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  • 251. Skog, Lars
    et al.
    Linde, Annika
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hauska, Hans
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Spatiotemporal characteristics of pandemic influenza2014In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 14, p. 378-Article in journal (Refereed)
    Abstract [en]

    Background: Prediction of timing for the onset and peak of an influenza pandemic is of vital importance for preventive measures. In order to identify common spatiotemporal patterns and climate influences for pandemics in Sweden we have studied the propagation in space and time of A(H1N1)pdm09 (10,000 laboratory verified cases), the Asian Influenza 1957-1958 (275,000 cases of influenza-like illness (ILI), reported by local physicians) and the Russian Influenza 1889-1890 (32,600 ILI cases reported by physicians shortly after the end of the outbreak). Methods: All cases were geocoded and analysed in space and time. Animated video sequences, showing weekly incidence per municipality and its geographically weighted mean (GWM), were created to depict and compare the spread of the pandemics. Daily data from 1957-1958 on temperature and precipitation from 39 weather stations were collected and analysed with the case data to examine possible climatological effects on the influenza dissemination. Results: The epidemic period lasted 11 weeks for the Russian Influenza, 10 weeks for the Asian Influenza and 9 weeks for the A(H1N1)pdm09. The Russian Influenza arrived in Sweden during the winter and was immediately disseminated, while both the Asian Influenza and the A(H1N1)pdm09 arrived during the spring. They were seeded over the country during the summer, but did not peak until October-November. The weekly GWM of the incidence moved along a line from southwest to northeast for the Russian and Asian Influenza but northeast to southwest for the A(H1N1)pdm09. The local epidemic periods of the Asian Influenza were preceded by falling temperature in all but one of the locations analysed. Conclusions: The power of spatiotemporal analysis and modeling for pandemic spread was clearly demonstrated. The epidemic period lasted approximately 10 weeks for all pandemics. None of the pandemics had its epidemic period before late autumn. The epidemic period of the Asian Influenza was preceded by falling temperatures. Climate influences on pandemic spread seem important and should be further investigated.

  • 252.
    Song, Tianyan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Duperthuy, Marylise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sub-Optimal Treatment of Bacterial Biofilms2016In: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 5, no 2, article id 23Article, review/survey (Refereed)
    Abstract [en]

    Bacterial biofilm is an emerging clinical problem recognized in the treatment of infectious diseases within the last two decades. The appearance of microbial biofilm in clinical settings is steadily increasing due to several reasons including the increased use of quality of life-improving artificial devices. In contrast to infections caused by planktonic bacteria that respond relatively well to standard antibiotic therapy, biofilm-forming bacteria tend to cause chronic infections whereby infections persist despite seemingly adequate antibiotic therapy. This review briefly describes the responses of biofilm matrix components and biofilm-associated bacteria towards sub-lethal concentrations of antimicrobial agents, which may include the generation of genetic and phenotypic variabilities. Clinical implications of bacterial biofilms in relation to antibiotic treatments are also discussed.

  • 253.
    Song, Tianyan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sabharwal, Dharmesh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gurung, Jyoti Mohan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Cheng, Andrew T.
    Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, United States of America.
    Sjöström, Annika E.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Yildiz, Fitnat H.
    Department of Microbiology and Environmental Toxicology, University of California Santa Cruz, Santa Cruz, California, United States of America.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Vibrio cholerae Utilizes Direct sRNA Regulation in Expression of a Biofilm Matrix Protein2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e101280Article in journal (Refereed)
    Abstract [en]

    Vibrio cholerae biofilms contain exopolysaccharide and three matrix proteins RbmA, RbmC and Bap1. While much is known about exopolysaccharide regulation, little is known about the mechanisms by which the matrix protein components of biofilms are regulated. VrrA is a conserved, 140-nt sRNA of V. cholerae, whose expression is controlled by sigma factor sigma(E). In this study, we demonstrate that VrrA negatively regulates rbmC translation by pairing to the 5' untranslated region of the rbmC transcript and that this regulation is not stringently dependent on the RNA chaperone protein Hfq. These results point to VrrA as a molecular link between the sigma(E)-regulon and biofilm formation in V. cholerae. In addition, VrrA represents the first example of direct regulation of sRNA on biofilm matrix component, by-passing global master regulators.

  • 254. Sothiselvam, Shanmugapriya
    et al.
    Liu, Bo
    Han, Wei
    Ramu, Haripriya
    Klepacki, Dorota
    Atkinson, Gemma Catherine
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Brauer, Age
    Remm, Maido
    Tenson, Tanel
    Schulten, Klaus
    Vazquez-Laslop, Nora
    Mankin, Alexander S
    Macrolide antibiotics allosterically predispose the ribosome for translation arrest2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 27, p. 9804-9809Article in journal (Refereed)
    Abstract [en]

    Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.

  • 255. Starosta, Agata L.
    et al.
    Lassak, Jürgen
    Peil, Lauri
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Tartu, Estonia.
    Virumäe, Kai
    Tenson, Tanel
    Remme, Jaanus
    Jung, Kirsten
    Wilson, Daniel N.
    Translational stalling at polyproline stretches is modulated by the sequence context upstream of the stall site2014In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, no 16, p. 10711-10719Article in journal (Refereed)
    Abstract [en]

    The polymerization of amino acids into proteins occurs on ribosomes, with the rate influenced by the amino acids being polymerized. The imino acid proline is a poor donor and acceptor for peptide-bond formation, such that translational stalling occurs when three or more consecutive prolines (PPP) are encountered by the ribosome. In bacteria, stalling at PPP motifs is rescued by the elongation factor P (EF-P). Using SILAC mass spectrometry of Escherichia coli strains, we identified a subset of PPP-containing proteins for which the expression patterns remained unchanged or even appeared up-regulated in the absence of EF-P. Subsequent analysis using in vitro and in vivo reporter assays revealed that stalling at PPP motifs is influenced by the sequence context upstream of the stall site. Specifically, the presence of amino acids such as Cys and Thr preceding the stall site suppressed stalling at PPP motifs, whereas amino acids like Arg and His promoted stalling. In addition to providing fundamental insight into the mechanism of peptide-bond formation, our findings suggest how the sequence context of polyproline-containing proteins can be modulated to maximize the efficiency and yield of protein production.

  • 256.
    Stenmark, Stephan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lindgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Tärnvik, Arne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    T-cell-dependent and independent protection against Francisella tularensisManuscript (preprint) (Other academic)
  • 257. Steptoe, A
    et al.
    Gylfe, Åsa
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Shamaei-Tousi, A
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Henderson, B
    Pathogen burden and cortisol profiles over the day2009In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 137, no 12, p. 1816-1824Article in journal (Refereed)
    Abstract [en]

    Hypothalamic-pituitary-adrenocortical (HPA) regulation in adults is influenced by early psychosocial adversity, but the role of infectious disease history is poorly understood. We studied the association between cumulative pathogen burden and cortisol profile over the day in a sample of 317 healthy men and women aged 51-72 years. Cumulative pathogen burden was defined as positive serostatus for Chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1). Salivary cortisol was sampled repeatedly over the day. The cortisol slope was defined as the decrease across the day and evening. Age, gender, grade of employment, body mass index, smoking status, self-rated health, cardiovascular medication, depressed mood and time of waking were included as covariates. The pathogen burden averaged 1.76 (S.D. = 0.92). The cortisol slope was inversely associated with pathogen burden after controlling for covariates. When individual pathogens were studied, only CMV was associated with flatter cortisol rhythms in isolation. We conclude that pathogen burden is independently associated with flatter cortisol slopes over the day, and may contribute to disturbed neuroendocrine regulation.

  • 258. Stoner, Marie C. D.
    et al.
    Dennis, Ann M.
    Hughes, James P.
    Eshleman, Susan H.
    Sivay, Marisa, V
    Hudelson, Sarah E.
    Grabowski, M. Kate
    Gomez-Olive, E. Xavier
    MacPhail, Catherine
    Piwowar-Manning, Estelle
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. INDEPTH Network, Accra, Ghana.
    Pettifor, Audrey
    Characteristics Associated With Human Immunodeficiency Virus Transmission Networks Involving Adolescent Girls and Young Women in Human Immunodeficiency Virus Prevention Trials Network 068 Study2019In: Sexually Transmitted Diseases, ISSN 0148-5717, E-ISSN 1537-4521, Vol. 46, no 5, p. E46-E49Article in journal (Refereed)
    Abstract [en]

    We combined behavioral survey data from the human immunodeficiency virus (HIV) Prevention Trials Network 068 study with phylogenetic information to determine if cluster membership was associated with characteristics of young women and their partners. Clusters were more likely to involve young women from specific villages and schools, indicating some localized transmission.

  • 259. Stoner, Marie C. D.
    et al.
    Edwards, Jessie K.
    Miller, William C.
    Aiello, Allison E.
    Halpern, Carolyn T.
    Julien, Aimee
    Rucinski, Katherine B.
    Selin, Amanda
    Twine, Rhian
    Hughes, James P.
    Wang, Jing
    Agyei, Yaw
    Gómez-Olivé, Francesc Xavier
    Wagner, Ryan G.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Laeyendecker, Oliver
    Macphail, Catherine
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Pettifor, Audrey
    Does Partner Selection Mediate the Relationship Between School Attendance and HIV/Herpes Simplex Virus-2 Among Adolescent Girls and Young Women in South Africa: An Analysis of HIV Prevention Trials Network 068 Data2018In: Journal of Acquired Immune Deficiency Syndromes, ISSN 1525-4135, E-ISSN 1944-7884, Vol. 79, no 1, p. 20-27Article in journal (Refereed)
    Abstract [en]

    Objective: School attendance prevents HIV and herpes simplex virus-2 (HSV-2) in adolescent girls and young women, but the mechanisms to explain this relationship remain unclear. Our study assesses the extent to which characteristics of sex partners, partner age, and number mediate the relationship between attendance and risk of infection in adolescent girls and young women in South Africa.

    Design: We use longitudinal data from the HIV Prevention Trials Network 068 randomized controlled trial in rural South Africa, where girls were enrolled in early adolescence and followed in the main trial for more than 3 years. We examined older partners and the number of partners as possible mediators.

    Methods: We used the parametric g-formula to estimate 4-year risk differences for the effect of school attendance on the cumulative incidence of HIV/HSV-2 overall and the controlled direct effect (CDE) for mediation. We examined mediation separately and jointly for the mediators of interest.

    Results: We found that young women with high attendance in school had a lower cumulative incidence of HIV compared with those with low attendance (risk difference = -1.6%). Partner age difference (CDE = -1.2%) and the number of partners (CDE = -0.4%) mediated a large portion of this effect. In fact, when we accounted for the mediators jointly, the effect of schooling on HIV was almost removed, showing full mediation (CDE = -0.3%). The same patterns were observed for the relationship between school attendance and cumulative incidence of HSV-2 infection.

    Conclusion: Increasing school attendance reduces the risk of acquiring HIV and HSV-2. Our results indicate the importance of school attendance in reducing partner number and partner age difference in this relationship.

  • 260.
    Strand, Mårten
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Islam, Koushikul
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Öberg, Christopher T
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergström, Tomas
    Univ Gothenburg, Sahlgrenska Acad, Dept Virol, Gothenburg, Sweden.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 22012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 11, p. 5735-5743Article in journal (Refereed)
    Abstract [en]

    Herpes simplex viruses (HSV-1 and HSV-2) are responsible for life-long latent infections in humans, with periods of viral reactivation associated with recurring ulcerations in the orofacial and genital tract. In immunosuppressed patients and neonates, HSV infections are associated with severe morbidity, and in some cases even mortality. Today, acyclovir is the standard therapy for management of HSV infections. However, the need for novel antiviral agents is apparent since HSV isolates resistant to acyclovir therapy are frequently isolated in immunosuppressed patients. In this study, we assessed the anti-HSV activity of the anti-adenoviral compounds 2-[2-(2-benzoylamino)-benzoylamino]benzoic acid, (Benzavir-1) and 2-[4,5-difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, (Benzavir-2) on HSV-1 and HSV-2. Both compounds were active against both viruses. Importantly, Benzavir-2 had similar potency to acyclovir against both HSV types and it was active against clinical acyclovir-resistant HSV isolates.

  • 261. Sundling, Christopher
    et al.
    Ronnberg, Caroline
    Yman, Victor
    Asghar, Muhammad
    Jahnmatz, Peter
    Lakshmikanth, Tadepally
    Chen, Yang
    Mikes, Jaromir
    Forsell, Mattias N.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sonden, Klara
    Achour, Adnane
    Brodin, Petter
    Persson, Kristina E. M.
    Farnert, Anna
    B cell profiling in malaria reveals expansion and remodeling of CD11c+ B cell subsets2019In: JCI Insight, ISSN 2379-3708, Vol. 4, no 9, article id e126492Article in journal (Refereed)
    Abstract [en]

    Humoral immunity is important in limiting clinical disease in malaria, yet the longitudinal B cell response to infection remains unclear. We performed a 1-year prospective study in patients treated for acute Plasmodium fakiporum malaria for the first time or with previous exposure to the disease. Using an unbiased exploratory approach with mass cytometry, followed by targeted flow cytometry, we found that approximately 80% of mature B cells that proliferated in response to acute infection expressed CD11c. Only approximately 40% of CD11c+ B cells displayed an atypical B cell phenotype, with the remaining cells primarily made up of activated and resting memory B cells. The CD11c+ B cells expanded rapidly following infection, with previous exposure to malaria resulting in a significantly larger increase compared with individuals with primary infection. This was attributed to an expansion of switched CD11c+ B cells that was absent in primary infected individuals. The rate of contraction of the CD11c+ B cell compartment was independent of previous exposure to malaria and displayed a slow decay, with a half-life of approximately 300 days. Collectively, these results identify CD11c as a marker of B cells responding to malaria and further highlight differences in primary and secondary B cell responses during infection.

  • 262.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 358Article in journal (Refereed)
    Abstract [en]

    Background: Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism.

    Methods: Detection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA (R)) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis).

    Results: Forty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls.

    Conclusions: It was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed.

  • 263.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy
    Karlsson, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nelson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kyamanwa, Patrick
    Karenzi, Ben
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. nfectious Diseases Institute, School of Medicine and Health Sciences, Makerere University, Uganda.
    Metabolic signature profiling as a diagnostic and prognostic tool in paediatric Plasmodium falciparum malaria2015In: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 2, no 2Article in journal (Refereed)
    Abstract [en]

    Background: Accuracy in malaria diagnosis and staging is vital in order to reduce mortality and post infectious sequelae. Herein we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods: A group of 421 patients between six months and six years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192 and 122 individuals respectively. A multivariate design was used as basis for representative selection of twenty patients in each category. Patient plasma was subjected to Gas Chromatography-Mass Spectrometry analysis and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in-vivo model where metabolic profiles were discernible over time of infection. Results: A two-component principal component analysis (PCA) revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, two sub-groups could be identified in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusion: Metabolite signature profiling could be used both for decision support in disease staging and prognostication.

  • 264.
    Svensson, Kerstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Genetic genealogy and epidemiology of Francisella2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is about analyzing genetic differences among isolates of Francisella tularensis – the tularemia-causing bacterium. To elucidate how these bacterial isolates are related, and their geographical and genetic origins, I have developed typing assays for Francisella and used them to study the epidemiology of tularemia.

    Tularemia is an infectious disease of humans and other mammals found throughout the Northern Hemisphere. The severity of the disease depends on the type of F. tularensis causing the infection. In Sweden, as in other countries of Europe and Eurasia, tularemia is caused by F. tularensis subsp. holarctica, while other varieties of the bacterium occur in Middle Asia and North America. It is important to identify a tularemia infection promptly in order to initiate the correct antibiotic treatment. A rapid identification of the causative F. tularensis variety gives additional clinical information. In recent years, several genomes of various Francisella strains have been sequenced, and in this thesis, I have utilized these genomes to identify genetic markers.

    In studies reported in the first paper (I) appended to the thesis, we identified and analyzed insertion/deletion mutations (INDELs) inferred to have resulted from a sequence repeat-mediated excision mechanism. We found eight new Regions of Difference (RDs) among Francisella strains. Using RDs together with single nucleotide polymorphisms (SNPs), we were able to predict an evolutionary scenario for F. tularensis in which Francisella novicida was the oldest variety while F. tularensis subsp. holarctica was the youngest. We also found that all virulence-attenuated isolates analyzed had deletions at two specific genetic regions - denoted RD18 and RD19 – suggesting that repeat-mediated excision is a mechanism of attenuation in F. tularensis.

    In subsequent studies (presented in paper II), we developed a combined analysis of INDELs lacking flanking repeats and variable number of tandem repeats (VNTRs). Both markers could be assayed using the same analytical equipment. The inclusion of INDELs provided increased phylogenetic robustness compared with the use of VNTRs alone, while still maintaining a high level of genetic resolution.

    In analyses described in the next paper (III), we selected INDELs from paper (II) and discovered novel SNPs by DNA comparisons of multiple Francisella strains. Thirty-four phylogenetically informative genetic markers were included in a hierarchical real-time PCR array for rapid and robust characterization of Francisella. We successfully used the assay to genotype 14 F. tularensis isolates from tularemia patients and DNA in six clinical ulcer specimens.

    Finally, in paper (IV) we demonstrated a strategy to enhance epidemiological investigations of tularemia by combining GIS-mapping of disease-transmission place collected from patient interviews, with high-resolution genotyping of F. tularensis subsp. holarctica isolates recovered from tularemia patients. We found the geographic distributions of specific F. tularensis subsp. holarctica sub-populations to be highly localized during outbreaks (infections by some genotypes being restricted to areas as small as 2 km2), indicative of a landscape epidemiology of tularemia with distinct point sources of infection.

    In conclusion, the results acquired during the studies underlying this thesis contribute to our understanding of the genetic genealogy of tularemia at both global and local outbreak scales.

  • 265.
    Svensson, Kerstin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bäck, Erik
    Örebro universitet.
    Berglund, Lennart
    Eliasson, Henrik
    Granberg, M
    Karlsson, Lena
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Forsman, Mats
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    A high-resolution landscape epidemiology of tularemia exposed by genetic analysis of the causative agent isolated from infected humansManuscript (Other academic)
  • 266.
    Svensson, Kerstin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bäck, Erik
    Örebro Universitetssjukhus.
    Eliasson, Henrik
    Örebro Universitetssjukhus.
    Berglund, Lennart
    Granberg, Malin
    Karlsson, Linda
    Swedish Defense Research Agency, Umea, Sweden.
    Larsson, Pär
    Swedish Defense Research Agency, Umea, Sweden.
    Forsman, Mats
    Swedish Defense Research Agency, Umea, Sweden.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Landscape epidemiology of tularemia outbreaks in Sweden2009In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 15, no 12, p. 1937-1947Article in journal (Refereed)
    Abstract [en]

    Summer outbreaks of tularemia that occurred from 1995 through 2005 in 2 locations in Sweden affected 441 persons. We performed an epidemiologic investigation of these outbreaks using a novel strategy, involving high-resolution genotyping of Francisella tularensis isolates obtained from 136 patients (using 18 genetic markers developed from 6 F. tularensis genome sequences) and interviews with the patients. Strong spatial associations were found between F. tularensis subpopulations and the places of disease transmission; infection by some subpopulations occurred within areas as small as 2 km(2), indicating unidentified environmental point sources of tularemia. In both locations, disease clusters were associated with recreational areas beside water, and genetic subpopulations were present throughout the tularemia season and persisted over years. High-resolution genotyping in combination with patients' statements about geographic places of disease transmission provided valuable indications of likely sources of infection and the causal genotypes during these tularemia outbreaks.

  • 267.
    Svensson, Kerstin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Division of CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden .
    Granberg, Malin
    Karlsson, Linda
    Neubauerova, Vera
    Forsman, Mats
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Division of CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden .
    A real-time PCR array for hierarchical identification of Francisella isolates2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 12, article id e8360Article in journal (Refereed)
    Abstract [en]

    A robust, rapid and flexible real-time PCR assay for hierarchical genetic typing of clinical and environmental isolates of Francisella is presented. Typing markers were found by multiple genome and gene comparisons, from which 23 canonical single nucleotide polymorphisms (canSNPs) and 11 canonical insertion-deletion mutations (canINDELs) were selected to provide phylogenetic guidelines for classification from genus to isolate level. The specificity of the developed assay, which uses 68 wells of a 96-well real-time PCR format with a detection limit of 100 pg DNA, was assessed using 62 Francisella isolates of diverse genetic and geographical origins. It was then successfully used for typing 14 F. tularensis subsp. holarctica isolates obtained from tularemia patients in Sweden in 2008 and five more genetically diverse Francisella isolates of global origins. When applied to human ulcer specimens for direct pathogen detection the results were incomplete due to scarcity of DNA, but sufficient markers were identified to detect fine-resolution differences among F. tularensis subsp. holarctica isolates causing infection in the patients. In contrast to other real-time PCR assays for Francisella, which are typically designed for specific detection of a species, subspecies, or strain, this type of assay can be easily tailored to provide appropriate phylogenetic and/or geographical resolution to meet the objectives of the analysis.

  • 268.
    Tafazoli, Farideh
    et al.
    Division of Medical Microbiology, Department of Health and Environment, Linköping University, Linköping, Sweden.
    Holmström, Anna
    Swedish Defence Research Agency, Division of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Forsberg, Åke
    Department of Microbiology, National Defence Research Establishment, Umeå, Sweden.
    Magnusson, Karl-Eric
    Division of Medical Microbiology, Department of Health and Environment, Linköping University, Linköping, Sweden.
    Apically exposed, tight junction-associated beta1-integrins allow binding and YopE-mediated perturbation of epithelial barriers by wild-type Yersinia bacteria2000In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 68, no 9, p. 5335-5343Article in journal (Refereed)
    Abstract [en]

    Using polarized epithelial cells, primarily MDCK-1, we assessed the mode of binding and effects on epithelial cell structure and permeability of Yersinia pseudotuberculosis yadA-deficient mutants. Initially, all bacteria except the invasin-deficient (inv) mutant adhered apically to the tight junction areas. These contact points of adjacent cells displayed beta1-integrins together with tight junction-associated ZO-1 and occludin proteins. Indeed, beta1-integrin expression was maximal in the tight junction area and then gradually decreased along the basolateral membranes. Wild-type bacteria also opened gradually the tight junction to paracellular permeation of different-sized markers, viz., 20-, 40-, and 70-kDa dextrans and 45-kDa ovalbumin, as well as to their own translocation between adjacent cells in intimate contact with beta1-integrins. The effects on the epithelial cells and their barrier properties could primarily be attributed to expression of the Yersinia outer membrane protein YopE, as the yopE mutant bound but caused no cytotoxicity. Moreover, the apical structure of filamentous actin (F-actin) was disturbed and tight junction-associated proteins (ZO-1 and occludin) were dispersed along the basolateral membranes. It is concluded that the Yersinia bacteria attach to beta1-integrins at tight junctions. Via this localized injection of YopE, they perturb the F-actin structure and distribution of proteins forming and regulating tight junctions. Thereby they promote paracellular translocation of bacteria and soluble compounds.

  • 269. Takata, Tohru
    et al.
    Miyazaki, Motoyasu
    Futo, Maki
    Hara, Shuji
    Shiotsuka, Shouichi
    Kamimura, Hidetoshi
    Yoshimura, Hisae
    Matsunaga, Akira
    Nishida, Takeshi
    Ishikura, Hiroyasu
    Ishikawa, Takahiko
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tamura, Kazuo
    Tsuji, Brian T.
    Presence of both heterogeneous vancomycin-intermediate resistance and beta-lactam antibiotic-induced vancomycin resistance phenotypes is associated with the outcome in methicillin-resistant Staphylococcus aureus bloodstream infection2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 3, p. 203-212Article in journal (Refereed)
    Abstract [en]

    Background: Although the individual expression of heterogeneous vancomycin-intermediate resistance (hVISA) and beta-lactam antibiotic-induced vancomycin resistance (BIVR) phenotypes has been associated with treatment failure and recurrence in methicillin-resistant Staphylococcus aureus (MRSA) infections, the effect of the co-expression of these phenotypic profiles on clinical outcome has not been fully elucidated. The aim of this study was to determine the impact of the combination of hVISA and BIVR phenotypes on the clinical outcome in MRSA bacteremia. Methods: One hundred and sixty-two MRSA blood isolates from a 21-y period, 1987-2007, were randomly selected. Screening for hVISA was done by the macromethod Etest and confirmed by population analysis profiles. BIVR was identified using Mu3 agar containing 4 mu g/ml of vancomycin. Results: Thirty (18.5%) and 39 (24.1%) of the 162 MRSA blood isolates were positive for the hVISA and BIVR phenotypes, respectively. Eighteen (11.1%) isolates possessed both hVISA and BIVR phenotypes (hVISA(+)/BIVR(+)). In a subset of patients who received initial treatment with glycopeptides, only the patients whose isolates were hVISA(+)/BIVR(+) displayed a significantly higher mortality rate in comparison to those with non-hVISA(+)/BIVR(+) (80.0% vs 31.3%, p = 0.004). The presence of both hVISA and BIVR phenotypes was a predictor of mortality using a logistic regression analysis (p = 0.025). Conclusions: The combined phenotype of hVISA and BIVR was associated with a higher probability of mortality in patients with MRSA bacteremia. Further prospective studies are warranted to delineate the clinical significance of the combined phenotype of hVISA and BIVR.

  • 270. Talagrand-Reboul, Emilie
    et al.
    Boyer, Pierre H.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vial, Laurence
    Boulanger, Nathalie
    Relapsing Fevers: Neglected Tick-Borne Diseases2018In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 98Article, review/survey (Refereed)
    Abstract [en]

    Relapsing fever still remains a neglected disease and little is known on its reservoir, tick vector and physiopathology in the vertebrate host. The disease occurs in temperate as well as tropical countries. Relapsing fever borreliae are spirochaetes, members of the Borreliaceae family which also contain Lyme disease spirochaetes. They are mainly transmitted by Ornithodoros soft ticks, but some species are vectored by ixodid ticks. Traditionally a Borrelia species is associated with a specific vector in a particular geographical area. However, new species are regularly described, and taxonomical uncertainties deserve further investigations to better understand Borrelia vector/host adaptation. The medical importance of Borrelia miyamotoi, transmitted by Ixodes spp., has recently spawned new interest in this bacterial group. In this review, recent data on tick-host-pathogen interactions for tick-borne relapsing fevers is presented, with special focus on B. miyamotoi.

  • 271. Tissera, Hasitha
    et al.
    Rathore, Abhay P. S.
    Leong, Wei Yee
    Pike, Brian L.
    Warkentien, Tyler E.
    Farouk, Farouk S.
    Syenina, Ayesa
    Ooi, Eng Eong
    Gubler, Duane J.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
    John, Ashley L. St.
    Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients2017In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 216, no 9, p. 1112-1121Article in journal (Refereed)
    Abstract [en]

    Background. Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels. Methods. Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS. Results. An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF. Conclusions. These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients.

  • 272.
    Tärnvik, Arne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Management of complicated skin and skin structure infections: a call for infectious disease specialists2018In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 50, no 2, p. 117-118Article in journal (Other academic)
  • 273. Tükenmez, Hasan
    et al.
    Edström, Isabel
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ummanni, Ramesh
    Fick, Stina Berglund
    Sundin, Charlotta
    Elofsson, Mikael
    Larsson, Christer
    Mycobacterium tuberculosis virulence inhibitors discovered by Mycobacterium marinum high-throughput screening2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 26Article in journal (Refereed)
    Abstract [en]

    High-throughput screening facilities do not generally support biosafety level 3 organisms such as Mycobacterium tuberculosis. To discover not only antibacterials, but also virulence inhibitors with either bacterial or host cell targets, an assay monitoring lung fibroblast survival upon infection was developed and optimized for 384-plate format and robotic liquid handling. By using Mycobacterium marinum as surrogate organism, 28,000 compounds were screened at biosafety level 2 classification, resulting in 49 primary hits. Exclusion of substances with unfavourable properties and known antimicrobials resulted in 11 validated hits of which 7 had virulence inhibiting properties and one had bactericidal effect also in wild type Mycobacterium tuberculosis. This strategy to discover virulence inhibitors using a model organism in high-throughput screening can be a valuable tool for other researchers working on drug discovery against tuberculosis and other biosafety level 3 infectious agents.

  • 274.
    Urban, Constantin F
    et al.
    Department for Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Ermert, David
    Schmid, Monika
    Abu-Abed, Ulrike
    Goosmann, Christian
    Nacken, Wolfgang
    Brinkmann, Volker
    Jungblut, Peter R
    Zychlinsky, Arturo
    Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans2009In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 5, no 10, article id e1000639Article in journal (Refereed)
    Abstract [en]

    Neutrophils are the first line of defense at the site of an infection. They encounter and kill microbes intracellularly upon phagocytosis or extracellularly by degranulation of antimicrobial proteins and the release of Neutrophil Extracellular Traps (NETs). NETs were shown to ensnare and kill microbes. However, their complete protein composition and the antimicrobial mechanism are not well understood. Using a proteomic approach, we identified 24 NET-associated proteins. Quantitative analysis of these proteins and high resolution electron microscopy showed that NETs consist of modified nucleosomes and a stringent selection of other proteins. In contrast to previous results, we found several NET proteins that are cytoplasmic in unstimulated neutrophils. We demonstrated that of those proteins, the antimicrobial heterodimer calprotectin is released in NETs as the major antifungal component. Absence of calprotectin in NETs resulted in complete loss of antifungal activity in vitro. Analysis of three different Candida albicans in vivo infection models indicated that NET formation is a hitherto unrecognized route of calprotectin release. By comparing wild-type and calprotectin-deficient animals we found that calprotectin is crucial for the clearance of infection. Taken together, the present investigations confirmed the antifungal activity of calprotectin in vitro and, moreover, demonstrated that it contributes to effective host defense against C. albicans in vivo. We showed for the first time that a proportion of calprotectin is bound to NETs in vitro and in vivo.

  • 275.
    Valeru, Soni Priya
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rompikuntal, Pramod Kumar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ishikawa, Takahiko
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vaitkevicius, Karolis
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sjöling, Åsa
    Dolganov, Nadia
    Zhu, Jun
    Schoolnik, Gary
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Role of melanin pigment in expression of Vibrio cholerae virulence factors2009In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 77, no 3, p. 935-942Article in journal (Refereed)
    Abstract [en]

    We identified the mutated gene locus in a pigment-overproducing Vibrio cholerae mutant of strain A1552. The deduced gene product is suggested to be an oxidoreductase based on partial homology to putative homogentisate 1,2-dioxygenase in Pseudomonas aeruginosa and Mesorhizobium loti, and we propose that the gene VC1345 in the V. cholerae genome be denoted hmgA in accordance with the nomenclature for other species. The hmgA:: mini-Tn5 mutant showed a nonpigmented phenotype after complementation with a plasmid clone carrying the WT hmgA(+) locus. Microarray transcription analysis revealed that expression of hmgA and the neighboring genes encoding a postulated two-component sensor system was growth phase dependent. Results from quantitative reverse transcription-PCR analysis showed that hmgA operon expression was reduced in the rpoS mutant, but pigment production by the WT V. cholerae or the hmgA mutant was not detectably influenced by the stationary-phase regulator RpoS. The pigmented mutant showed increased UV resistance in comparison with the WT strain. Interestingly, the pigment-producing mutant expressed more toxin-coregulated pilus and cholera toxin than WT V. cholerae. Moreover, the hmgA mutant showed a fivefold increase in the ability to colonize the intestines of infant mice. A possible mechanism by which pigment production might cause induction of the ToxR regulon due to generation of hydrogen peroxide was supported by results from tests showing that externally supplied H2O2 led to higher TcpA levels. Taken together, our findings suggest that melanin pigment formation may play a role in V. cholerae virulence factor expression.

  • 276. van Schaarenburg, Rosanne A.
    et al.
    Schejbel, Lone
    Truedsson, Lennart
    Topaloglu, Rezan
    Al-Mayouf, Sulaiman M.
    Riordan, Andrew
    Simon, Anna
    Kallel-Sellami, Maryam
    Arkwright, Peter D.
    Ahlin, Anders
    Hagelberg, Stefan
    Nielsen, Susan
    Shayesteh, Alexander
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Morales, Adelaida
    Tam, Schuman
    Genel, Ferah
    Berg, Stefan
    Ketel, Arnoldus G.
    van den Berg, J. Merlijn
    Kuijpers, Taco W.
    Olsson, Richard F.
    Huizinga, Tom W. J.
    Lankester, Arjan C.
    Trouw, Leendert A.
    Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency2015In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 62, p. 39-44Article in journal (Refereed)
    Abstract [en]

    Objective: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease.

    Methods: We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published.

    Results: Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages.

    Conclusion: Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach.

  • 277. Vanha-aho, Leena-Maija
    et al.
    Anderl, Ines
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    Vesala, Laura
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Laboratory of Genetic Immunology, BioMediTech, University of Tampere, Tampere, Finland.
    Valanne, Susanna
    Rämet, Mika
    Edin expression in the fat body is required in the defense against parasitic wasps in Drosophila melanogaster2015In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 5, article id e1004895Article in journal (Refereed)
    Abstract [en]

    The cellular immune response against parasitoid wasps in Drosophila involves the activation, mobilization, proliferation and differentiation of different blood cell types. Here, we have assessed the role of Edin (elevated during infection) in the immune response against the parasitoid wasp Leptopilina boulardi in Drosophila melanogaster larvae. The expression of edin was induced within hours after a wasp infection in larval fat bodies. Using tissue-specific RNAi, we show that Edin is an important determinant of the encapsulation response. Although edin expression in the fat body was required for the larvae to mount a normal encapsulation response, it was dispensable in hemocytes. Edin expression in the fat body was not required for lamellocyte differentiation, but it was needed for the increase in plasmatocyte numbers and for the release of sessile hemocytes into the hemolymph. We conclude that edin expression in the fat body affects the outcome of a wasp infection by regulating the increase of plasmatocyte numbers and the mobilization of sessile hemocytes in Drosophila larvae.

  • 278. Vesikari, Timo
    et al.
    Richardus, Jan Hendrik
    Berglund, Johan
    Korhonen, Tiina
    Flodmark, Carl-Erik
    Lindstrand, Ann
    Silfverdal, Sven Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Bambure, Vinod
    Caplanusi, Adrian
    Dieussaert, Ilse
    Roy-Ghanta, Sumita
    Vaughn, David W.
    Immunogenicity and Safety of a Trivalent Inactivated Influenza Vaccine in Children 6 Months to 17 Years of Age, Previously Vaccinated with an AS03-Adjuvanted A(H1N1)Pdm09 Vaccine Two Open-label, Randomized Trials2015In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 34, no 7, p. 774-782Article in journal (Refereed)
    Abstract [en]

    Background: During the influenza pandemic 2009-2010, an AS03-adjuvanted A(H1N1) pdm09 vaccine was used extensively in children 6 months of age and older, and during the 2010-2011 influenza season, the A(H1N1) pdm09 strain was included in the seasonal trivalent inactivated influenza vaccine (TIV) without adjuvant. We evaluated the immunogenicity and safety of TIV in children previously vaccinated with the AS03-adjuvanted A(H1N1) pdm09 vaccine. Methods: Healthy children were randomized (1:1) to receive TIV or a control vaccine. Children were aged 6 months to 9 years (n = 154) and adolescents 10-17 years (n = 77) when they received AS03-adjuvanted A(H1N1) pdm09 vaccine at least 6 months before study enrolment. Hemagglutination inhibition (HI) and neutralizing antibody responses against the A(H1N1) pdm09 strain were evaluated before (day 0) and at day 28 and month 6 after study vaccination. Reactogenicity was assessed during the 7 day postvaccination period, and safety was assessed for 6 months. Results: At day 0, >93.9% of all children had HI titers >= 1:40 for the A(H1N1) pdm09 strain, which increased to 100% at both day 28 and month 6 in the TIV group. Between days 0 and 28, HI antibody geometric mean titers against A(H1N1) pdm09 increased by 9-fold and 4-fold in children 6 months to 9 years of age and 10-17 years of age, respectively. Conclusion: AS03-adjuvanted A(H1N1) pdm09 vaccine-induced robust immune responses in children that persisted into the next season, yet were still boosted by TIV containing A(H1N1) pdm09. The reactogenicity and safety profile of TIV did not appear compromised by prior receipt of AS03adjuvanted A(H1N1) pdm09 vaccine.

  • 279.
    Vesterlund, Agnes
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Complications related to central venous catheters at Norrland University hospital (Nus), 2016-20172018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 280. Vogt, Alexander
    et al.
    Scull, Margaret A
    Friling, Tamar
    Horwitz, Joshua A
    Donovan, Bridget M
    Dorner, Marcus
    Gerold, Gisa
    Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA.
    Labitt, Rachael N
    Rice, Charles M
    Ploss, Alexander
    Recapitulation of the hepatitis C virus life-cycle in engineered murine cell lines2013In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 444, no 1-2, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) remains a major medical problem. In-depth study of HCV pathogenesis and immune responses is hampered by the lack of suitable small animal models. The narrow host range of HCV remains incompletely understood. We demonstrate that the entire HCV life-cycle can be recapitulated in mouse cells. We show that antiviral signaling interferes with HCV RNA replication in mouse cells. We were able to infect mouse cells expressing human CD81 and occludin (OCLN)-the minimal set of entry factor factors required for HCV uptake into mouse cells. Infected mouse cells sustain HCV RNA replication in the presence of miR122 and release infectious particles when mouse apoE is supplied. Our data demonstrate that the barriers of HCV interspecies transmission can be overcome by engineering a suitable cellular environment and provide a blue-print towards constructing a small animal model for HCV infection.

  • 281.
    Vågberg, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Humoral immune response to influenza vaccine in natalizumab-treated MS patients2012In: Neurological Research, ISSN 0161-6412, E-ISSN 1743-1328, Vol. 34, no 7, p. 730-733Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Natalizumab is a drug with documented efficacy in relapsing?remitting multiple sclerosis (RRMS). The mechanism of action of natalizumab has immunosuppressive properties and it is not yet investigated if treatment with natalizumab affects the immunological response to vaccination. This study aims to investigate the humoral immune response to influenza vaccine while undergoing treatment with natalizumab.

    METHODS: A cohort of 17 RRMS patients treated with natalizumab and 10 healthy controls received trivalent influenza A/B vaccine. Influenza-specific immunoglobulin G (IgG) levels were determined at baseline and after 4, 8, and 12 weeks.

    RESULTS: Both groups experienced a significant increase in anti-influenza B IgG after the vaccination. Both groups also experienced a smaller increase in anti-influenza A IgG, but this was only significant for the natalizumab group. The IgG titers compared between the groups did not differ significantly at any of the time points.

    DISCUSSION: These results indicate that vaccination against influenza in patients treated with natalizumab yields a humoral immune response comparable to that achieved in healthy individuals.

  • 282. Wallensten, A
    et al.
    Munster, VJ
    Fouchier, RAM
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Research Institute of Zoonotic Ecology and Epidemiology., Kalmar, Sweden.
    Avian Influenza A virus in ducks migrating through Sweden2004In: Options for the control of influenza V / [ed] Kawaoka, Y, Amsterdam: Elsevier, 2004, p. 771-772Conference paper (Refereed)
    Abstract [en]

    In order to investigate the prevalence and ecology of the Avian Influenza A virus (AIV) in western Palearctic wild birds, migrating ducks, mainly Mallards (Anas platyrhynchos), have been caught in a funnel trap at the Ottenby Bird Observatory on the Swedish Island Oland. After banding and collection of biometrical data, every individual was sampled for AIV Since the fall of 2002, more than 3200 samples from 1900 birds have been collected showing a prevalence of AIV of 12%. Several subtypes have been found, including the low pathogenic H5N2. Some ducks are re-caught both during fall and spring migration, and the recruiting and wintering areas of the birds are known enabling us to draw conclusions about the geographical and reservoir distribution of AIV. (C) 2003 Elsevier B.V All rights reserved.

  • 283.
    Wang, He
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Avican, Kemal
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Erttmann, Saskia F.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nuss, Aaron M.
    Dersch, Petra
    Fällman, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Edgren, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Increased plasmid copy number is essential for Yersinia T3SS function and virulence2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 353, no 6298, p. 492-495Article in journal (Refereed)
    Abstract [en]

    Pathogenic bacteria have evolved numerous virulence mechanisms that are essential for establishing infections. The enterobacterium Yersinia uses a type III secretion system (T3SS) encoded by a 70-kilobase, low-copy, IncFII-class virulence plasmid. We report a novel virulence strategy in Y. pseudotuberculosis in which this pathogen up-regulates the plasmid copy number during infection. We found that an increased dose of plasmid-encoded genes is indispensable for virulence and substantially elevates the expression and function of the T3SS. Remarkably, we observed direct, tight coupling between plasmid replication and T3SS function. This regulatory pathway provides a framework for further exploration of the environmental sensing mechanisms of pathogenic bacteria.

  • 284. Warvsten, Anna
    et al.
    Bjornfors, Martin
    Arvidsson, Michael
    Vaziri-Sani, Fariba
    Jonsson, Ida
    Olsson, Gert E.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Larsson, Helena Elding
    Lernmark, Ake
    Nilsson, Anna-Lena
    Islet autoantibodies present in association with Ljungan virus infection in bank voles (Myodes glareolus) in northern Sweden2017In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 89, no 1, p. 24-31Article in journal (Refereed)
    Abstract [en]

    Bank voles are known reservoirs for Puumala hantavirus and probably also for Ljungan virus (LV), a suggested candidate parechovirus in type 1 diabetes etiology and pathogenesis. The aim of this study was to determine whether wild bank voles had been exposed to LV and if exposure associated to autoantibodies against insulin (IAA), glutamic acid decarboxylase 65 (GADA), or islet autoantigen-2 (IA-2A). Serum samples from bank voles (Myodes glareolus) captured in early summer or early winter of 1997 and 1998, respectively, were analyzed in radio binding assays for antibodies against Ljungan virus (LVA) and Puumala virus (PUUVA) as well as for IAA, GADA, and IA-2A. LVA was found in 25% (189/752), IAA in 2.5% (18/723), GADA in 2.6% (15/615), and IA-2A in 2.5% (11/461) of available bank vole samples. LVA correlated with both IAA (P=0.007) and GADA (P<0.001), but not with IA-2A (P=0.999). There were no correlations with PUUVA, detected in 17% of the bank voles. Compared to LVA negative bank voles, LVA positive animals had higher levels of both IAA (P=0.002) and GADA (P<0.001), but not of IA-2A (P=0.205). Levels of LVA as well as IAA and GADA were higher in samples from bank voles captured in early summer. In conclusion, LVA was detected in bank voles and correlated with both IAA and GADA but not with IA-2A. These observations suggest that exposure to LV may be associated with islet autoimmunity. It remains to be determined if islet autoantibody positive bank voles may develop diabetes in the wild.

  • 285. Watanabe, Yasuyoshi
    et al.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Natelson, Benjamin H
    Jason, Leonard A
    Kuratsune, Hirohiko
    Fatigue Science for Human Health2008 (ed. 1)Book (Other (popular science, discussion, etc.))
    Abstract [en]

    Fatigue is quite a familiar sensation, one that everyone is likely to have experienced. Its moleuclar and neural mechanisms have not yet been elucidated, however, probably because of the complicated nature of its causes. To provide a broad forum for discussion, the International Conference on Fatigue Science was organiszed, the first being held in 2002 in Sandhamn, Sweden, and the second in 2005 in Karuizawa, Japan. Subsequently it was decided that the papers presented at the two conferences should be collected and incorporated in this pioneering work, Fatique Science for Human Health. The book summarizes fatigue researchers' achievements, explains the status of the reserch on fatigue, and presents perspectives on remedies for chonic fatigue and chronic fatigue syndrome. The result is an authoritative guide to recent progress in the molucular and neural mechanisms of fatigue and in the development of the ways to prevent and overcome fatigue and in the development of the ways to prevent and overcome fatigue and chronic fatigue. This book provides a valuable resource not only for physicians but for all who work in public health.

  • 286. Wertheim, Herman
    et al.
    Chuc, Nguyen Thi Kim
    Punpuing, Sureeporn
    Khan, Wasif Ali
    Gyapong, Margaret
    Asante, Kwaku Poku
    Munguambe, Khatia
    Gómez-Olivé, Xavier
    Ariana, Proochista
    John-Langba, Johannes
    Sigauque, Betuel
    Toan, Tran Khanh
    Tollman, Stephen
    Cremers, Amelieke
    Do, Nga
    Nadjm, Behzad
    van Doorn, Rogier
    Kinsman, John
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sankoh, Osman
    Community-level antibiotic access and use (ABACUS) in low- and middle-income countries: Finding targets for social interventions to improve appropriate antimicrobial use: an observational multi-centre study2017In: Wellcome Open Research, ISSN 2398-502X, Vol. 2, article id 58Article in journal (Refereed)
    Abstract [en]

    In many low- and middle-income countries (LMICs), a poor link between antibiotic policies and practices exists. Numerous contextual factors may influence the degree of antibiotic access, appropriateness of antibiotic provision, and actual use in communities. Therefore, improving appropriateness of antibiotic use in different communities in LMICs probably requires interventions tailored to the setting of interest, accounting for cultural context. Here we present the ABACUS study (AntiBiotic ACcess and USe), which employs a unique approach and infrastructure, enabling quantitative validation, contextualization of determinants, and cross-continent comparisons of antibiotic access and use. The community infrastructure for this study is the INDEPTH-Network (International Network for the Demographic Evaluation of Populations and Their Health in Developing Countries), which facilitates health and population research through an established health and demographic surveillance system. After an initial round of formative qualitative research with community members and antibiotic suppliers in three African and three Asian countries, household surveys will assess the appropriateness of antibiotic access, provision and use. Results from this sample will be validated against a systematically conducted inventory of suppliers. All potential antibiotic suppliers will be mapped and characterized. Subsequently, their supply of antibiotics to the community will be measured through customer exit interviews, which tend to be more reliable than bulk purchase or sales data. Discrepancies identified between reported and observed antibiotic practices will be investigated in further qualitative interviews. Amartya Sen’s Capability Approach will be employed to identify the conversion factors that determine whether or not, and the extent to which appropriate provision of antibiotics may lead to appropriate access and use of antibiotics. Currently, the study is ongoing and expected to conclude by 2019. ABACUS will provide important new insights into antibiotic practices in LMICs to inform social interventions aimed at promoting optimal antibiotic use, thereby preserving antibiotic effectiveness.

  • 287. Westling, Katarina
    et al.
    Jorup-Rönström, Christina
    Evengård, Birgitta
    Department of Laboratory Medicine, Division of Clinical Bacteriology, Karolinska University Hospital/Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Toxoplasmosis not transmitted by cat bite, but high prevalence of antibodies to toxoplasma gondii in patients bitten by their own cat2010In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 42, no 9, p. 687-690Article in journal (Refereed)
    Abstract [en]

    The aims of the study were to investigate the prevalence of antibodies to Toxoplasma gondii in a group of patients bitten by cats, and also to determine if toxoplasmosis can be transferred by cat bite. Seventy-two patients who attended the emergency wards at 3 hospitals in Stockholm, Sweden, due to infection by cat bite, were investigated for specific IgM and IgG antibodies to T. gondii in the acute phase, as well as in the convalescent phase about 2 weeks later. Specific IgG antibodies to T. gondii (> or =8 IU/ml) were found in 17/72 patients (24%) in the acute phase. No case of seroconversion occurred. Patients who were bitten by their own cat had positive antibody titres to T. gondii significantly more often than those bitten by a foreign cat; 30% and 5%, respectively (p = 0.02). This suggests that regular contact with cats may contribute to the transmission of the parasite.

  • 288. Westman, G.
    et al.
    Studahl, M.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Eriksson, B. M.
    Persson, B.
    Rönnelid, J.
    Schliamser, S.
    Aurelius, E.
    N-methyl-D-aspartate receptor autoimmunity affects cognitive performance in herpes simplex encephalitis2016In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 22, no 11, p. 934-940Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the prevalence and temporal development of N-methyl-D-aspartate receptor (NMDAR) autoantibodies in relation to neurocognitive performance in patients with herpes simplex encephalitis (HSE).

    Methods: This prospective observational study enrolled a total of 49 HSE patients within a randomized controlled trial of valacyclovir. Cerebrospinal fluid and serum samples were drawn in the initial stage of disease, after 2 to 3 weeks and after 3 months. Anti-NMDAR IgG was detected with HEK293 cells transfected with plasmids encoding the NMDA NR1 type glutamate receptor. A batch of neurocognitive tests, including the Mattis Dementia Rating Scale (MDRS), Glasgow Coma Scale (GCS), Reaction Level Scale (RLS85), Mini-Mental State Examination (MMSE) and National Institutes of Health (NIH) stroke scale, was performed during 24 months' follow-up.

    Results: Anti-NMDAR IgG was detected in 12 of 49 participants. None were antibody positive in the initial stage of disease. In ten of 12 positive cases, specific antibodies were detectable only after 3 months. Notably, the development of NMDAR autoantibodies was associated with significantly impaired recovery of neurocognitive performance. After 24 months' follow-up, the median increase in MDRS total score was 1.5 vs. 10 points in antibody-positive and -negative participants (p = 0.018).

    Conclusions: Anti-NMDAR autoimmunity is a common complication to HSE that develops within 3 months after onset of disease. The association to impaired neurocognitive recovery could have therapeutical implications, as central nervous system autoimmunity is potentially responsive to immunotherapy. 

  • 289. Westman, Gabriel
    et al.
    Sohrabian, Azita
    Aurelius, Elisabeth
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Schliamser, Silvia
    Sund, Fredrik
    Studahl, Marie
    Rönnelid, Johan
    Clinical significance of IgM and IgA class anti-NMDAR antibodies in herpes simplex encephalitis2018In: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 103, p. 75-80Article in journal (Refereed)
    Abstract [en]

    Background: Herpes simplex encephalitis (HSE) is a devastating disease, often leaving patients with severe disabilities. It has been shown that IgG anti-N-methyl-o-aspartate receptor (NMDAR) antibodies appear in approximately 25% of HSE patients and could be associated with impaired recovery of cognitive performance. Objectives: To characterize the prevalence of IgM and IgA anti-NMDAR antibodies in HSE patients, in relation to subsequent development of IgG anti-NMDAR and correlation to cognitive performance. Study design: A total of 48 subjects were included from a previously described cohort of patients with HSE verified by HSV-1 PCR. Cerebrospinal fluid (CSF) and serum samples drawn close to onset of disease, after 14-21 days of iv aciclovir treatment and after 90 days of follow-up, were analyzed for the presence of IgM and IgA anti-NMDAR, and related to IgG anti-NMDAR. Antibody levels were correlated to the recovery of cognitive performance, as estimated by the Mattis Dementia Rating Scale (MDRS), for a total of 24 months. Results: In total, 27 of 48 (56%) study subjects were anti-NMDAR positive, defined as the presence of IgG (12/ 48, 25%), IgM (14/48, 29%) or IgA (13/48, 27%) antibodies in CSF and/or serum. IgM or IgA anti-NMDAR did not predict subsequent IgG autoimmunization and did not correlate to cognitive outcome. IgG anti-NMDAR serostatus, but not antibody titers, correlated to impaired recovery of cognitive performance. Conclusions: A majority of HSE patients develop IgG, IgM or IgA anti-NMDAR antibodies. However, the predictive value and clinical relevance of non-IgG isotypes remains to be shown in this setting.

  • 290.
    Widerström, Micael
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Molecular epidemiology of coagulase-negative staphylococci in hospitals and in the community2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Coagulase-negative staphylococci (CoNS) and in particular Staphylococcus epidermidis have emerged as major pathogens primarily causing nosocomial infections in patients with indwelling medical devices. These infections are often caused by multidrug-resistant strains of S. epidermidis (MDRSE). Other clinical entities due to CoNS are lower urinary tract infections (UTI) in women and native valve endocarditis. The purpose of this work was to investigate the frequency of antibiotic resistance and the molecular epidemiology of both hospital and community-associated isolates of S. epidermidis in order to examine if certain clones are related to MDRSE infections. Furthermore, we aimed to explore if specific clones of S. saprophyticus are associated with UTI in women.

    Methods

    A total of 359 hospital-associated methicillin-resistant isolates of CoNS obtained from 11 hospitals in northern Europe and 223 community-associated staphylococcal isolates were examined. Furthermore, 126 isolates of S. saprophyticus isolated from women with uncomplicated UTI from five different locations in northern Europe were analyzed. Pulsed-field gel electrophoresis (PFGE) was used for genotyping. Additionally, some of the S. epidermidis isolates were analyzed with multilocus sequence typing (MLST). Antibiotic susceptibility was determined for all isolates by the disc diffusion test.

    Results

    293 of the 359 (82%) hospital-associated and 124 of the 223 (56%) community-associated isolates belonged to the species S. epidermidis. Among the hospital-associated S. epidermidis isolates, two dominating PFGE types (type A and B) were distinguished, comprising 78 (27%) and 51 (17%) isolates, respectively. Type A, which was detected in a Norwegian and eight Swedish hospitals, corresponded with a novel sequence type (ST215). Type B was discovered in a German, a Danish and seven Swedish hospitals and corresponded with ST2. In contrast, community-associated isolates of S. epidermidis were genetically extremely diverse with no predominating genotype, and showed a low rate of antibiotic resistance; only two (1.6%) methicillin-resistant strains were detected.

    Among 126 analyzed isolates of S. saprophyticus, 47 different PFGE profiles were identified. Several clusters of genetically highly related isolates were detected among isolates obtained from different locations and periods of time.

    Conclusion

    We have demonstrated the occurrence, persistence and potential dissemination of two multidrug-resistant S. epidermidis (MDRSE) genotypes, including a novel sequence type (ST215), within hospitals in northern Europe. Community-associated isolates of S. epidermidis showed a low rate of methicillin-resistance and were genetically heterogeneous. These results indicate that MDRSE by large are confined to the hospital setting in our region. Moreover, although the S. saprophyticus population was quite heterogeneous, indistinguishable isolates of S. saprophyticus causing lower UTI in women were identified in different countries 11 years apart, indicating the persistence and geographical spread of some clones of S. saprophyticus.

  • 291.
    Widerström, Micael
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Monsen, Tor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Karlsson, Carina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Edebro, Helén
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Wiström, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Clonality among multidrug-resistant hospital-associated Staphylococcus epidermidis in northern Europe2009In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 41, no 9, p. 642-649Article in journal (Refereed)
    Abstract [en]

    Using pulsed-field gel electrophoresis (PFGE) we have previously described the occurrence and possible dissemination of a clone of multidrug-resistant Staphylococcus epidermidis (MDRSE) in 2 hospitals in northern Sweden during 2001-2003. The aims of the present study were to investigate if this clone still persisted, 7 y later, in these 2 hospitals and whether this specific clone was detectable among clinical isolates from 9 other hospitals, 6 Swedish as well as a Norwegian, Danish and a German hospital. In total, 173 clinical isolates of MDRSE isolated during 2003 to 2008 were analysed using PFGE, of which 22 isolates were also characterized by multilocus sequence typing (MLST). Two dominating PFGE types (types A and B) were identified, consisting of 56 (32%) and 38 (22%) isolates, respectively. Type A, which was detected in the Norwegian and all Swedish hospitals, proved indistinguishable to the clone previously identified in 2001-2003 and corresponded with a novel sequence type (ST215). Type B was discovered in the German, Danish and in 7 Swedish hospitals and corresponded with ST2. In conclusion, we have demonstrated the occurrence, persistence and potential dissemination of 2 MDRSE genotypes, including a novel sequence type (ST215), within hospitals in northern Europe.

  • 292.
    Widerström, Micael
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Jämtland Cty Council, Östersund, Sweden.
    Schönning, Caroline
    Lilja, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Lebbad, Marianne
    Ljung, Thomas
    Allestam, Görel
    Ferm, Martin
    Björkholm, Britta
    Hansen, Anette
    Hiltula, Jan I.
    Långmark, Jonas
    Löfdahl, Margareta
    Omberg, Maria
    Reuterwall, Christina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Samuelsson, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Widgren, Katarina
    Wallensten, Anders
    Lindh, Johan
    Large outbreak of cryptosporidium hominis infection transmitted through the public water supply, Sweden2014In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 20, no 4, p. 581-589Article in journal (Refereed)
    Abstract [en]

    In November 2010, approximate to 27,000 (approximate to 45%) inhabitants of Östersund, Sweden, were affected by a waterborne outbreak of cryptosporidiosis. The outbreak was characterized by a rapid onset and high attack rate, especially among young and middle-aged persons. Young age, number of infected family members, amount of water consumed daily, and gluten intolerance were identified as risk factors for acquiring cryptosporidiosis. Also, chronic intestinal disease and young age were significantly associated with prolonged diarrhea. Identification of Ctyptosporidium hominis subtype lbA10G2 in human and environmental samples and consistently low numbers of oocysts in drinking water confirmed insufficient reduction of parasites by the municipal water treatment plant. The current outbreak shows that use of inadequate microbial barriers at water treatment plants can have serious consequences for public health. This risk can be minimized by optimizing control of raw water quality and employing multiple barriers that remove or inactivate all groups of pathogens.

  • 293.
    Widerström, Micael
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Wiström, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Edebro, Helén
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Marklund, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Backman, Mattias
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Monsen, Tor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Colonization of patients, healthcare workers, and the environment with healthcare-associated Staphylococcus epidermidis genotypes in an intensive care unit: a prospective observational cohort study2016In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 16, article id 743Article in journal (Refereed)
    Abstract [en]

    Background: During the last decades, healthcare-associated genotypes of methicillin-resistant Staphylococcus epidermidis (HA-MRSE) have been established as important opportunistic pathogens. However, data on potential reservoirs on HA-MRSE is limited. The aim of the present study was to investigate the dynamics and to which extent HA-MRSE genotypes colonize patients, healthcare workers (HCWs) and the environment in an intensive care unit (ICU).

    Methods: Over 12 months in 2006-2007, swab samples were obtained from patients admitted directly from the community to the ICU and patients transferred from a referral hospital, as well as from HCWs, and the ICU environment. Patients were sampled every third day during hospitalization. Antibiotic susceptibility testing was performed according to EUCAST guidelines. Pulsed-field gel electrophoresis and multilocus sequence typing were used to determine the genetic relatedness of a subset of MRSE isolates.

    Results: We identified 620 MRSE isolates from 570 cultures obtained from 37 HCWs, 14 patients, and 14 environmental surfaces in the ICU. HA-MRSE genotypes were identified at admission in only one of the nine patients admitted directly from the community, of which the majority subsequently were colonized by HA-MRSE genotypes within 3 days during hospitalization. Almost all (89%) of HCWs were nasal carriers of HA-MRSE genotypes. Similarly, a significant proportion of patients transferred from the referral hospital and fomites in the ICU were widely colonized with HA-MRSE genotypes.

    Conclusions: Patients transferred from a referral hospital, HCWs, and the hospital environment serve as important reservoirs for HA-MRSE. These observations highlight the need for implementation of effective infection prevention and control measures aiming at reducing HA-MRSE transmission in the healthcare setting.

  • 294.
    Widerström, Micael
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Wiström, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ek, Elin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Edebro, Helen
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Monsen, Tor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Near absence of methicillin-resistance and pronounced genetic diversity among Staphylococcus epidermidis isolated from healthy persons in northern Sweden2011In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 119, no 8, p. 505-512Article in journal (Refereed)
    Abstract [en]

    The main aim of the study was to examine if hospital-associated clones of multidrug-resistant Staphylococcus epidermidis (MDRSE), commonly identified in hospitals in our region, also are spread among healthy persons in the community. A total of 124 isolates of S. epidermidis sampled from subjects attending a Travel health clinic, Umeå, Sweden during 2008 were examined with antibiotic susceptibility testing and pulsed field gel electrophoresis (PFGE) analysis.

    Resistance to methicillin or any antibiotic was detected in two and 26 of the isolates, respectively. PFGE analysis showed an extensive genetic diversity with 86 different PFGE types, of whom 62 were singletons. No isolates belonged to the previously described hospital-associated MDRSE genotypes, indicating that MDRSE by large are confined to the hospital setting in our region. In conclusion, community-associated isolates of S. epidermidis showed a low level of methicillin-resistance and were genetically extremely diverse with no predominating genotype.

  • 295. Wielkoszynski, Tomasz
    et al.
    Moghaddam, Aliyeh
    Backman, Assar
    Broden, Jessica
    Piotrowski, Rafal
    Mond-Paszek, Renata
    Kozarenko, Alexander
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Omnio AB, Umeå, Sweden.
    Novel diagnostic ELISA test for discrimination between infections with Yersinia enterocolitica and Yersinia pseudotuberculosis2018In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 37, no 12, p. 2301-2306Article in journal (Refereed)
    Abstract [en]

    Yersiniosis is a foodborne infection caused by Yersinia enterocolitica or Yersinia pseudotuberculosis. Although yersiniosis is most often self-limiting, some patients develop chronic infections, such as reactive arthritis, glomerulonephritis, or myocarditis, which require an antibiotic treatment. Whereas early infections can be diagnosed by direct detection of bacteria, chronic infections can only be identified by serological tests. At this point, a serological method for differentiation between infections with the two Yersinia species is important since antibiotic susceptibility of these bacteria is different. Traditional immunoassays do not distinguish between infections with Y. enterocolitica and Y. pseudotuberculosis. The only test that allows for this differentiation is Mikrogen's strip test where discrimination between the two types of infection is based on two recombinant bacterial proteins, MyfA and PsaA (specific for Y. enterocolitica and Y. pseudotuberculosis, respectively). Here, we show that Y. enterocolitica and Y. pseudotuberculosis, cultured under the conditions that mimic the natural rout of infection, express surface antigens different from MyfA and PsaA that can also be used in a discrimination test. Further, we describe a new ELISA that is based on the whole bacteria and recombinant MyfA and PsaA as antigens, and that allows the differentiation between infections with Y. enterocolitica and Y. pseudotuberculosis and simultaneous detection of yersiniosis.

  • 296.
    Wilder-Smith, Annelies
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; London School of Hygiene and Tropical Medicine, Department of Disease Control, London, UK.
    Chang, Chui Rhong
    Leong, Wei Yee
    Zika in travellers 1947-2017: a systematic review2018In: Journal of Travel Medicine, ISSN 1195-1982, E-ISSN 1708-8305, Vol. 25, article id tay044Article in journal (Refereed)
    Abstract [en]

    Introduction: Travellers contributed substantially to the rapid spread of Zika virus (ZIKV). They act as sentinel and may unmask ongoing ZIKV transmission in countries where outbreaks have not yet been reported. Our objectives were to (i) describe the burden of ZIKV infections in international travellers over time; (ii) estimate the proportion of birth defects as a result of maternal ZIKV infection in travellers; (iii) track the extent of sexual transmission; (iv) summarize ZIKV infections in returning travellers as reported by the GeoSentinel network; and (v) identify countries without reports on local ZIKV transmission where travellers served as sentinel.

    Methods: We performed a systematic review from 1947 to April 2017 on travel-associated ZIKV infections. We also compared published reports on autochthonous ZIKV transmission in Asia with published reports on exportations from travellers in Asia.

    Results: Of 314 papers that fit the inclusion criteria, 61 were eligible for final analysis. There was an exponential increase in the number of reported ZIKV infected travellers from the years 2013 to 2016, which declined in 2017. Amongst pregnant women with ZIKV infection, (5%) resulted in a fetus or infant with ZIKV-associated birth defects. An estimated 1% of the total number of ZIKV cases reported in the USA and Europe were acquired through sexual transmission. Through the GeoSentinel network, five countries (Indonesia, Philippines, Thailand, Vietnam, Cameroon) were identified as sentinel markers where ZIKV was exported despite the absence of reported local transmission.

    Conclusions: Mobility patterns and travel volumes can help to identify the most likely origin of importation, and also in predicting further propagation. Studies on pregnant returning travellers have contributed to a better understanding of the risk estimates of congenital Zika syndrome/microcephaly as a result of maternal ZIKV infection, and the relative contribution of sexual transmission.

  • 297.
    Wilder-Smith, Annelies
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
    Quam, Mikkel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sessions, O.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Liu-Helmersson, Jing
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Franco, L.
    Khan, K.
    The 2012 dengue outbreak in Madeira: exploring the origins2014In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 19, no 8, p. 20718-Article in journal (Refereed)
    Abstract [en]

    In 2012, Madeira reported its first major outbreak of dengue. To identify the origin of the imported dengue virus, we investigated the interconnectivity via air travel between dengue-endemic countries and Madeira, and compared available sequences against GenBank. There were 22,948 air travellers to Madeira in 2012, originating from twenty-nine dengue-endemic countries; 89.6% of these international travellers originated from Venezuela and Brazil. We developed an importation index that takes into account both travel volume and the extent of dengue incidence in the country of origin. Venezuela and Brazil had by far the highest importation indices compared with all other dengue-endemic countries. The importation index for Venezuela was twice as high as that for Brazil. When taking into account seasonality in the months preceding the onset of the Madeira outbreak, this index was even seven times higher for Venezuela than for Brazil during this time. Dengue sequencing shows that the virus responsible for the Madeira outbreak was most closely related to viruses circulating in Venezuela, Brazil and Columbia. Applying the importation index, Venezuela was identified as the most likely origin of importation of dengue virus via travellers to Madeira. We propose that the importation index is a new additional tool that can help to identify and anticipate the most probable country of origin for importation of dengue into currently non-endemic countries.

  • 298.
    Wilder-Smith, Annelies
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Immunization, Vaccines & Biologicals, World Health Organization, Geneva, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
    Vannice, Kirsten
    Durbin, Anna
    Hombach, Joachim
    Thomas, Stephen J.
    Thevarjan, Irani
    Simmons, Cameron P.
    Zika vaccines and therapeutics: landscape analysis and challenges ahead2018In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 16, article id 84Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Various Zika virus (ZIKV) vaccine candidates are currently in development. Nevertheless, unique challenges in clinical development and regulatory pathways may hinder the licensure of high-quality, safe, and effective ZIKV vaccines.

    DISCUSSION: Implementing phase 3 efficacy trials will be difficult given the challenges of the spatio-temporal heterogeneity of ZIKV transmission, the unpredictability of ZIKV epidemics, the broad spectrum of clinical manifestations making a single definite endpoint difficult, a lack of sensitive and specific diagnostic assays, and the need for inclusion of vulnerable target populations. In addition to a vaccine, drugs for primary prophylaxis, post-exposure prophylaxis, or treatment should also be developed to prevent or mitigate the severity of congenital Zika syndrome.

    CONCLUSION: Establishing the feasibility of immune correlates and/or surrogates are a priority. Given the challenges in conducting phase 3 trials at a time of waning incidence, human challenge trials should be considered to evaluate efficacy. Continued financial support and engagement of industry partners will be essential to the successful development, licensure, and accessibility of Zika vaccines or therapeutics.

  • 299. Wilhelmsson, Peter
    et al.
    Fryland, Linda
    Lindblom, Pontus
    Sjöwall, Johanna
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Berglund, Johan
    Haglund, Mats
    Henningsson, Anna J
    Nolskog, Peter
    Nordberg, Marika
    Nyberg, Clara
    Ornstein, Katharina
    Nyman, Dag
    Ekerfelt, Christina
    Forsberg, Pia
    Lindgren, Per-Eric
    A prospective study on the incidence of Borrelia burgdorferi sensu lato infection after a tick bite in Sweden and On the Åland Islands, Finland (2008-2009)2016In: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 7, no 1, p. 71-79Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis (LB) is a common and increasing tick-borne disease in Europe. The risk of acquiring a Borrelia infection after a tick bite is not fully known. Therefore, we investigated the incidence of Borrelia infection after a bite by a Borrelia-infected tick and if the Borrelia load and/or the duration of tick-feeding influenced the risk of infection. During 2008-2009, ticks and blood samples were collected from 1546 tick-bitten persons from Sweden and the Åland Islands, Finland. Follow-up blood samples were taken 3 months after the tick bite. The duration of tick feeding was microscopically estimated and Borrelia was detected and quantified in ticks by real-time PCR. Anti-Borrelia antibodies were detected in sera using ELISA tests and immunoblot. Five percent (78/1546) of the study participants developed Borrelia infection (LB diagnosis and/or seroconversion) after a tick bite (45% bitten by Borrelia-infected ticks and 55% bitten by uninfected ticks). Of these, 33 developed LB (whereof 9 also seroconverted) while 45 participants seroconverted only. Experience of non-specific symptoms was more frequently reported by Borrelia-infected participants compared to uninfected participants. All who seroconverted removed "their" ticks significantly later than those who did not. The Borrelia load in the ticks did not explain the risk of seroconversion. Regional and sex differences in the Borrelia seroprevalence were found. The risk of developing a Borrelia infection after a bite by a Borrelia-infected tick is small but increases with the duration of tick feeding.

  • 300.
    Winblad, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Experimental studies on the pathogenesis of infections of the male uro-genital tract caused by Mycobacterium tuberculosis var. hominis and Candida albicans1975Doctoral thesis, comprehensive summary (Other academic)
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