerable impact on both activity and composition of the microorganisms. Many studies have measured inflow/outflow water quality in treatment systems. Such “black box” studies describe the treatment efficiency but add little to an increased understanding of theorganisms performing the treatment or the spatial distribution of their activities and treatment processes.

    In this thesis we investigated seasonal and annual changes in potential nitrification and denitrification, and in the corresponding bacterial communities in constructed wetlands treating landfill leachates. Variations in the potential activity in full-scale systems were investigated over several years, using short-term incubation. The composition of the bacterial communities was investigated using a group-specific PCR primer pair targeting the 16S rRNA genes or a primer pair targeting the funtional gene nosZ. The PCR products were analysed by denaturing gradient gelelectrophoresis and subsequent nucleotide sequencing and phylogentic analysis.

    A stable ammonia-oxidising bacterial (AOB) community composition and potential ammonia-oxidation (PAO) were detected in the system with a year-round operation. On the other hand, changes in the AOB community composition which followed the operational schedule were detected in the overland flow area (OFA) running seasonally. Furthermore, the influence of operational strategy was indicated by a low PAO in the wastewater overland flow area and compact constructed wetland receiving high hydraulic loads, indicating the value of aeration. Higher PAO was detected in the OFAs where the hydraulic load followed literature guidelines.

    All systems supported diverse AOB communities, represented by several Nitrosomonas and Nitrosospira populations. The number of different populations detected in these wetlands was much higher than reported in municipal wastewater treatment plants, and differed from those in a parallel OFA treating municipal wastewater. Furthermore, the large variation in both potential activity and sequences detected in replicate samples suggests that such systems are spatially heterogenic.

    List of papers
    1. Overland flow systems for treatment of landfill leachates: Potential nitrification and structure of the ammonia-oxidising bacterial community during a growing season
    Open this publication in new window or tab >>Overland flow systems for treatment of landfill leachates: Potential nitrification and structure of the ammonia-oxidising bacterial community during a growing season
    2007 (English)In: Soil Biology and Biochemistry, ISSN 0038-0717, E-ISSN 1879-3428, Vol. 39, no 1, p. 127-138Article in journal (Refereed) Published
    Abstract [en]

    Overland flow systems are useful for treating landfill leachates, because they provide favourable conditions for nitrification and they are easy to maintain. However, little is known about the microbial communities in such systems or the nitrification capacity of those microorganisms. In this study, seasonal variations in potential nitrification and in community composition of nitrifying bacteria were investigated in two overland flow areas receiving leachate from landfills at Korslöt and Hagby, Sweden. Samples were collected in the settling ponds sediment and at two depths in the overland flow areas (the macrophyte litter layer and the rhizosphere) in May, August and November 2003. A short-term incubation method was used to measure potential oxidation of ammonia and nitrite (designated PAO and PNO). The ammonia-oxidising bacterial (AOB) community was investigated using a 16S rRNA gene approach that included PCR amplification and analysis of PCR products by denaturing gradient gel electrophoresis (DGGE), followed by nucleotide sequencing and phylogenetic analysis.

    PAO was determined in the range 5–2700 (NO2−+NO3−)-N g−1 dw d−1 and PNO in the range 60–2000 μg NO2−-N g−1 dw d−1. At Korslöt, PAO and PNO showed similar temporal variation in the different ecosystems, whereas no such relationship was noticed at Hagby. Considering both sites, there was no obvious change in the composition of the AOB community over the growing season. However, the composition did differ between the ecosystems: Nitrosomonas-like sequences were more common in the ponds, and in the litter layers they were found as often as Nitrosospira-like sequences, whereas Nitrosospira-like sequences were more common in the rhizospheres. Altogether, we found nine different AOB sequences, five Nitrosomonas-like and four Nitrosospira-like, which belonged to clusters 0, 2, 3b, 6a, 6b and 7. There was no apparent relationship between the number of AOB populations and the PAO in different soil layers and sediments.

    Place, publisher, year, edition, pages
    Elesevire, 2007
    Keywords
    Ammonia-oxidising bacterial community; Landfill leachates; Nitrification; Overland flow; 16S rDNA; Denaturing gradient gel electrophoresis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17919 (URN)10.1016/j.soilbio.2006.06.016 (DOI)
    Available from: 2009-04-24 Created: 2009-04-24 Last updated: 2018-03-13Bibliographically approved
    2. Potential nitrification and denitrification and the corresponding composition of the bacterial communities in a compact constructed wetland treating landfill leachates
    Open this publication in new window or tab >>Potential nitrification and denitrification and the corresponding composition of the bacterial communities in a compact constructed wetland treating landfill leachates
    2007 (English)In: Water Science and Technology, ISSN 0273-1223, E-ISSN 1996-9732, Vol. 56, no 3, p. 159-166Article in journal (Refereed) Published
    Abstract [en]

    Constructed wetlands can be used to decrease the high ammonium concentrations in landfill leachates. We investigated nitrification/denitrification activity and the corresponding bacterial communities in landfill leachate that was treated in a compact constructed wetland, Tveta Recycling Facility, Sweden. Samples were collected at three depths in a filter bed and the sediment from a connected open pond in July, September and November 2004. Potential ammonia oxidation was measured by short-term incubation method and potential denitrification by the acetylene inhibition technique. The ammonia-oxidising and the denitrifying bacterial communities were investigated using group-specific PCR primers targeting 16S rRNA genes and the functional gene nosZ, respectively. PCR products were analysed by denaturing gradient gel electrophoresis and nucleotide sequencing. The same degree of nitrification activity was observed in the pond sediment and at all levels in the filter bed, whereas the denitrification activity decreased with filter bed depth. Denitrification rates were higher in the open pond, even though the denitrifying bacterial community was more diverse in the filter bed. The ammonia-oxidising community was also more varied in the filter bed. In the filter bed and the open pond, there was no obvious relationship between the nitrification/denitrification activities and the composition of the corresponding bacterial communities.

    Keywords
    Denitrification, DGGE, landfill leachates, nitrification; nosZ, 16S rrNA
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17920 (URN)10.2166/wst.2007.524 (DOI)17802851 (PubMedID)
    Available from: 2009-04-24 Created: 2009-04-24 Last updated: 2018-03-13Bibliographically approved
    3. Development of the community structure and activity of ammoniaoxidising bacteria in overland flow systems used to treat landfill leachates
    Open this publication in new window or tab >>Development of the community structure and activity of ammoniaoxidising bacteria in overland flow systems used to treat landfill leachates
    2009 (English)In: Journal of Applied Microbiology, ISSN 1364-5072, E-ISSN 1365-2672Article in journal (Other academic) Submitted
    Abstract [en]

    Ammonium in landfill leachates can be nitrified in overland flow areas (OFA). We studied OFAs to investigate if changes occur in the ammonium oxidizing community as the ecosystem develops, and the influence of different operating conditions. Samples were collected from the macrophyte litter layers, the rhizospheres and the sediments in their associated settling ponds in May, August, and November during four years. Potential ammonia oxidation (PAO) was investigated by a short-term slurry incubation method. The composition of the ammonia-oxidising bacteria (AOB) communities was investigated by PCR, using a group-specific primer pair, followed by denaturing gradient gel electrophoresis and subsequent sequencing.

    A shift from a Nitrosomonas community to a mixture of Nitrosomonas and Nitrosospira was and a gradual increase in PAO was observed, but only in the litter layer in the youngest OFA. Both OFAs had diverse AOB communities belonging to six different clusters. Nitrosomonas clusters predominated in the OFA with higher PAO, whereas Nitrosospira clusters were more common in the OFA with lower PAO. There was a seasonal increase of AOB populations in the OFA that was not in use during winter, and a more stable composition of the AOB community and the PAO in the OFA with year-round application. Keywords: Ammonia-oxidising bacterial community; Landfill leachates; Nitrification; Overland flow; 16S rDNA; Denaturing gradient gel electrophoresis.

    Keywords
    Ammonia-oxidising bacterial community, Landfill leachates, Nitrification, Overland flow, 16S rDNA, Denaturing gradient gel electrophoresis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17921 (URN)
    Available from: 2009-04-24 Created: 2009-04-24 Last updated: 2018-03-13Bibliographically approved
    4. Ammonia oxidation and the corresponding bacterial communities in two overland flow areas treating landfill leachate or wastewater
    Open this publication in new window or tab >>Ammonia oxidation and the corresponding bacterial communities in two overland flow areas treating landfill leachate or wastewater
    2011 (English)In: Overland Flow and Surface Runoff / [ed] Tommy S W Wong, Nova Science Publishers, Inc., 2011, p. 346-Chapter in book (Refereed)
    Abstract [en]

    A high diversity of ammonium oxidising bacteria (AOB) has been observed in overland flow areas (OFA) treating ammonia-rich landfill leachate. The current section aimed to explore if treatment OFAs in general supports more diverse AOB communities than conventional treatment systems, or if it is a result of effluent composition. The potential ammonium oxidation and the AOB community composition were studied during three seasons in an OFA where one part received wastewater and the other landfill leachate. The AOB communities were investigated using group-specific PCR primers targeting the 16S rRNA gene, and analysed by DGGE and nucleotide sequencing. The potential ammonia oxidation, studied by short-time slurry incubation, was higher in the landfill OFA than in the wastewater area and highest in the litter layer. Higher activity correlated with the appearance of Nitrosomonas sp. belonging to cluster 7. Both overland flow areas supported a more diverse AOB community than in common wastewater treatment plants. Fifteen different AOB sequences were detected, but only three were observed in both OFAs, pointing to the impact of the effluent quality and/or the hydraulic load. The wastewater OFA, which received a higher load of effluents with 5-10 times lower ammonia concentrations, was dominated by AOB populations that are usually found in less favourable conditions.

    Place, publisher, year, edition, pages
    Nova Science Publishers, Inc., 2011
    Keywords
    Runoff -- Mathematical models, Streamflow -- Mathematical models, Frictional resistance (Hydrodynamics), ´Water Pollution, Nitrifying bacteria, SCIENCE / Earth Sciences / Hydrology, SCIENCE / Earth Sciences / Hydrology
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-17922 (URN)978-1-61122-868-7 (ISBN)
    Available from: 2009-04-24 Created: 2009-04-24 Last updated: 2018-03-13Bibliographically approved
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  • 193.
    Sundberg, Carina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Stendahl, Jenny S. K.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Sundblad-Tonderski, Karin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Overland flow systems for treatment of landfill leachates: Potential nitrification and structure of the ammonia-oxidising bacterial community during a growing season2007In: Soil Biology and Biochemistry, ISSN 0038-0717, E-ISSN 1879-3428, Vol. 39, no 1, p. 127-138Article in journal (Refereed)
    Abstract [en]

    Overland flow systems are useful for treating landfill leachates, because they provide favourable conditions for nitrification and they are easy to maintain. However, little is known about the microbial communities in such systems or the nitrification capacity of those microorganisms. In this study, seasonal variations in potential nitrification and in community composition of nitrifying bacteria were investigated in two overland flow areas receiving leachate from landfills at Korslöt and Hagby, Sweden. Samples were collected in the settling ponds sediment and at two depths in the overland flow areas (the macrophyte litter layer and the rhizosphere) in May, August and November 2003. A short-term incubation method was used to measure potential oxidation of ammonia and nitrite (designated PAO and PNO). The ammonia-oxidising bacterial (AOB) community was investigated using a 16S rRNA gene approach that included PCR amplification and analysis of PCR products by denaturing gradient gel electrophoresis (DGGE), followed by nucleotide sequencing and phylogenetic analysis.

    PAO was determined in the range 5–2700 (NO2−+NO3−)-N g−1 dw d−1 and PNO in the range 60–2000 μg NO2−-N g−1 dw d−1. At Korslöt, PAO and PNO showed similar temporal variation in the different ecosystems, whereas no such relationship was noticed at Hagby. Considering both sites, there was no obvious change in the composition of the AOB community over the growing season. However, the composition did differ between the ecosystems: Nitrosomonas-like sequences were more common in the ponds, and in the litter layers they were found as often as Nitrosospira-like sequences, whereas Nitrosospira-like sequences were more common in the rhizospheres. Altogether, we found nine different AOB sequences, five Nitrosomonas-like and four Nitrosospira-like, which belonged to clusters 0, 2, 3b, 6a, 6b and 7. There was no apparent relationship between the number of AOB populations and the PAO in different soil layers and sediments.

  • 194.
    Sundberg, Carina
    et al.
    Linköping University, The Tema Institute, Department of Water and Environmental Studies. Linköping University, Faculty of Arts and Sciences.
    Sundblad-Tonderski, Karin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ammonia oxidation and the corresponding bacterial communities in two overland flow areas treating landfill leachate or wastewater2011In: Overland Flow and Surface Runoff / [ed] Tommy S W Wong, Nova Science Publishers, Inc., 2011, p. 346-Chapter in book (Refereed)
    Abstract [en]

    A high diversity of ammonium oxidising bacteria (AOB) has been observed in overland flow areas (OFA) treating ammonia-rich landfill leachate. The current section aimed to explore if treatment OFAs in general supports more diverse AOB communities than conventional treatment systems, or if it is a result of effluent composition. The potential ammonium oxidation and the AOB community composition were studied during three seasons in an OFA where one part received wastewater and the other landfill leachate. The AOB communities were investigated using group-specific PCR primers targeting the 16S rRNA gene, and analysed by DGGE and nucleotide sequencing. The potential ammonia oxidation, studied by short-time slurry incubation, was higher in the landfill OFA than in the wastewater area and highest in the litter layer. Higher activity correlated with the appearance of Nitrosomonas sp. belonging to cluster 7. Both overland flow areas supported a more diverse AOB community than in common wastewater treatment plants. Fifteen different AOB sequences were detected, but only three were observed in both OFAs, pointing to the impact of the effluent quality and/or the hydraulic load. The wastewater OFA, which received a higher load of effluents with 5-10 times lower ammonia concentrations, was dominated by AOB populations that are usually found in less favourable conditions.

  • 195.
    Sundberg, Carina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Sundblad-Tonderski, Karin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Development of the community structure and activity of ammoniaoxidising bacteria in overland flow systems used to treat landfill leachates2009In: Journal of Applied Microbiology, ISSN 1364-5072, E-ISSN 1365-2672Article in journal (Other academic)
    Abstract [en]

    Ammonium in landfill leachates can be nitrified in overland flow areas (OFA). We studied OFAs to investigate if changes occur in the ammonium oxidizing community as the ecosystem develops, and the influence of different operating conditions. Samples were collected from the macrophyte litter layers, the rhizospheres and the sediments in their associated settling ponds in May, August, and November during four years. Potential ammonia oxidation (PAO) was investigated by a short-term slurry incubation method. The composition of the ammonia-oxidising bacteria (AOB) communities was investigated by PCR, using a group-specific primer pair, followed by denaturing gradient gel electrophoresis and subsequent sequencing.

    A shift from a Nitrosomonas community to a mixture of Nitrosomonas and Nitrosospira was and a gradual increase in PAO was observed, but only in the litter layer in the youngest OFA. Both OFAs had diverse AOB communities belonging to six different clusters. Nitrosomonas clusters predominated in the OFA with higher PAO, whereas Nitrosospira clusters were more common in the OFA with lower PAO. There was a seasonal increase of AOB populations in the OFA that was not in use during winter, and a more stable composition of the AOB community and the PAO in the OFA with year-round application. Keywords: Ammonia-oxidising bacterial community; Landfill leachates; Nitrification; Overland flow; 16S rDNA; Denaturing gradient gel electrophoresis.

  • 196.
    Sundberg, Carina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Sundblad-Tonderski, Karin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lindgren, Per-Erik
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Potential nitrification and denitrification and the corresponding composition of the bacterial communities in a compact constructed wetland treating landfill leachates2007In: Water Science and Technology, ISSN 0273-1223, E-ISSN 1996-9732, Vol. 56, no 3, p. 159-166Article in journal (Refereed)
    Abstract [en]

    Constructed wetlands can be used to decrease the high ammonium concentrations in landfill leachates. We investigated nitrification/denitrification activity and the corresponding bacterial communities in landfill leachate that was treated in a compact constructed wetland, Tveta Recycling Facility, Sweden. Samples were collected at three depths in a filter bed and the sediment from a connected open pond in July, September and November 2004. Potential ammonia oxidation was measured by short-term incubation method and potential denitrification by the acetylene inhibition technique. The ammonia-oxidising and the denitrifying bacterial communities were investigated using group-specific PCR primers targeting 16S rRNA genes and the functional gene nosZ, respectively. PCR products were analysed by denaturing gradient gel electrophoresis and nucleotide sequencing. The same degree of nitrification activity was observed in the pond sediment and at all levels in the filter bed, whereas the denitrification activity decreased with filter bed depth. Denitrification rates were higher in the open pond, even though the denitrifying bacterial community was more diverse in the filter bed. The ammonia-oxidising community was also more varied in the filter bed. In the filter bed and the open pond, there was no obvious relationship between the nitrification/denitrification activities and the composition of the corresponding bacterial communities.

  • 197.
    Sundén, Birgitta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences.
    Forsum, Urban
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Microbiology.
    Lindh, Magnus
    University of Gothenburg.
    Ydrenius, Liselotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Åkerlind, Britt
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Microbiology.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Real-time PCR detection of Human Herpesvirus 1-5 in patients lacking clinical signs of a viral CNS infection2011In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 11, no 220Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Infections of the central nervous system (CNS) with herpes- or enterovirus can be self-limiting and benign, but occasionally result in severe and fatal disease. The polymerase chain reaction (PCR) has revolutionized the diagnostics of viral pathogens, and by multiple displacement amplification (MDA) prior to real-time PCR the sensitivity might be further enhanced. The aim of this study was to investigate if herpes- or enterovirus can be detected in cerebrospinal fluid (CSF) from patients without symptoms.

    METHODS:

    Cerebrospinal fluid (CSF) samples from 373 patients lacking typical symptoms of viral CNS infection were analysed by real-time PCR targeting herpesviruses or enteroviruses with or without prior MDA.

    RESULTS:

    In total, virus was detected in 17 patients (4%). Epstein-Barr virus (EBV) was most commonly detected, in general from patients with other conditions (e.g. infections, cerebral hemorrhage). MDA satisfactorily amplified viral DNA in the absence of human nucleic acids, but showed poor amplification capacity for viral DNA in CSF samples, and did not increase the sensitivity for herpes virus-detection with our methodology.

    CONCLUSIONS:

    Viral pathogens are rarely detected in CSF from patients without signs of CNS infection, supporting the view that real-time PCR is a highly specific method to detect symptomatic CNS-infection caused by these viruses. However, EBV may be subclinically reactivated due to other pathological conditions in the CNS.

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  • 198.
    Surapureddi, Sailesh
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Svartz, Jesper
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Hammarström, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderström, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Colocalization of leukotriene C synthase and microsomal glutathione S-transferase elucidated by indirect immunofluorescence analysis2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 480, no 2-3, p. 239-243Article in journal (Refereed)
    Abstract [en]

    We have previously shown that the two membrane bound enzymes leukotriene C synthase and microsomal glutathione S-transferase interact in vitro and in vivo. Rat basophilic leukemia cells and murine mastocytoma cells, two well-known sources of leukotriene C synthase, both expressed microsomal glutathione S-transferase as determined by Western blot analyses. Several human tissues were found to contain both leukotriene C synthase and microsomal glutathione S-transferase mRNA. These data suggest that the interaction may be physiologically important. To study this further, expression vectors encoding the two enzymes were cotransfected into mammalian cells and the subcellular localization of the enzymes was determined by indirect immunofluorescence using confocal laser scanning microscopy. The results showed that leukotriene C synthase and microsomal glutathione S-transferase were both localized on the nuclear envelope and adjacent parts of the endoplasmic reticulum. Image overlay demonstrated virtually identical localization. We also observed that coexpression substantially reduced the catalytic activity of each enzyme suggesting that a mechanism involving protein–protein interaction may contribute to the regulation of LTC4 production.

  • 199.
    Särndahl, Eva
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Bergström, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Brodin, Veronika Patcha
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nijm, Johnny
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Lundqvist Setterud, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Neutrophil activation status in stable coronary artery disease.2007In: PLoS ONE, ISSN 1932-6203, Vol. 2, no 10, p. e1056-Article in journal (Refereed)
    Abstract [en]

    Background: During the last years, neutrophils have emerged as important players in atherogenesis. They are highly activated in peripheral blood of patients with unstable angina. Moreover, a primed state of circulating neutrophils has been proposed in patients with stable angina. Our aim was to investigate the neutrophil activation status in patients with stable coronary artery disease (CAD) at conventional drug treatment.

    Methodology and principal findings: Thirty patients with stable CAD and 30 healthy controls were included using a paired design. The neutrophil expression of CD18 and high-affinity state of CD11b was analysed by flow cytometry before and after stimulation with chemoattractants. Also, the production of reactive oxygen species (ROS) was determined by chemiluminescence. During basal conditions, the neutrophil expression of CD18 or high-affinity state of CD11b did not differ between patients and controls. Chemoattractants (Interleukin-8 and Leukotriene B(4)) did not increase either the expression or the amount of high-affinity CD11b/CD18-integrins in CAD patients compared to controls, and had no effect on the production of ROS. On the other hand, the ROS production in response to C3bi-opsonised yeast particles and the neutrophils' inherent capacity to produce ROS were both significantly decreased in patients.

    Conclusion/Significance: We could not find any evidence that neutrophils in patients with stable CAD were primed, i.e. more prone to activation, compared to cells from healthy controls. According to our data, the circulating neutrophils in CAD patients rather showed an impaired activation status. It remains to be elucidated whether the neutrophil dysfunction in CAD is mainly a marker of chronic disease, an atherogenic factor or a consequence of the drug treatment.

  • 200.
    Särndahl, Eva
    et al.
    Department of Biomedicine, School of Health and Medical Sciences, Örebro University, Sweden.
    Bergström, Ida
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Nijm, Johnny
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Perretti, Mauro
    William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
    Jonasson, Lena
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease2010In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 59, no 3, p. 443-440Article in journal (Refereed)
    Abstract [en]

    Background: A dysregulated cortisol response in patients with stable coronary artery disease (CAD) is related to systemic inflammatory activity. Moreover, a dysfunctional activation status of neutrophils in CAD has been discussed. The anti-inflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1), a protein mainly expressed by innate immune cells. An altered expression of glucocorticoid receptors (GR) and ANXA1 has been associated with glucocorticoid resistance.

    Methods and Results: Salivary cortisol levels were measured in the morning and evening during 3 consecutive days in 30 CAD patients and 30 healthy individuals. The neutrophil expression of GR and ANXA1 was determined by flow cytometry. The effect of exogenous ANXA1 was determined in neutrophil stimulation assays. The patients showed a flattened diurnal cortisol pattern compared to healthy subjects, involving higher levels in the evening. The neutrophil expression of GRtotal and GRα, as well as the ratio of GRα:GRβ expression was significantly decreased in patients, whereas the GRβ expression did not differ compared to controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 suppressed LTB4-induced ROS production in neutrophils from patients, but not from controls. On the other hand, ANXA1 impaired the LTB4-induced up-regulation of β2-integrins in both patients and controls.

    Conclusion: CAD patients displayed a more flattened diurnal cortisol rhythm caused by higher cortisol levels in the evening compared to healthy subjects. Our findings indicate a chronic overactivation of the hypothalamic-pituitary-adrenal (HPA) axis but give no conclusive evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The data rather point towards an increased anti-inflammatory potential in neutrophils from patients with stable CAD.

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