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  • 201. Munster, Vincent J
    et al.
    Wallensten, Anders
    Baas, Chantal
    Rimmelzwaan, Guus F
    Schutten, Martin
    Olsen, Björn
    Kalmar University, Kalmar, Sweden..
    Osterhaus, Albert D M E
    Fouchier, Ron A M
    Mallards and highly pathogenic avian influenza ancestral viruses, northern Europe2005In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 11, no 10, p. 1545-1551Article in journal (Refereed)
    Abstract [en]

    Outbreaks of highly pathogenic avian influenza (HPAI), which originate in poultry upon transmission of low pathogenic viruses from wild birds, have occurred relatively frequently in the last decade. During our ongoing surveillance studies in wild birds, we isolated several influenza A viruses of hemagglutinin subtype H5 and H7 that contain various neuraminidase subtypes. For each of the recorded H5 and H7 HPAI outbreaks in Europe since 1997, our collection contained closely related virus isolates recovered from wild birds, as determined by sequencing and phylogenetic analyses of the hemagglutinin gene and antigenic characterization of the hemagglutinin glycoprotein. The minor genetic and antigenic diversity between the viruses recovered from wild birds and those causing HPAI outbreaks indicates that influenza A virus surveillance studies in wild birds can help generate prototypic vaccine candidates and design and evaluate diagnostic tests, before outbreaks occur in animals and humans.

  • 202.
    Müller, Daniel C.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kauppi, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders B.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Phospholipid Levels in Blood during Community-Acquired Pneumonia2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0216379Article in journal (Refereed)
    Abstract [en]

    Phospholipids, major constituents of bilayer cell membranes, are present in large amounts in pulmonary surfactant and play key roles in cell signaling. Here, we aim at finding clinically useful disease markers in community-acquired pneumonia (CAP) using comprehensive phospholipid profiling in blood and modeling of changes between sampling time points. Serum samples from 33 patients hospitalized with CAP were collected at admission, three hours after the start of intravenous antibiotics, Day 1 (at 12–24 h), Day 2 (at 36–48 h), and several weeks after recovery. A profile of 75 phospholipid species including quantification of the bioactive lysophosphatidylcholines (LPCs) was determined using liquid chromatography coupled to time-of-flight mass spectrometry. To control for possible enzymatic degradation of LPCs, serum autotaxin levels were examined. Twenty-two of the 33 patients with a clinical diagnosis of CAP received a laboratory-verified CAP diagnosis by microbial culture or microbial DNA detection by qPCR. All major phospholipid species, especially the LPCs, were pronouncedly decreased in the acute stage of illness. Total and individual LPC concentrations increased shortly after the initiation of antibiotic treatment, concentrations were at their lowest 3h after the initiation, and increased after Day 1. The total LPC concentration increased by a change ratio of 1.6–1.7 between acute illness and Day 2, and by a ratio of 3.7 between acute illness and full disease resolution. Autotaxin levels were low in acute illness and showed little changes over time, contradicting a hypothesis of enzymatic degradation causing the low levels of LPCs. In this sample of patients with CAP, the results demonstrate that LPC concentration changes in serum of patients with CAP closely mirrored the early transition from acute illness to recovery after the initiation of antibiotics. LPCs should be further explored as potential disease stage biomarkers in CAP and for their potential physiological role during recovery.

  • 203. Na, Manli
    et al.
    Wang, Wanzhong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fei, Ying
    Josefsson, Elisabet
    Ali, Abukar
    Jin, Tao
    Both anti-TNF and CTLA4 Ig treatments attenuate the disease severity of staphylococcal dermatitis in mice2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0173492Article in journal (Refereed)
    Abstract [en]

    Background RA patients being treated with biologics are known to have an increased risk of infections. We recently demonstrated that both CTLA4 Ig and anti-TNF treatment aggravate systemic Staphylococcus aureus (S. aureus) infection in mice, but with distinct clinical manifestations. However, the effects of CTLA4 Ig and anti-TNF treatments on a local S. aureus infection (e.g., skin infection) might differ from their effects on a systemic infection. Aims The aim of this study was to examine the differential effects of anti-TNF versus CTLA4 Ig treatment on S. aureus skin infections in mice. Method Abatacept (CTLA4 Ig), etanercept (anti-TNF treatment) or PBS was given to NMRI mice subcutaneously inoculated with S. aureus strain SH1000. The clinical signs of dermatitis, along with histopathological changes due to skin infection, were compared between the groups. Results Both CTLA4 Ig and anti-TNF treatment resulted in less severe skin infections and smaller post-infectious hyperpigmentation compared with controls. Consistent with the clinical signs of dermatitis, smaller lesion size, more epithelial hyperplasia and more granulation were found in skin biopsies from mice receiving anti-TNF compared with PBS controls. However, both CTLA4 Ig and anti-TNF therapy tended to prolong the healing time, although this finding was not statistically significant. Serum MCP-1 levels were elevated in the anti-TNF group relative to the CTLA4 Ig and PBS groups, whereas IL-6 levels were higher in PBS controls than in the other two groups. Both anti-TNF and CTLA4 Ig treatments tended to down-regulate the necrosis/apoptosis ratio in the locally infected skin tissue. Importantly, no tangible difference was found in the bacterial burden among groups. Conclusion Both CTLA4 Ig and anti-TNF therapies attenuate disease severity but may prolong the healing time required for S. aureus skin infections. Neither treatment has an impact on bacterial clearance in skin tissues.

  • 204. Napier, Brooke A
    et al.
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bina, James E
    Miller, Mark A
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Weiss, David S
    Link between intraphagosomal biotin and rapid phagosomal escape in Francisella2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 44, p. 18084-18089Article in journal (Refereed)
    Abstract [en]

    Cytosolic bacterial pathogens require extensive metabolic adaptations within the host to replicate intracellularly and cause disease. In phagocytic cells such as macrophages, these pathogens must respond rapidly to nutrient limitation within the harsh environment of the phagosome. Many cytosolic pathogens escape the phagosome quickly (15-60 min) and thereby subvert this host defense, reaching the cytosol where they can replicate. Although a great deal of research has focused on strategies used by bacteria to resist antimicrobial phagosomal defenses and transiently pass through this compartment, the metabolic requirements of bacteria in the phagosome are largely uncharacterized. We previously identified a Francisella protein, FTN_0818, as being essential for intracellular replication and involved in virulence in vivo. We now show that FTN_0818 is involved in biotin biosynthesis and required for rapid escape from the Francisella-containing phagosome (FCP). Addition of biotin complemented the phagosomal escape defect of the FTN_0818 mutant, demonstrating that biotin is critical for promoting rapid escape during the short time that the bacteria are in the phagosome. Biotin also rescued the attenuation of the FTN_0818 mutant during infection in vitro and in vivo, highlighting the importance of this process. The key role of biotin in phagosomal escape implies biotin may be a limiting factor during infection. We demonstrate that a bacterial metabolite is required for phagosomal escape of an intracellular pathogen, providing insight into the link between bacterial metabolism and virulence, likely serving as a paradigm for other cytosolic pathogens.

  • 205.
    Negash Atsbeha, Maasho
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Biomedicinprogrammet.
    The role of H-NS in the expression of virulence factors in Escherichia coli and Acinetobacter baumannii: Diverse virulence phenotypes among A. baumannii clinical isolates2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 206.
    Negi, Neema
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ahmad, Aijaz
    Current updates on fungal endocarditis2018In: Fungal Biology Reviews, ISSN 1749-4613, E-ISSN 1878-0253, Vol. 32, no 1, p. 1-9Article, review/survey (Refereed)
    Abstract [en]

    Fungal endocarditis (FE) is a rare disease but in recent years its incidence as well as mortality is increasing particularly in developing nations. Candida and Aspergillus species occupy the prominent position as etiological agents of this invasive disease. Intravenous devices such as pacemakers, central line related thrombosis and prolonged use of antibiotics are major risk factors for FE. The epidemiology of endocarditis cases is also evolving over time with exceptionally rare species causing more invasive disease. Research over the last decade has also delineated the underlying pathogenic mechanism of FE. Improved understanding of these mechanisms will help to combat the increasing problem of antimicrobial drug resistance. The diagnosis of FE is dependent on the sensitivity and specificity of the method as fungi generally do not grow well in blood cultures. More advanced techniques including molecular and immunological assays now play a central role in accurate identification of causative fungal pathogens especially in culture negative scenario. In developing nations such as India, blood culture reports are generally negative due to prior antibiotic therapy. Echocardiography has emerged as the potential imaging technique for identifying invasive endocarditis including small masses of vegetation or abscess. Successful treatment often requires both the surgical interventions and prolonged antifungal therapy. In the present review, we briefly highlight the mechanisms of pathogenesis of this rare emerging disease along with the risk factors involved, the diagnostic criteria and the treatment strategy.

  • 207. Neumayr, Andreas
    et al.
    Muñoz, Jose
    Schunk, Mirjam
    Bottieau, Emmanuel
    Cramer, Jakob
    Calleri, Guido
    López-Vélez, Rogelio
    Angheben, Andrea
    Zoller, Thomas
    Visser, Leo
    Serre-Delcor, Núria
    Genton, Blaise
    Castelli, Francesco
    Van Esbroeck, Marjan
    Matteelli, Alberto
    Rochat, Laurence
    Sulleiro, Elena
    Kurth, Florian
    Gobbi, Federico
    Norman, Francesca
    Torta, Ilaria
    Clerinx, Jan
    Poluda, David
    Martinez, Miguel
    Calvo-Cano, Antonia
    Sanchez-Seco, Maria Paz
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Institute of Public Health, University of Heidelberg, Germany.
    Hatz, Christoph
    Franco, Leticia
    Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: TropNet data from the DengueTools Research Initiative2017In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 22, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012-13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent.

  • 208.
    Nkulu Kalengayi, Faustine Kyungu
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hurtig, Anna-Karin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Krantz, Ingela
    Skaraborg Inst Res & Dev, Skövde, Sweden.
    Fear of deportation may limit legal immigrants' access to HIV/AIDS-related care: a survey of Swedish language school students in Northern Sweden2012In: Journal of Immigrant and Minority Health, ISSN 1557-1912, E-ISSN 1557-1920, Vol. 14, no 1, p. 39-47Article in journal (Refereed)
    Abstract [en]

    The increasing rates of HIV infection that are currently being reported in high-income countries can be partly explained by migration from countries with generalized epidemics. Yet, early diagnosis of HIV/AIDS in immigrants remains a challenge. This study investigated factors that might be limiting immigrants' access to HIV/AIDS care. Data from 268 legal immigrant students of two Swedish language schools in Northern Sweden were analyzed using logistic regression. Thirty-seven percent reported reluctance to seek medical attention if they had HIV/AIDS. Fear of deportation emerged as the most important determinant of reluctance to seek care after adjusting for socio-demographic factors, knowledge level, stigmatizing attitudes and fear of disclosure. Targeted interventions should consider the heterogeneity of migrant communities and the complex interplay of various factors which may impede access to HIV-related services. The myth about deportation because of HIV/AIDS should be countered.

  • 209. Norling, Karin
    et al.
    Bernasconi, Valentina
    Hernandez, Victor Agmo
    Parveen, Na Ma
    Edwards, Katarina
    Lycke, Nils Y.
    Hook, Fredrik
    Bally, Marta
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Gel Phase 1,2-Distearoyl-sn-glycero-3-phosphocholine-Based Liposomes Are Superior to Fluid Phase Liposomes at Augmenting Both Antigen Presentation on Major Histocompatibility Complex Class II and Costimulatory Molecule Display by Dendritic Cells in Vitro2019In: ACS Infectious Diseases, ISSN 2373-8227, Vol. 5, no 11, p. 1867-1878Article in journal (Refereed)
    Abstract [en]

    Lipid-based nanoparticles have in recent years attracted increasing attention as pharmaceutical carriers. In particular, reports of them having inherent adjuvant properties combined with their ability to protect antigen from degradation make them suitable as vaccine vectors. However, the physicochemical profile of an ideal nanoparticle for vaccine delivery is still poorly defined. Here, we used an in vitro dendritic cell assay to assess the immunogenicity of a variety of liposome formulations as vaccine carriers and adjuvants. Using flow cytometry, we investigated liposome-assisted antigen presentation as well as the expression of relevant costimulatory molecules on the cell surface. Cytokine secretion was further evaluated with an enzyme-linked immunosorbent assay (ELISA). We show that liposomes can successfully enhance antigen presentation and maturation of dendritic cells, as compared to vaccine fusion protein (CTA1-3E alpha-DD) administered alone. In particular, the lipid phase state of the membrane was found to greatly influence the vaccine antigen processing by dendritic cells. As compared to their fluid phase counterparts, gel phase liposomes were more efficient at improving antigen presentation. They were also superior at upregulating the costimulatory molecules CD80 and CD86 as well as increasing the release of the cytokines IL-6 and IL-1 beta. Taken together, we demonstrate that gel phase liposomes, while nonimmunogenic on their own, significantly enhance the antigen-presenting ability of dendritic cells and appear to be a promising way forward to improve vaccine immunogenicity.

  • 210. Nykvist, Marie
    et al.
    Gillman, Anna
    Söderström Lindström, Hanna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tang, Chaojun
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fedorova, Ganna
    Lundkvist, Åke
    Latorre-Margalef, Neus
    Wille, Michelle
    Järhult, Josef D.
    In vivo mallard experiments indicate that zanamivir has less potential for environmental influenza A virus resistance development than oseltamivir2017In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 98, p. 2937-2949Article in journal (Refereed)
    Abstract [en]

    Neuraminidase inhibitors are a cornerstone of influenza pandemic preparedness before vaccines can be mass-produced and thus a neuraminidase inhibitor-resistant pandemic is a serious threat to public health. Earlier work has demonstrated the potential for development and persistence of oseltamivir resistance in influenza A viruses exposed to environmentally relevant water concentrations of the drug when infecting mallards, the natural influenza reservoir that serves as the genetic base for human pandemics. As zanamivir is the major second-line neuraminidase inhibitor treatment, this study aimed to assess the potential for development and persistence of zanamivir resistance in an in vivo mallard model; especially important as zanamivir will probably be increasingly used. Our results indicate less potential for development and persistence of resistance due to zanamivir than oseltamivir in an environmental setting. This conclusion is based on: (1) the lower increase in zanamivir IC50 conferred by the mutations caused by zanamivir exposure (2-17-fold); (2) the higher zanamivir water concentration needed to induce resistance (at least 10 µg l-1); (3) the lack of zanamivir resistance persistence without drug pressure; and (4) the multiple resistance-related substitutions seen during zanamivir exposure (V116A, A138V, R152K, T157I and D199G) suggesting lack of one straight-forward evolutionary path to resistance. Our study also adds further evidence regarding the stability of the oseltamivir-induced substitution H275Y without drug pressure, and demonstrates the ability of a H275Y-carrying virus to acquire secondary mutations, further boosting oseltamivir resistance when exposed to zanamivir. Similar studies using influenza A viruses of the N2-phylogenetic group of neuraminidases are recommended.

  • 211.
    Näslund, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lagerqvist, Nina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Habjan, Matthias
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Lundkvist, Ake
    Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Weber, Friedemann
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Bucht, Göran
    Swedish Defence Research Agency, Department of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Vaccination with virus-like particles protects mice from lethal infection of Rift Valley fever virus2009In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 385, no 2, p. 409-415Article in journal (Refereed)
    Abstract [en]

    Rift Valley Fever virus (RVFV) regularly accounts for severe and often lethal outbreaks among livestock and humans in Africa. Safe and effective veterinarian and human vaccines are highly needed. We present evidence that administration of RVF virus-like particles (VLPs) induces protective immunity in mice. In an accompanying paper, (Habjan, M., Penski, N., Wagner, V., Spiegel, M., Overby, A.K., Kochs, G., Huiskonen, J., Weber, F., 2009. Efficient production of Rift Valley fever virus-like particles: the antiviral protein MxA can inhibit primary transcription of Bunyaviruses. Virology 385, 400-408) we report the production of these VLPs in mammalian cells. After three subsequent immunizations with 1x10(6) VLPs/dose, high titers of virus-neutralizing antibodies were detected; 11 out of 12 mice were protected from challenge and only 1 out of 12 mice survived infection in the control groups. VLP vaccination efficiently suppressed replication of the challenge virus, whereas in the control animals high RNA levels and increasing antibody titers against the nucleocapsid protein indicated extensive viral replication. Our study demonstrates that the RVF VLPs are highly immunogenic and confer protection against RVFV infection in mice. In the test groups, the vaccinated mice did not exhibit any side effects, and the lack of anti-nucleocapsid protein antibodies serologically distinguished vaccinated animals from experimentally infected animals.

  • 212.
    Olfat, Farzad
    Umeå University, Faculty of Medicine, Odontology.
    Helicobacter pylori: bacterial adhesion and host response2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The gastric pathogen Helicobacter pylori infects more than half of the population worldwide. H. pylori manage to establish persistent infection, which would be life-long if not treated. In order to establish such an infection, this pathogen has to deal with the host immune system. H. pylori has certain characteristics which make the bacteria less announced to the host immune system. Additionally, for remaining in the harsh and acidic environment of the stomach with peristaltic movements and a high frequency of turnover of epithelial cells, H. pylori has developed different binding modes to structures present both in the mucus and on the surface of gastric cells and also to extracellular matrix proteins. Evidently, adhesion has a determinant role for a successful colonization by H. pylori. It has been shown that a small fraction of the H. pylori infection is in intimate contact and attached to the host epithelium. Despite its small proportion, this group maintains the persistency of infection. As there is no suitable in vitro system to mimic the human stomach for studies of H. pylori infection, we have developed the In Vitro Explant Culture technique (IVEC). By using this model we could show that H. pylori use the Lewis b blood group antigen to bind to the host gastric mucosa, during experimental conditions most similar to the in vivo situation. Furthermore, we could show that the host tissue responses to the bacterial attachment by expression of Interleukin 8 (IL- ), which will guide the inflammatory processes. Interestingly, by inhibition of bacterial adhesion through receptor competition i.e., by use of soluble Lewis b antigen, IL-8 production was hampered in the IVEC system, which further validates the presence of a tight relation between bacterial adhesion and induction of host immune responses. One of the inflammation signaling cursors in vivo is the upregulated sialylated Lewis x (sLex) antigen, an inflammation associated carbohydrate structure well established as a binding site for the selectin family of adhesion molecules. We could show that during chronic gastric inflammation, which is actually caused by the persistent H. pylori infection, the bacterial cells adapt their binding mode, and preferentially bind to sLex, which will provide an even more intimate contact with the host cells. This interaction is mediated by SabA, the H. pylori adhesin for sialylated oligosaccharides/glycoconjugates. By employing red blood cells as a model we could further demonstrate that SabA is identical to the “established” H. pylori hemagglutinin. We could also show that SabA binds to sialylated glycolipids (gangliosides) rather than glycoproteins on cell surfaces. Our result also revealed that SabA also binds to and activates human neutrophils. Such effect was unrelated to BabA and the H. pylori Neutrophil Activating Protein (HP- AP), which were not directly involved in the activation of neutrophils. Furthermore, phagocytosis of bacteria by neutrophils was demonstrated to be mainly dependent on presence of SabA. Interestingly, HP-NAP showed a possible role in guiding the bacterial adhesion during conditions of limited sialylation, i.e. equivalent to mild gastritis, when the tissue would be less inflamed and sialylated. In conclusion, H. pylori adhesion causes host tissue inflammation, then the bacteria will adapt to the new condition and bind to epithelial cells in a tighter mode by synergistic activities of BabA and SabA. Additionally, SabA bind to and activate human neutrophils, which will exacerbate inflammation responses and cause damage to host tissue. Thus, BabA and SabA are potential candidates to be targeted for therapeutic strategies against H. pylori and gastric disease.

  • 213.
    Olsson, Gert E
    et al.
    Institutionen för vilt, fisk och miljö, Sveriges lantbruksuniversitet, Umeå.
    Hjertqvist, Marika
    Epidemiologiska avdelningen, Smittskyddsinstitutet, Solna.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hörnfeldt, Birger
    Institutionen för vilt, fisk och miljö, Sveriges lantbruksuniversitet, Umeå.
    Sorkfeberprognos: sorkdata pekar på nytt, stort utbrott2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 29-31, p. 1769-1770Article in journal (Other academic)
  • 214.
    Olsson, Gert E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    White, Neil
    Department of Primary Industries and Fisheries, Toowoomba, Australia.
    Hjältén, Joakim
    Department of Animal Ecology, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Habitat factors associated with bank voles (Clethrionomys glareolus) and concomitant hantavirus in northern Sweden2005In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 5, no 4, p. 315-323Article in journal (Refereed)
    Abstract [en]

    Puumala virus (PUUV), genus hantavirus, causes nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome in humans. In this study, bank voles, the natural reservoir of PUUV, were captured at locations of previous human PUUV exposure and paired controls within a region of high incidence in northern Sweden. The aim of the study was to evaluate the influence of environmental factors on the abundance of bank voles and the occurrence of PUUV. The total number of voles and the number of PUUV-infected voles did not differ between locations of previous human PUUV exposure and paired controls. The number of bank voles expressing antibodies to PUUV infection increased linearly with total bank vole abundance implying density independent transmission. Using principal component and partial correlation analysis, we found that particular environmental characteristics associated with old-growth moist forests (i.e., those dominated by Alectoria spp., Picea abies, fallen wood, and Vaccinium myrtillus) were also associated with increased abundance of bank vole and hence the number of PUUV-infected bank voles, whereas there were no correlations with factors associated with dry environments (i.e., Pinus sylvestris and V. vitis-idea). This suggests that circulation and persistence of PUUV within bank vole populations was influenced by habitat factors. Future modeling of risk of exposure to hantavirus and transmission of PUUV within vole populations should include the influence of these factors.

  • 215.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergh Drott, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Laurantzon, Lovisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Laurantzon, Oscar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Chronic prostatic infection and inflammation by propionibacterium acnes in a rat prostate infection model2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51434-Article in journal (Refereed)
    Abstract [en]

    Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the Gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic inflammation may be induced by P. acnes infection.

  • 216.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Laboratory Medicine, Clinical Microbiology, Umeå University Hospital, Umeå, Sweden.
    Honkala, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Blomqvist, Bert
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Laboratory Medicine, Clinical Microbiology, Umeå University Hospital, Umeå, Sweden.
    Kok, Eloise
    Weidung, Bodil
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Urea dilution of serum for reproducible anti-HSV1 IgG avidity index2019In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 19, article id 164Article in journal (Refereed)
    Abstract [en]

    Herpes simplex virus type 1 (HSV1), establishes life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe a protocol to generate a reliable and discriminative avidity index (AI) for anti-HSV1 IgG content in human sera. Human serum from two distinct cohorts; one a biobank collection (Betula) (n = 28), and one from a clinical diagnostics laboratory at Northern Sweden University Hospital (NUS) (n = 18), were assessed for presence of IgG antibodies against HSV1 by a commercially available ELISA-kit. Addition of urea at the incubation step reduces effective binding, and the ratio between urea treated sample and non-treated sample was used to express an avidity index (AI) for individual samples. AI score ranged between 43.2 and 73.4% among anti-HSV1 positive biobank sera. Clinical samples ranged between 36.3 and 74.9%. Reproducibility expressed as an intraclass correlation coefficient (ICC) was estimated at 0.948 (95% CI: 0.900-0.979) and 0.989 (95% CI 0.969-0.996) in the biobank and clinical samples, respectively. The method allows for AI scoring of anti-HSV1 IgG from individual human sera with a single measurement. The least significant change between two measurements at the p < 0.05 level was estimated at 5.4 and 3.2 points, respectively, for the two assessed cohorts.

  • 217.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kok, Eloise
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Herpes virus seroepidemiology in the adult Swedish population2017In: Immunity & Ageing, ISSN 1742-4933, E-ISSN 1742-4933, Vol. 14, article id 10Article in journal (Refereed)
    Abstract [en]

    Background: Herpes viruses establish a life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe the seroepidemiology of Herpes simplex type 1 (HSV1), Herpes simplex type 2 (HSV2), Cytomegalovirus (CMV), Varicella Zoster virus (VZV) and Human herpes virus type 6 (HHV6) in an adult Swedish population (35-95 years of age). Methods: Presence of antibodies against the respective viruses in serum from individuals in the Betula study was determined with an enzyme-linked immunosorbent assay (ELISA). Singular samples from 535 persons (53.9% women, mean age at inclusion 62.7 +/- 14.4 years) collected 2003-2005 were analyzed for the five HHVs mentioned above. In addition, samples including follow-up samples collected 1988-2010 from 3,444 persons were analyzed for HSV. Results: Prevalence of HSV1 was 79.4%, HSV2 12.9%, CMV 83.2%, VZV 97.9%, and HHV6 97.5%. Herpes virus infections were more common among women (p = 0.010) and a lower age-adjusted HSV seroprevalence was found in later birth cohorts (p < 0.001). The yearly incidence of HSV infection was estimated at 14.0/1000. Conclusion: Women are more often seropositive for HHV, especially HSV2. Age-adjusted seroprevalence for HSV was lower in later birth cohorts indicating a decreasing childhood and adolescent risk of infection.

  • 218. O'Reilly, Kathleen M.
    et al.
    Lowe, Rachel
    Edmunds, W. John
    Mayaud, Philippe
    Kucharski, Adam
    Eggo, Rosalind M.
    Funk, Sebastian
    Bhatia, Deepit
    Khan, Kamran
    Kraemer, Moritz U. G.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Department of Disease Control, London School of Hygiene & Tropical Medicine, London, UK; Institute of Public Health, University of Heidelberg, Heidelberg, Germany.
    Rodrigues, Laura C.
    Brasil, Patricia
    Massad, Eduardo
    Jaenisch, Thomas
    Cauchemez, Simon
    Brady, Oliver J.
    Yakob, Laith
    Projecting the end of the Zika virus epidemic in Latin America: a modelling analysis2018In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 16, article id 180Article in journal (Refereed)
    Abstract [en]

    Background: Zika virus (ZIKV) emerged in Latin America and the Caribbean (LAC) region in 2013, with serious implications for population health in the region. In 2016, the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern following a cluster of associated neurological disorders and neonatal malformations. In 2017, Zika cases declined, but future incidence in LAC remains uncertain due to gaps in our understanding, considerable variation in surveillance and the lack of a comprehensive collation of data from affected countries.

    Methods: Our analysis combines information on confirmed and suspected Zika cases across LAC countries and a spatio-temporal dynamic transmission model for ZIKV infection to determine key transmission parameters and projected incidence in 90 major cities within 35 countries. Seasonality was determined by spatio-temporal estimates of Aedes aegypti vectorial capacity. We used country and state-level data from 2015 to mid-2017 to infer key model parameters, country-specific disease reporting rates, and the 2018 projected incidence. A 10-fold cross-validation approach was used to validate parameter estimates to out-of-sample epidemic trajectories.

    Results: There was limited transmission in 2015, but in 2016 and 2017 there was sufficient opportunity for wide-spread ZIKV transmission in most cities, resulting in the depletion of susceptible individuals. We predict that the highest number of cases in 2018 would present within some Brazilian States (Sao Paulo and Rio de Janeiro), Colombia and French Guiana, but the estimated number of cases were no more than a few hundred. Model estimates of the timing of the peak in incidence were correlated (p < 0.05) with the reported peak in incidence. The reporting rate varied across countries, with lower reporting rates for those with only confirmed cases compared to those who reported both confirmed and suspected cases.

    Conclusions: The findings suggest that the ZIKV epidemic is by and large over within LAC, with incidence projected to be low in most cities in 2018. Local low levels of transmission are probable, but the estimated rate of infection suggests that most cities have a population with high levels of herd immunity.

  • 219. Orikiiriza, Judy
    et al.
    Surowiec, Izabella
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindquist, Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bonde, Mari
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    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, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lipid response patterns in acute phase paediatric Plasmodium falciparum malaria2017In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, no 4, article id 41Article in journal (Refereed)
    Abstract [en]

    Introduction: Several studies have observed serum lipid changes during malaria infection in humans. All of them were focused at analysis of lipoproteins, not specific lipid molecules. The aim of our study was to identify novel patterns of lipid species in malaria infected patients using lipidomics profiling, to enhance diagnosis of malaria and to evaluate biochemical pathways activated during parasite infection.

    Methods: Using a multivariate characterization approach, 60 samples were representatively selected, 20 from each category (mild, severe and controls) of the 690 study participants between age of 0.5–6 years. Lipids from patient’s plasma were extracted with chloroform/methanol mixture and subjected to lipid profiling with application of the LCMS-QTOF method.

    Results: We observed a structured plasma lipid response among the malaria-infected patients as compared to healthy controls, demonstrated by higher levels of a majority of plasma lipids with the exception of even-chain length lysophosphatidylcholines and triglycerides with lower mass and higher saturation of the fatty acid chains. An inverse lipid profile relationship was observed when plasma lipids were correlated to parasitaemia.

    Conclusions: This study demonstrates how mapping the full physiological lipid response in plasma from malaria-infected individuals can be used to understand biochemical processes during infection. It also gives insights to how the levels of these molecules relate to acute immune responses.

  • 220. Orsborne, James
    et al.
    DeRaedt Banks, Sarah
    Hendy, Adam
    Gezan, Salvador A.
    Kaur, Harparkash
    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.
    Lindsay, Steve W.
    Logan, James G.
    Personal Protection of Permethrin-Treated Clothing against Aedes aegypti, the Vector of Dengue and Zika Virus, in the Laboratory2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0152805Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The dengue and Zika viruses are primarily transmitted by Aedes aegypti mosquitoes, which are most active during day light hours and feed both in and outside of the household. Personal protection technologies such as insecticide-treated clothing could provide individual protection. Here we assessed the efficacy of permethrin-treated clothing on personal protection in the laboratory.

    METHODS: The effect of washing on treated clothing, skin coverage and protection against resistant and susceptible Ae. aegypti was assessed using modified WHO arm-in-cage assays. Coverage was further assessed using free-flight room tests to investigate the protective efficacy of unwashed factory-dipped permethrin-treated clothing. Clothing was worn as full coverage (long sleeves and trousers) and partial coverage (short sleeves and shorts). Residual permethrin on the skin and its effect on mosquitoes was measured using modified WHO cone assays and quantified using high-pressure liquid chromatography (HPLC) analysis.

    RESULTS: In the arm-in-cage assays, unwashed clothing reduced landing by 58.9% (95% CI 49.2-66.9) and biting by 28.5% (95% CI 22.5-34.0), but reduced to 18.5% (95% CI 14.7-22.3) and 11.1% (95% CI 8.5-13.8) respectively after 10 washes. Landing and biting for resistant and susceptible strains was not significantly different (p<0.05). In free-flight room tests, full coverage treated clothing reduced landing by 24.3% (95% CI 17.4-31.7) and biting by 91% (95% CI 82.2-95.9) with partial coverage reducing landing and biting by 26.4% (95% CI 20.3-31.2) and 49.3% (95% CI 42.1-59.1) respectively with coverage type having no significant difference on landing (p<0.05). Residual permethrin was present on the skin in low amounts (0.0041mg/cm2), but still produced a KD of >80% one hour after wearing treated clothing.

    CONCLUSION: Whilst partially covering the body with permethrin-treated clothing provided some protection against biting, wearing treated clothing with long sleeves and trousers provided the highest form of protection. Washing treated clothing dramatically reduced protection provided. Permethrin-treated clothing could provide protection to individuals from Ae. aegypti that show permethrin resistance. Additionally, it could continue to provide protection even after the clothing has been worn. Field trials are urgently needed to determine whether clothing can protect against dengue and Zika.

  • 221. Paixao, Enny S.
    et al.
    Leong, Wei-Yee
    Rodrigues, Laura C.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Asymptomatic Prenatal Zika Virus Infection and Congenital Zika Syndrome2018In: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 5, no 4Article in journal (Refereed)
    Abstract [en]

    To investigate to what extent asymptomatic vs symptomatic prenatal Zika virus infections contribute to birth defects, we identified 3 prospective and 8 retrospective studies. The ratio varied greatly in the retrospective studies, most likely due to recruitment and recall bias. The prospective studies revealed a ratio of 1: 1 for asymptomatic vs symptomatic maternal Zika infections resulting in adverse fetal outcomes.

  • 222.
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Importance of wild birds in the spread of Salmonella2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Salmonella is one of the most important enteropathogenic bacteria. It is responsible for about 5000 reported cases of human gastroenteritis each year in Sweden. Salmonellosis is a zoonotic disease, and the bacterium has the ability to infect a variety of both domestic and wild animal species.

    In studies of Swedish wild bird populations, we found that Black-headed gull may be the main reservoir for Salmonella in birds, and that Salmonella infection is expressed as carriage with no obvious disease manifestations. Black-headed gull is a migratory bird and can transport strains of Salmonella with virulence traits like antibiotic resistance, from sources outside Sweden. Genetic molecular methods, PFGE and IS200, also demonstrate that Black-headed gull play a role in the transmission chain of Salmonella in Sweden.

    In a study of the Swedish Peregrine Falcon population, Salmonella amager and Campylobacter jejuni were found. There were indications, based on serotyping of Salmonella and genetical typing by PFGE of Campylobacter that these isolates were transmitsted to the falcons from a human or domestic animal source. This bird of prey has sparse contact with humans but may be infected by Salmonella of human origin by feeding on other birds, like gull.

    Salmonella was found in penguins, albatrosses and mainly in seals in a study in Antarctica. Several features of the Salmonella serotypes found indicate a human source for Salmonella infection in these animals, and also a spread of Salmonella within and between animal species in Antarctica.

  • 223.
    Palmgren, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Meningococcal disease and climate2009In: Global Health Action, ISSN 1654-9716, E-ISSN 1654-9880, Vol. 2Article in journal (Refereed)
  • 224.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Aspán, A.
    Department of Bacteriology, National Veterinary Institute, SE-750 07 Uppsala, Sweden.
    Bengtsson, K.
    Broman, Tina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Blomquist, L.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Wollin, R.
    Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Salmonella carriage in European Black headed gulls (Larus ridibundus) in SwedenManuscript (preprint) (Other academic)
  • 225.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Broman, Tina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Waldenström, Jonas
    Research Institute for Zoonotic Ecology and Epidemiology, Färjestaden, Sweden and Department of Animal Ecology, Ecology Building, Lund University, Lund, Sweden .
    Lindberg, Peter
    Department of Zoology, University of Göteborg, Göteborg, Sweden .
    Aspán, Anna
    Department of Bacteriology, National Veterinary Institute, Uppsala, Sweden .
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Research Institute for Zoonotic Ecology and Epidemiology, Färjestaden, Sweden.
    Salmonella Amager, Campylobacter jejuni, and urease-positive thermophilic Campylobacter found in free-flying peregrine falcons (Falco peregrinus) in Sweden2004In: Journal of Wildlife Diseases, ISSN 0090-3558, E-ISSN 1943-3700, Vol. 40, no 3, p. 583-587Article in journal (Refereed)
    Abstract [en]

    Rare species with small population sizes are vulnerable to perturbations such as disease, inbreeding, or random events. The threat arising from microbial pathogens could be large and other species could act as reservoirs for pathogens. We report finding three enteric bacterial species, Salmonella Amager, Campylobacter jejuni, and urease-positive thermophilic Campylobacter, in nestling free-flying peregrine falcons (Falco peregrinus) in Sweden in 2000. Campylobacter jejuni isolates exhibited marked genetic similarities to an isolate from a human, providing a possible association between a human-associated strain of this bacterium and peregrine falcons.

  • 226.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    McCafferty, D.
    British Antarctic SurŠey, National EnŠironment Research Council, Cambridge, UK.
    Aspán, A.
    Department of Bacteriology, National Veterinary Institute, Uppsala, Sweden.
    Broman, Tina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Wollin, R.
    Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Department of Infectious Diseases, Kalmar County Hospital, S-381 95 Kalmar, Sweden.
    Salmonella in sub-Antarctica: low heterogeneity in salmonella serotypes in South Georgian seals and birds2000In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 125, no 2, p. 257-262Article in journal (Refereed)
    Abstract [en]

    The number of human visitors to Antarctica is increasing rapidly, and with it a risk of introducing infectious organisms to native animals. To study the occurrence of salmonella serotypes in sub- Antarctic wildlife, faecal samples were collected from gentoo penguins, macaroni penguins, gray-headed albatrosses, black-browed albatrosses and Antarctic fur seals on Bird Island in the South Georgian archipelago during the austral summer of 1996 and 1998. In 1996, S. havana, S. typhimurium and S. enteritidis were isolated from 7% of gentoo penguins and 4% of fur seals. In 1998, however, 22% of fur seals were found to be infected with S. havana, S. enteritidis and S. newport. All isolates, except one, showed identical pulsed-field gel electrophoresis-patterns within each serotype, irrespective of sampling year and animal reservoir. No significant antibiotic resistance was found. The very low heterogeneity in the salmonella isolates found could either indicate a high genetic adaptation of the bacteria to the environment or a recent introduction of salmonella into the area.

  • 227.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Enteropathogenic Bacteria in Migrating Birds Arriving in Sweden1997In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 29, no 6, p. 565-568Article in journal (Refereed)
    Abstract [en]

    Birds have been thought to play a role in transmitting infectious agents like influenza, Borrelia and Salmonella. To investigate the role of migrating birds in the dispersal of enteropathogenic bacteria, stool samples from 151 wild birds (50 gulls and 101 passerines) just entering Sweden from their winter grounds were analysed for Salmonella spp., Campylobacter spp. and EHEC O157:H7. The thermophilic isolated enteropathogens found were further analysed by antibiograms. Among the 50 gulls examined, we found 2 isolates of Salmonella typhimurium with multiple antibiotic resistance. Three isolates of C. jejuni were found in the 101 stool samples from passerines. We did not isolate EHEC O157:H7 in any of the bird stools examined.

  • 228.
    Palmquist, Eva
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Claeson, Anna-Sara
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Neely, Gregory
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Stenberg, Berndt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Overlap in prevalence between various types of environmental intolerance2014In: International journal of hygiene and environmental health (Print), ISSN 1438-4639, E-ISSN 1618-131X, Vol. 217, no 4-5, p. 427-434Article in journal (Refereed)
    Abstract [en]

    Environmental intolerance (EI) is characterized by attribution of several, multisystem symptoms to specific environmental exposures, such as exposure to odorous/pungent chemicals, certain buildings, electromagnetic fields (EMFs) and everyday sounds. The symptoms are medically unexplained, non-specific and the symptoms overlap between different types of EI. To approach the issue of underlying mechanisms the matter of overlap in prevalence between intolerances can provide valuable information. The aim of the study was to examine if the overlap between intolerance to odorous/pungent chemicals, certain buildings, EMFs and sounds is larger than the expected overlap if no association would exist between them. The study was using cross-sectional data from the Västerbotten Environmental Health Study in Sweden; a large questionnaire-based survey. 8520 adults (18-79 years) were randomly selected after stratification for age and sex, of whom 3406 (40%) participated. Individuals with the four types of intolerance were identified either through self-report, or by having been physician-diagnosed with a specific EI. The overlaps between the four EIs were greater than predictions based on coincidence for both self-reported and diagnosed cases (except for the overlap between diagnosed intolerance to sounds and EMFs). The results raise the question whether different types of EI share similar underlying mechanisms, or at least that the sufferers of EI share some predisposition to acquire the conditions.

  • 229. Parkinson, Alan
    et al.
    Koch, Anders
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Infectious disease in the Arctic: a panorama in transition2015In: The new Arctic / [ed] Birgitta Evengård, Joan Nymand Larsen, Øyvind Paasche, Cham: Springer, 2015, p. 239-257Chapter in book (Refereed)
    Abstract [en]

    Many interconnected factors are responsible for the continuing and growing importance of infectious diseases in the Arctic. Many of these factors not only contribute to the risk of infectious diseases but also are broad determinants of the populations overall health. In the last part of the nineteenth and first part of the twentieth centuries, infectious diseases were major causes of mortality in Arctic communities. However the health of indigenous peoples of the circumpolar region has improved over the last 50 years. Despite these improvements, rates of viral hepatitis, tuberculosis, respiratory tract infections, invasive bacterial infections, sexually transmitted diseases, infections caused by Helicobacter pylori, and certain zoonotic and parasitic infections are higher in the Arctic indigenous peoples when compared to their respective national population rates. More recently the climate and ecosystem driven emergence of climate sensitive infectious diseases and disease patterns in the Arctic region presents an emerging challenge to those living in the Arctic. As in other parts of the world, a key component of prevention and control of infectious diseases is surveillance. The use of circumpolar health networks, together with effective coordinated surveillance can facilitate timely control of infectious disease outbreaks, inform public health officials’ decisions on resource allocation, provide data to adjust prevention and control strategies to maximize their effects, and inform future research needs.

  • 230. Pecl, Gretta T.
    et al.
    Araujo, Miguel B.
    Bell, Johann D.
    Blanchard, Julia
    Bonebrake, Timothy C.
    Chen, I-Ching
    Clark, Timothy D.
    Colwell, Robert K.
    Danielsen, Finn
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Falconi, Lorena
    Ferrier, Simon
    Frusher, Stewart
    Garcia, Raquel A.
    Griffis, Roger B.
    Hobday, Alistair J.
    Janion-Scheepers, Charlene
    Jarzyna, Marta A.
    Jennings, Sarah
    Lenoir, Jonathan
    Linnetved, Hlif I.
    Martin, Victoria Y.
    McCormack, Phillipa C.
    McDonald, Jan
    Mitchell, Nicola J.
    Mustonen, Tero
    Pandolfi, John M.
    Pettorelli, Nathalie
    Popova, Ekaterina
    Robinson, Sharon A.
    Scheffers, Brett R.
    Shaw, Justine D.
    Sorte, Cascade J. B.
    Strugnell, Jan M.
    Sunday, Jennifer M.
    Tuanmu, Mao-Ning
    Verges, Adriana
    Villanueva, Cecilia
    Wernberg, Thomas
    Wapstra, Erik
    Williams, Stephen E.
    Biodiversity redistribution under climate change: Impacts on ecosystems and human well-being2017In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 355, no 6332, article id eaai9214Article, review/survey (Refereed)
    Abstract [en]

    Distributions of Earth's species are changing at accelerating rates, increasingly driven by human-mediated climate change. Such changes are already altering the composition of ecological communities, but beyond conservation of natural systems, how and why does this matter? We review evidence that climate-driven species redistribution at regional to global scales affects ecosystem functioning, human well-being, and the dynamics of climate change itself. Production of natural resources required for food security, patterns of disease transmission, and processes of carbon sequestration are all altered by changes in species distribution. Consideration of these effects of biodiversity redistribution is critical yet lacking in most mitigation and adaptation strategies, including the United Nation's Sustainable Development Goals.

  • 231.
    Pettersson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hantavirus-specific IgA in saliva and viral antigen in the parotid gland in patients with hemorrhagic fever with renal syndrome2011In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 83, no 5, p. 864-870Article in journal (Refereed)
    Abstract [en]

    The Hantavirus genus comprises rodent borne, zoonotic viruses of the Bunyaviridae family that cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Rodent saliva contains infectious hantavirus and evidence suggests that hantavirus is also shed in human saliva, but person-to-person transmission is rare. In saliva, immunoglobulin (Ig) A is the predominant immunoglobulin class. Secretory IgA serves as an important first line of defence on epithelial surfaces and the binding of secretory IgA to pathogens can inhibit adherence of microorganisms to mucosal cells and neutralize viruses. This study investigated the presence and importance of salivary IgA in relation to viral antigen in the saliva by testing Puumala hantavirus (PUUV) specific IgA, and RNA in saliva in acutely ill patients with HFRS. In saliva samples, PUUV specific IgA was detected in 12 of 33 (36%) patients with HFRS and 20 (61%) were PUUV RNA positive. There was a statistically significant inverse association between the presence of salivary IgA antibodies and PUUV RNA in the saliva. PUUV-specific IgA in saliva was not found in a long-term follow-up, while PUUV IgA in serum was detected in three patients, 28-32 months after the initial study. Notably, both PUUV RNA and PUUV nucleocapsid antigen were detected in endothelial cells within the parotid gland of a deceased patient with HFRS. J. Med. Virol. 83:864-870, 2011. © 2011 Wiley-Liss, Inc.

  • 232.
    Pettersson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Klingström, Jonas
    Department of medicine, Center for Infectious Medicine, Karolinska institutet, Stockholm.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment2014In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 3, p. 235-241Article in journal (Refereed)
    Abstract [en]

    Hantaviruses are the causative agents of haemorrhagic fever with renal syndrome (HFRS) in Eurasia and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The case fatality rate varies between different hantaviruses and can be up to 40%. At present, there is no specific treatment available. The hantavirus pathogenesis is not well understood, but most likely, both virus-mediated and host-mediated mechanisms are involved. The aim of the present study was to investigate the association among Puumala hantavirus (PUUV) viral RNA load, humoral immune response and disease severity in patients with HFRS. We performed a study of 105 PUUV-infected patients that were followed during the acute phase of disease and for up to 1-3 months later. Fifteen of the 105 patients (14%) were classified as having moderate/severe disease. A low PUUV-specific IgG response (p <0.05) and also a higher white blood cell count (p <0.001) were significantly associated with more severe disease. The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset; however, PUUV RNA load or longevity of viraemia were not significantly associated with disease severity. We conclude that a low specific IgG response was associated with disease severity in patients with HFRS, whereas PUUV RNA load did not seem to affect the severity of HFRS. Our results raise the possibility of passive immunotherapy as a useful treatment for hantavirus-infected patients.

  • 233. Pilo, Paola
    et al.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Frey, Joachim
    Identification of Francisella tularensis cluster in Central and Western Europe2009In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 15, no 12, p. 2049-2051Article in journal (Refereed)
    Abstract [en]

    We conducted a molecular analysis of Francisella Marensis strains isolated in Switzerland and identified a specific subpopulation belonging to a cluster of F tularensis subsp. holarctica that is widely dispersed in central and western continental Europe. This subpopulation was present before the tularemia epidemics on the Iberian Peninsula.

  • 234. Pons, Benoît J
    et al.
    Bezine, Elisabeth
    Hanique, Mélissa
    Guillet, Valérie
    Mourey, Lionel
    Chicher, Johana
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
    Vignard, Julien
    Mirey, Gladys
    Cell transfection of purified cytolethal distending toxin B subunits allows comparing their nuclease activity while plasmid degradation assay does not2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 3, article id e0214313Article in journal (Refereed)
    Abstract [en]

    The Cytolethal Distending Toxin (CDT) is produced by many pathogenic bacteria. CDT is known to induce genomic DNA damage to host eukaryotic cells through its catalytic subunit, CdtB. CdtB is structurally homologous to DNase I and has a nuclease activity, dependent on several key residues. Yet some differences between various CdtB subunit activities, and discrepancies between biochemical and cellular data, have been observed. To better characterise the role of CdtB in the induction of DNA damage, we affinity-purified wild-type and mutants of CdtB, issued from E. coli and H. ducreyi, under native and denaturing conditions. We then compared their nuclease activity by a classic in vitro assay using plasmid DNA, and two different eukaryotic assays-the first assay where host cells were transfected with a plasmid encoding CdtB, the second assay where host cells were directly transfected with purified CdtB. We show here that in vitro nuclease activities are difficult to quantify, whereas CdtB activities in host cells can be easily interpreted and confirmed the loss of function of the catalytic mutant. Our results highlight the importance of performing multiple assays while studying the effects of bacterial genotoxins, and indicate that the classic in vitro assay should be complemented with cellular assays.

  • 235. Povey, Michael
    et al.
    Henry, Ouzama
    Bergsaker, Marianne A. Riise
    Chlibek, Roman
    Esposito, Susanna
    Flodmark, Carl-Erik
    Gothefors, Leif
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. The Public Health Agency of Sweden.
    Man, Sorin
    Silfverdal, Sven-Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Štéfkovičová, Mária
    Usonis, Vytautas
    Wysocki, Jacek
    Gillard, Paul
    Prymula, Roman
    Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: 10-year follow-up of a phase 3 multicentre, observer-blind, randomised, controlled trial2019In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 19, no 3, p. 287-297Article in journal (Refereed)
    Abstract [en]

    Background: The duration of protection provided by varicella vaccines is unclear. We assessed the 10-year vaccine efficacy of two doses of a combined measles-mumps-rubella-varicella vaccine (MMRV), one live attenuated varicella vaccine (V) dose given after one measles-mumps-rubella vaccine (MMR) dose (MMR + V), versus two MMR doses (control vaccine) for the prevention of confirmed varicella.

    Methods: This was a phase 3b follow-up of an observer-blinded, randomised, controlled trial. In phase a, children aged 12-22 months (at first vaccination) from Czech Republic (Czechia), Greece, Italy, Lithuania, Norway, Poland, Romania, Russia, Slovakia, and Sweden were randomly assigned by computer-generated randomisation list (3: 3: 1) to receive two doses of MMRV, one dose of MMR and one dose of varicella vaccine, or two doses of MMR, 42 days apart. Varicella cases were confirmed by detection of viral DNA, or epidemiological link and clinical assessment, by an independent data monitoring committee; disease severity was based on a modified Vazquez scale. Hazard ratios for MMRV and MMR + V versus MMR estimated in the per-protocol cohort using a Cox proportional hazards regression model were used to calculate vaccine efficacy and 95% CI. Serious adverse events were recorded throughout the study in all vaccinated children. Study objectives were secondary and descriptive. The trial is registered at ClinicalTrials.gov, number NCT00226499.

    Findings: Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14.2 months, SD 2.5) were vaccinated. The per-protocol cohort included 2279 children from the MMRV group, 2266 from the MMR + V group, and 744 from the MMR group. From baseline to a median follow-up of 9.8 years, 76 (3%) children in the MMRV group, 469 (21%) in the MMR + V group, and 352 (47%) in the MMR group had varicella. Vaccine efficacy against all varicella was 95.4% (95% CI 94.0-96.4) for MMRV and 67.2% (62.3-71.5) for MMR + V; vaccine efficacy against moderate or severe varicella was 99.1% (97.9-99.6) for MMRV and 89.5% (86.1-92.1) for MMR + V. During phase b, serious adverse events were reported by 290 (15%) of 1961 children in the MMRV group, 317 (16%) of 1978 in the MMR + V group, and 93 (15%) of 641 in the MMR group. There were no treatment-related deaths.

    Interpretation: The 10-years vaccine efficacy observed, suggests that a two-dose schedule of varicella vaccine provided optimum long-term protection for the prevention of varicella by offering individual protection against all severities of disease and leading to a potential reduction in transmission, as observed in the US experience with universal mass vaccination.

  • 236. Prymula, Roman
    et al.
    Szenborn, Leszek
    Silfverdal, Sven-Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wysocki, Jacek
    Albrecht, Piotr
    Traskine, Magali
    Gardev, Asparuh
    Song, Yue
    Borys, Dorota
    Safety, reactogenicity and immunogenicity of two investigational pneumococcal protein-based vaccines: results from a randomized phase II study in infants2017In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 35, no 35B, p. 4603-4611Article in journal (Refereed)
    Abstract [en]

    Introduction: Vaccination with formulations containing pneumococcal protein antigens such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) may extend serotype-related protection of pneumococcal conjugate vaccines (PCVs) against Streptococcus pneumoniae.

    Methods: This phase II, multi-center, observer-blind trial conducted in Europe (NCT01204658) assessed 2 investigational vaccines containing 10 serotype-specific polysaccharide conjugates of PHiD-CV and either 10 or 30 mu g of dPly and PhtD each. Infants randomized 1:1:1:1 received 4 doses of PHiD-CV/dPly/PhtD-10, PHiD-CV/c1Ply/PhtD-30, PHiD-CV, or 13-valent PCV (PCV13), co-administered with DTPa-HBV-IPV/Flib, at ages 2, 3, 4 and 12-15 months. Occurrences of fever >40.0 degrees C following primary vaccination with PHiD-CV/dPly/PhtD vaccines compared to PHiD-CV (non-inferiority objective), dose superiority, safety and immunogenicity were assessed.

    Results: 575 children received primary vaccination, and 564 booster vaccination. The non-inferiority objective was met; no fever >40.0 degrees C causally related to vaccination was reported during primary vaccination. Incidence of adverse events appeared similar between the 3 PHiD-CV groups. Serious adverse events were reported in 13, 9, 21 (1 related to vaccination), and 17 children in the PHiD-CV/c1Ply/PhtD-10, PHiD-CV/dPly/PhtD-30, PHiD-CV, and PCV13 groups, respectively. PHiD-CV/dPly/PhtD-30 was superior to PHiD-CV/c1Ply/PhtD-10 in terms of post-dose 3 anti-Ply and Anti-PhtD antibody levels. Anti-Ply and anti-PhtD antibody levels were higher in both PHiD-CV/dPly/PhtD groups than in controls and increased from post-primary to post-booster timepoint. Post-primary and booster vaccination, for each PHiD-CV serotype, >= 98.5% of participants in PHiD-CV/dPly/PhtD groups had antibody concentrations >= 0.2 mu g/mL, except for 6B (>= 72.3%) and 23 F (>= 82.7%) post-primary vaccination. Similar results were observed in the PHiD-CV group. Immune responses to protein D and DTPa-HBV-IPV/Hib were within similar ranges for the 3 PHiD-CV groups.

    Conclusion: Both PHiD-CV/dPly/PhtD formulations co-administered with DTPa-HBV-IPV/Hib in infants were well-tolerated and immunogenic for dPly and PhtD antigens, while immune responses to serotype-specific, protein D and co-administered antigens did not appear altered in comparison to PHiD-CV group. 

  • 237.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cardiopulmonary involvement in Puumala hantavirus infection2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in Europe. After inhalation of virus shed by bank voles, the virus systemically targets the vascular endothelium leading to vascular dysfunction and leakage. Many patients with PUUV infection experience cardiopulmonary manifestations but the underlying mechanisms have not been determined.

    The aims of the studies presented were to describe cardiopulmonary manifestations, investigate pathogenetic mechanisms including presence of virus in the lungs and the local immune response in PUUV infection.

    The results showed cardiopulmonary involvement of varying severity in almost all studied patients. High-resolution computed tomography frequently revealed vascular leakage into the lungs or pleural cavities. Pulmonary function tests generally showed reduced gas diffusing capacity, evidenced in patients as dyspnea, poor oxygenation and frequent need of oxygen treatment. Among patients who were not fully recovered at 3 months follow-up, remaining decreased gas diffusing capacity was highly common.

    Echocardiography revealed mainly right heart dysfunction which was related to manifestations within the lungs, in terms of increased estimated pulmonary vascular resistance, mild to moderate pulmonary hypertension, and reduced right ventricular systolic function in patients with more pronounced lung involvement, as indicated by need of oxygen treatment.

    Analyses on bronchoalveolar lavage (BAL) and bronchial biopsies revealed a highly activated cytotoxic T cell (CTL) response in the lungs. The CTL response was not balanced by the expansion of regulatory T cells and high numbers of CTLs were associated with more severe disease. PUUV RNA was detected in almost all patients’ BAL samples and the viral load was inversely correlated to the number of CTLs.

    Three patients presenting with severe and fatal cardiopulmonary distress were also described. Autopsies revealed PUUV protein in vascular endothelium in all investigated organs, including the heart and lungs, along with a massive CTL response mainly in the lungs.

    In conclusion, cardiopulmonary involvement of varying severity was present in almost all patients with PUUV infection. Cytotoxic immune responses could contribute to disease development but also help in clearing the infection. Long lasting fatigue after hantavirus infection may be explained by remaining manifestations within the lungs. 

  • 238.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrman, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Haney, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus2011In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 30, no 5, p. 685-690Article in journal (Refereed)
    Abstract [en]

    Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.

  • 239.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Sörensen, Karen
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hedström, Magnus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cardiopulmonary involvement in Puumala hantavirus infection2013In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 13, no 1, p. 501-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hantavirus infections cause potentially life-threatening disease in humans world-wide. Infections with American hantaviruses may lead to hantavirus pulmonary syndrome characterised by severe cardiopulmonary distress with high mortality. Pulmonary involvement in European Puumala hantavirus (PUUV) infection has been reported, whereas knowledge of potential cardiac manifestations is limited. We aimed to comprehensively investigate cardiopulmonary involvement in patients with PUUV-infection.

    METHODS: Twenty-seven hospitalised patients with PUUV-infection were examined with lung function tests, chest high-resolution CT (HRCT), echocardiography including speckle tracking strain rate analysis, ECG and measurements of cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and troponin T. Patients were re-evaluated after 3 months. Twenty-five age and sex-matched volunteers acted as controls for echocardiography data.

    RESULTS: Two-thirds of the patients experienced respiratory symptoms as dry cough or dyspnoea. Gas diffusing capacity was impaired in most patients, significantly improving at follow-up but still subnormal in 38%. HRCT showed thoracic effusions or pulmonary oedema in 46% of the patients. Compared to controls, the main echocardiographic findings in patients during the acute phase were significantly higher pulmonary vascular resistance, higher systolic pulmonary artery pressure, lower left ventricular ejection fraction and impaired left atrial myocardial motion. Pathological ECG, atrial fibrillation or T-wave changes, was demonstrated in 26% of patients. NT-ProBNP concentrations were markedly increased and were inversely associated with gas diffusing capacity but positively correlated to pulmonary vascular resistance. Furthermore, patients experiencing impaired general condition at follow-up had significantly lower gas diffusing capacity and higher pulmonary vascular resistance, compared to those feeling fully recovered.

    CONCLUSIONS: In a majority of patients with PUUV-infection, both cardiac and pulmonary involvement was demonstrated with implications on patients' recovery. The results demonstrate vascular leakage in the lungs that most likely is responsible for impaired gas diffusing capacity and increased pulmonary vascular resistance with secondary pulmonary hypertension and right heart distress. Interestingly, NT-ProBNP was markedly elevated even in the absence of overt ventricular heart failure. The method of simultaneous investigations of important cardiac and respiratory measurements improves the interpretation of the underlying pathophysiologic mechanisms.

  • 240.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Linderholm, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Presence of activated airway T lymphocytes in human puumala hantavirus disease2011In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 140, no 3, p. 715-722Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hantaviruses cause two clinical syndromes; hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The clinical spectrum in HFRS also often involves respiratory symptoms. As information of the pulmonary pathogenesis in HFRS is limited, we aimed to further study the local airway immune response in the lower airways.

    METHODS: In 15 hospitalized HFRS patients, bronchoscopy was performed with sampling of endobronchial mucosal biopsies and bronchoalveolar lavage (BAL) fluid. Biopsies were stained for leukocytes, lymphocyte subsets and vascular endothelial adhesion molecules. BAL fluid and blood lymphocyte subsets were determined using flow cytometry. Fourteen healthy volunteers acted as control group.

    RESULTS: Compared to controls, endobronchial mucosal biopsies from HFRS patients revealed increased numbers of CD8(+) T cells in both epithelium and submucosa (p≤0.001), along with an increase in submucosal CD4(+) T cells (p=0.001). In contrast, patients' submucosal neutrophil and eosinophil numbers were reduced (p<0.001). The expression of vascular cell adhesion molecule-1 (VCAM-1) was enhanced in HFRS patients (p<0.001). In HFRS patients, analyses of T cell subsets in BAL fluid showed higher proportions of CD3(+) and CD8(+) T cells (p=0.011 and p=0.025), NK cells (p<0.001) together with an increased expression of activation markers HLA-DR and CD25 on T cells (p<0.001 and p<0.001).

    CONCLUSIONS: The present findings indicate a local immune response in terms of activated T lymphocytes in the lungs of patients with HFRS. The elevated expression of activation markers and VCAM-1 further implies the importance of cytotoxic lymphocytes in the pathogenesis of pulmonary involvement in HFRS.

  • 241.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection2016In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 35, no 4, p. 713-721Article in journal (Refereed)
    Abstract [en]

    Hantavirus infections may cause severe and sometime life-threatening lung failure. The pathogenesis is not fully known and there is an urgent need for effective treatment. We aimed to investigate the association between pulmonary viral load and immune responses, and their relation to disease severity. Bronchoscopy with sampling of bronchoalveolar lavage (BAL) fluid was performed in 17 patients with acute Puumala hantavirus infection and 16 healthy volunteers acting as controls. Lymphocyte subsets, granzyme concentrations, and viral load were determined by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Analyses of BAL fluid revealed significantly higher numbers of activated CD8+ T cells and natural killer (NK) cells, as well as higher concentrations of the cytotoxins granzymes A and B in hantavirus-infected patients, compared to controls. In patients, Puumala hantavirus RNA was detected in 88 % of BAL cell samples and correlated inversely to the T cell response. The magnitude of the pulmonary cytotoxic lymphocyte response correlated to the severity of disease and systemic organ dysfunction, in terms of need for supplemental oxygen treatment, hypotension, and laboratory data indicating renal failure, cardiac dysfunction, vascular leakage, and cell damage. Regulatory T cell numbers were significantly lower in patients compared to controls, and may reflect inadequate immune regulation during hantavirus infection. Hantavirus infection elicits a pronounced cytotoxic lymphocyte response in the lungs. The magnitude of the immune response was associated with disease severity. These results give insights into the pathogenesis and possibilities for new treatments.

  • 242. Rehn, Moa
    et al.
    Wallensten, Anders
    Widerström, Micael
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lilja, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Grunewald, Maria
    Stenmark, Stephan
    Kark, Malin
    Lindh, Johan
    Post-infection symptoms following two large waterborne outbreaks of Cryptosporidium hominis in Northern Sweden, 2010-20112015In: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 15, article id 529Article in journal (Refereed)
    Abstract [en]

    Background: In 2010-2011, two large waterborne outbreaks caused by Cryptosporidium hominis affected two cities in Sweden, Ostersund and Skelleftea. We investigated potential post-infection health consequences in people who had reported symptoms compatible with cryptosporidiosis during the outbreaks using questionnaires. Methods: We compared cases linked to these outbreaks with non-cases in terms of symptoms present up to eleven months after the initial infection. We examined if cases were more likely to report a list of symptoms at follow-up than non-cases, calculating odds ratios (OR) and 95 % confidence intervals (CI) obtained through logistic regression. Results: A total of 872 (310 cases) and 743 (149 cases) individuals responded to the follow-up questionnaires in Ostersund and Skelleftea respectively. Outbreak cases were more likely to report diarrhea (Ostersund OR: 3.3, CI: 2.0-5.3. Skelleftea OR: 3.6, CI: 2.0-6.6), watery diarrhea (Ostersund OR: 3.4, CI: 1.9-6.3. Skelleftea OR: 2.8, CI: 1.5-5.1) abdominal pain (Ostersund OR: 2.1, CI: 1.4-3.3, Skelleftea OR: 2.7, CI: 1.5-4.6) and joint pain (Ostersund OR: 2.0, CI: 1.2-3.3, Skelleftea OR: 2.0, CI: 1.1-3.6) at follow-up compared to non-cases. Conclusions: Our findings suggest that gastrointestinal-and joint symptoms can persist several months after the initial infection with Cryptosporidium and should be regarded as a potential cause of unexplained symptoms in people who have suffered from the infection.

  • 243. Reuterswärd, Philippa
    et al.
    Bergström, Sofia
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Svahn, Helene Andersson
    Ayoglu, Burcu
    Uhlén, Mathias
    Wahlgren, Mats
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ribacke, Ulf
    Nilsson, Peter
    Levels of human proteins in plasma associated with acute paediatric malaria2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 426Article in journal (Refereed)
    Abstract [en]

    Background: The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts.

    Results: An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values < 0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values < 10−14) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values < 0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria.

    Conclusion: In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis.

  • 244. Rha, Brian
    et al.
    Dahl, Rebecca M.
    Moyes, Jocelyn
    Binder, Alison M.
    Tempia, Stefano
    Walaza, Sibongile
    Bi, Daoling
    Groome, Michelle J.
    Variava, Ebrahim
    Naby, Fathima
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Treurnicht, Florette
    Cohen, Adam L.
    Gerber, Susan I.
    Madhi, Shabir A.
    Cohen, Cheryl
    Performance of Surveillance Case Definitions in Detecting Respiratory Syncytial Virus Infection Among Young Children Hospitalized With Severe Respiratory Illness: South Africa, 2009-20142019In: Journal of the Pediatric Infectious Diseases Society, ISSN 2048-7193, Vol. 8, no 4, p. 325-333Article in journal (Refereed)
    Abstract [en]

    Background: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection (ALRTI) in young children, but data on surveillance case definition performance in estimating burdens have been limited.

    Methods: We enrolled children aged <5 years hospitalized for ALRTI (or neonatal sepsis in young infants) through active prospective surveillance at 5 sentinel hospitals in South Africa and collected nasopharyngeal aspirates from them for RSV molecular diagnostic testing between 2009 and 2014. Clinical data were used to characterize RSV disease and retrospectively evaluate the performance of respiratory illness case definitions (including the World Health Organization definition for severe acute respiratory infection [SARI]) in identifying hospitalized children with laboratory-confirmed RSV according to age group (<3, 3-5, 6-11, 12-23, and 24-59 months).

    Results: Of 9969 hospitalized children, 2723 (27%) tested positive for RSV. Signs and symptoms in RSV-positive children varied according to age; fever was less likely to occur in children aged <3 months (57%; odds ratio [OR], 0.8 [95% CI, 0.7-0.9]) but more likely in those aged >= 12 months (82%; OR, 1.7-1.9) than RSV-negative children. The sensitivity (range, 55%-81%) and specificity (range, 27%-54%) of the SARI case definition to identify hospitalized RSV-positive children varied according to age; the lowest sensitivity was for infants aged <6 months. Using SARI as the case definition would have missed 36% of RSV-positive children aged <5 years and 49% of those aged <3 months; removing the fever requirement from the definition recovered most missed cases.

    Conclusion: Including fever in the SARI case definition lowers the sensitivity for RSV case detection among young children hospitalized with an ALRTI and likely underestimates its burden.

  • 245.
    Rocklöv, Joacim
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Tozan, Yesim
    Ramadona, Aditya Lia
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Sewe, Maquins Odhiambo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Sudre, Bertrand
    Garrido, Jon
    de Saint Lary, Chiara Bellegarde
    Lohr, Wolfgang
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Semenza, Jan C.
    Using Big Data to Monitor the Introduction and Spread of Chikungunya, Europe, 20172019In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 25, no 6, p. 1041-1049Article in journal (Refereed)
    Abstract [en]

    With regard to fully harvesting the potential of big data, public health lags behind other fields. To determine this potential, we applied big data (air passenger volume from international areas with active chikungunya transmission, Twitter data, and vectorial capacity estimates of Aedes albopictus mosquitoes) to the 2017 chikungunya outbreaks in Europe to assess the risks for virus transmission, virus importation, and short-range dispersion from the outbreak foci. We found that indicators based on voluminous and velocious data can help identify virus dispersion from outbreak foci and that vector abundance and vectorial capacity estimates can provide information on local climate suitability for mosquitoborne outbreaks. In contrast, more established indicators based on Wikipedia and Google Trends search strings were less timely. We found that a combination of novel and disparate datasets can be used in real time to prevent and control emerging and reemerging infectious diseases.

  • 246. Rohmer, Laurence
    et al.
    Fong, Christine
    Abmayr, Simone
    Wasnick, Michael
    Larson Freeman, Theodore J
    Radey, Matthew
    Guina, Tina
    Svensson, Kerstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hayden, Hillary S
    Jacobs, Michael
    Gallagher, Larry A
    Manoil, Colin
    Ernst, Robert K
    Drees, Becky
    Buckley, Danielle
    Haugen, Eric
    Bovee, Donald
    Zhou, Yang
    Chang, Jean
    Levy, Ruth
    Lim, Regina
    Gillett, Will
    Guenthener, Don
    Kang, Allison
    Shaffer, Scott A
    Taylor, Greg
    Chen, Jinzhi
    Gallis, Byron
    D'Argenio, David A
    Forsman, Mats
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olson, Maynard V
    Goodlett, David R
    Kaul, Rajinder
    Miller, Samuel I
    Brittnacher, Mitchell J
    Comparison of Francisella tularensis genomes reveals evolutionary events associated with the emergence of human pathogenic strains2007In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 8, no 6, article id R102Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Francisella tularensis subspecies tularensis and holarctica are pathogenic to humans, whereas the two other subspecies, novicida and mediasiatica, rarely cause disease. To uncover the factors that allow subspecies tularensis and holarctica to be pathogenic to humans, we compared their genome sequences with the genome sequence of Francisella tularensis subspecies novicida U112, which is nonpathogenic to humans. RESULTS: Comparison of the genomes of human pathogenic Francisella strains with the genome of U112 identifies genes specific to the human pathogenic strains and reveals pseudogenes that previously were unidentified. In addition, this analysis provides a coarse chronology of the evolutionary events that took place during the emergence of the human pathogenic strains. Genomic rearrangements at the level of insertion sequences (IS elements), point mutations, and small indels took place in the human pathogenic strains during and after differentiation from the nonpathogenic strain, resulting in gene inactivation. CONCLUSION: The chronology of events suggests a substantial role for genetic drift in the formation of pseudogenes in Francisella genomes. Mutations that occurred early in the evolution, however, might have been fixed in the population either because of evolutionary bottlenecks or because they were pathoadaptive (beneficial in the context of infection). Because the structure of Francisella genomes is similar to that of the genomes of other emerging or highly pathogenic bacteria, this evolutionary scenario may be shared by pathogens from other species.

  • 247. Roos, K.
    et al.
    Simark-Mattsson, C.
    Grahn Håkansson, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Larsson, L.
    Sandberg, T.
    Ahren, C.
    Can probiotic lactobacilli eradicate persistent carriage of meticillin-resistant Staphylococcus aureus?2011In: Journal of Hospital Infection, ISSN 0195-6701, E-ISSN 1532-2939, Vol. 78, no 1, p. 77-78Article in journal (Refereed)
  • 248. Rosjo, Egil
    et al.
    Lossius, Andreas
    Abdelmagid, Nada
    Lindstrom, Jonas C.
    Kampman, Margitta T.
    Jorgensen, Lone
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olsson, Tomas
    Steffensen, Linn H.
    Torkildsen, Oivind
    Holmoy, Trygve
    Effect of high-dose vitamin D-3 supplementation on antibody responses against Epstein-Barr virus in relapsing-remitting multiple sclerosis2017In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 3, p. 395-402Article in journal (Refereed)
    Abstract [en]

    Background: Elevated antibody levels against Epstein–Barr virus (EBV) and a poor vitamin D status are environmental factors that may interact in relapsing-remitting multiple sclerosis (RRMS) aetiology.

    Objectives: To examine effects of high-dose oral vitamin D3 supplementation on antibody levels against EBV nuclear antigen 1 (EBNA1) in RRMS.

    Methods: Serum 25-hydroxyvitamin D3 (25(OH)D) and immunoglobulin G antibody levels against EBNA1 (whole protein and amino acid 385–420 fragment), EBV viral capsid antigen (VCA), cytomegalovirus (CMV) and varicella zoster virus (VZV) were measured in 68 RRMS patients enrolled in a 96-week randomised double-blinded placebo-controlled clinical trial of oral vitamin D3 supplementation (20,000 IU/week) (NCT00785473).

    Results: The mean 25(OH)D level more than doubled in the vitamin D group and was significantly higher than in the placebo group at study conclusion (123.2 versus 61.8 nmol/L, p < 0.001). Compared to the placebo group, both anti-EBNA1 protein and fragment antibody levels decreased in the vitamin D group from baseline to week 48 (p = 0.038 and p = 0.004, respectively), but not from baseline to week 96. Vitamin D3 supplementation did not affect antibodies against VCA, CMV or VZV.

    Conclusion: The results indicate that high-dose oral vitamin D3 supplementation can affect humoral immune responses against the latent EBV antigen EBNA1 in RRMS.

  • 249. Ruzek, Daniel
    et al.
    Zupanc, Tatjana Avsic
    Borde, Johannes
    Chrdle, Ales
    Eyer, Ludek
    Karganova, Galina
    Kholodilov, Ivan
    Knap, Natasa
    Kozlovskaya, Liubov
    Matveev, Andrey
    Miller, Andrew D.
    Osolodkin, Dmitry I.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Tikunova, Nina
    Tkachev, Sergey
    Zajkowska, Joanna
    Tick-borne encephalitis in Europe and Russia: review of pathogenesis, clinical features, therapy, and vaccines2019In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 164, p. 23-51Article, review/survey (Refereed)
    Abstract [en]

    Tick-borne encephalitis (TBE) is an illness caused by tick-borne encephalitis virus (TBEV) infection which is often limited to a febrile illness, but may lead to very aggressive downstream neurological manifestations. The disease is prevalent in forested areas of Europe and northeastern Asia, and is typically caused by infection involving one of three TBEV subtypes, namely the European (TBEV-Eu), the Siberian (TBEV-Sib), or the Far Eastern (TBEV-FE) subtypes. In addition to the three main TBEV subtypes, two other subtypes; i.e., the Baikalian (TBEV-Bkl) and the Himalayan subtype (TBEV-Him), have been described recently. In Europe, TBEV-Eu infection usually results in only mild TBE associated with a mortality rate of < 2%. TBEV-Sib infection also results in a generally mild TBE associated with a non-paralytic febrile form of encephalitis, although there is a tendency towards persistent TBE caused by chronic viral infection. TBE-FE infection is considered to induce the most severe forms of TBE. Importantly though, viral subtype is not the sole determinant of TBE severity; both mild and severe cases of TBE are in fact associated with infection by any of the subtypes. In keeping with this observation, the overall TBE mortality rate in Russia is similar to 2%, in spite of the fact that TBEV-Sib and TBEV-FE subtypes appear to be inducers of more severe TBE than TBEV-Eu. On the other hand, TBEV-Sib and TBEV-FE subtype infections in Russia are associated with essentially unique forms of TBE rarely seen elsewhere if at all, such as the hemorrhagic and chronic (progressive) forms of the disease. For post-exposure prophylaxis and TBE treatment in Russia and Kazakhstan, a specific anti-TBEV immunoglobulin is currently used with well-documented efficacy, but the use of specific TBEV immunoglobulins has been discontinued in Europe due to concerns regarding antibody-enhanced disease in naive individuals. Therefore, new treatments are essential. This review summarizes available data on the pathogenesis and clinical features of TBE, plus different vaccine preparations available in Europe and Russia. In addition, new treatment possibilities, including small molecule drugs and experimental immunotherapies are reviewed. The authors caution that their descriptions of approved or experimental therapies should not be considered to be recommendations for patient care.

  • 250.
    Rydén, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Björk, Rafael
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Schäfer, Martina L
    Lundström, Jan O
    Petersén, Bodil
    Lindblom, Anders
    Forsman, Mats
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence2012In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 205, no 2, p. 297-304Article in journal (Refereed)
    Abstract [en]

    Background. We aimed to evaluate the potential association of mosquito prevalence in a boreal forest area with transmission of the bacterial disease tularemia to humans, and model the annual variation of disease using local weather data.

    Methods. A prediction model for mosquito abundance was built using weather and mosquito catch data. Then a negative binomial regression model based on the predicted mosquito abundance and local weather data was built to predict annual numbers of humans contracting tularemia in Dalarna County, Sweden.

    Results. Three hundred seventy humans were diagnosed with tularemia between 1981 and 2007, 94% of them during 7 summer outbreaks. Disease transmission was concentrated along rivers in the area. The predicted mosquito abundance was correlated (0.41, P < .05) with the annual number of human cases. The predicted mosquito peaks consistently preceded the median onset time of human tularemia (temporal correlation, 0.76; P < .05). Our final predictive model included 5 environmental variables and identified 6 of the 7 outbreaks.

    Conclusions. This work suggests that a high prevalence of mosquitoes in late summer is a prerequisite for outbreaks of tularemia in a tularemia-endemic boreal forest area of Sweden and that environmental variables can be used as risk indicators.

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