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  • 51.
    Hedlund, Sebastian
    et al.
    Division of Medical Microbiology, Department of Molecular and Clinical Medicine, Linköping University, Linköping, Sweden.
    Persson, Alexander
    Division of Medical Microbiology, Department of Molecular and Clinical Medicine, Linköping University, Linköping, Sweden.
    Vujic, Ana
    Division of Medical Microbiology, Department of Molecular and Clinical Medicine, Linköping University, Linköping, Sweden.
    Che, Karlhans Fru
    Division of Molecular Virology, Department of Molecular and Clinical Medicine, Linköping University, Linköping, Sweden.
    Stendahl, Olle
    Division of Medical Microbiology, Department of Molecular and Clinical Medicine, Linköping University, Linköping, Sweden.
    Larsson, Marie
    Division of Molecular Virology, Department of Molecular and Clinical Medicine, Linköping University, Linköpin, Sweden.
    Dendritic cell activation by sensing Mycobacterium tuberculosis-induced apoptotic neutrophils via DC-SIGN2010In: Human Immunology, ISSN 0198-8859, E-ISSN 1879-1166, Vol. 71, no 6, p. 535-40Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) manipulates cells of the innate immune system to provide the bacteria with a sustainable intracellular niche. Mtb spread through aerosol carrying them deep into the lungs, where they are internalized by phagocytic cells, such as neutrophils (PMNs), dendritic cells (DCs), and macrophages. PMNs undergo accelerated apoptosis after interaction with the bacterium, and apoptotic cells are sequestered by neighboring phagocytes. Removal of aged apoptotic cells because of natural tissue turnover is described as an immunologically silent process facilitating resolution of inflammation and inhibition of DC maturation. Silencing of immune cells could be favorable for intracellular bacteria. The aim of this study was to clarify the interaction between Mtb-induced apoptotic PMNs and DCs, and evaluate whether this interaction follows the proposed anti-inflammatory pathway. In contrast to aged apoptotic cells, Mtb-induced apoptotic PMNs induced functional DC maturation. We found that the cell fraction from Mtb-induced apoptotic PMNs contained almost all stimulatory capacity, suggesting that cell-cell interaction is crucial for DC activation. Inhibitory studies showed that this cell contact-dependent activation required binding of the PMN Mac-1 (CD11b/CD18) to the DC via DC-SIGN and endocytic activity involving the alpha(v)beta(5) but did not involve the scavenger receptor CD36. Taken together, this study demonstrates that the DCs can distinguish between normal and infected apoptotic PMNs via cellular crosstalk, where the DCs can sense the presence of danger on the Mtb-infected PMNs and modulate their response accordingly.

  • 52.
    Hesselmark, Eva
    et al.
    Center for Psychiatry Research, Department of clinical neuroscience, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bejerot, Susanne
    Örebro University, School of Medical Sciences. Center for Psychiatry Research, Department of clinical neuroscience, Karolinska Institutet, Stockholm, Sweden; School of Medical Sciences, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS): Sensitivity and specificity of the Cunningham Panel2017In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 312, p. 31-37Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Pediatric Acute Neuropsychiatric Syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are conditions marked by sudden onset of obsessive-compulsive disorder (OCD), tics, or avoidant/restrictive food intake in combination with multiple psychiatric symptoms. A diagnosis of PANS or PANDAS may be supported by the Cunningham Panel, a commercially available set of immunologic assays currently in clinical use. However, the relationship between Cunningham Panel results and patient symptoms remains unclear. This study was done to assess the diagnostic accuracy of the Cunningham Panel in patients with suspected PANS or PANDAS.

    METHOD: All Swedish patients who had taken the Cunningham Panel prior to June 2014 (n=154) were invited and 53 patients participated in the study. Based on comprehensive psychiatric assessment (the reference standard of diagnosis), subjects were classified as PANS, PANDAS, or neither. Prior Cunningham Panel test results were collected from patient records, and new blood samples were similarly analyzed within the scope of this study. In addition, results were compared to healthy controls (n=21) and a test-retest reliability analysis was performed.

    RESULTS: Sensitivities of individual biomarkers in the Cunningham Panel ranged from 15 to 60%, and specificities from 28 to 92%. Positive predictive values ranged from 17 to 40%, and negative predictive values from 44 to 74%. A majority of the healthy controls had pathological Cunningham Panel results and test-retest reliability proved insufficient.

    CONCLUSION: Clinical use of the Cunningham Panel in diagnosing PANS or PANDAS is not supported by this study.

  • 53.
    Hesselmark, Eva
    et al.
    Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bejerot, Susanne
    Örebro University, School of Medical Sciences. University Health Care Research Center, Region Örebro County, Örebro, Sweden.
    Corrigendum to Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS): Sensitivity and specificity of the Cunningham Panel [J. Neuroimmunol. 312. (2017) 31-37]2017In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 313, p. 116-117Article in journal (Refereed)
  • 54.
    Holmberg, K
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Neuropediatric unit, Sachs’ Children and Youth Hospital, South General Hospital, Stockholm, Sweden.
    Lundholm, C
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Anckarsäter, H
    Institute of Neuroscience and Physiology, Forensic Psychiatry, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, C
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Lung and allergy unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Impact of asthma medication and familial factors on the association between childhood asthma and attention-deficit/hyperactivity disorder: a combined twin- and register-based study2015In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 45, no 5, p. 964-973Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Asthma and attention-deficit/hyperactivity disorder (ADHD) are prevalent in childhood and may cause functional impairment and stress in families. Previous research supports an association between asthma and ADHD in children, but several aspects of this relationship are unclear.

    OBJECTIVE: Our aim was to study whether the association between asthma and ADHD is restricted to either the inattentive or the hyperactive/impulsive symptoms of ADHD, to explore the impact of asthma severity and asthma medication and the contribution of shared genetic and environmental risk factors on the asthma-ADHD relationship.

    METHODS: Data on asthma, ADHD, zygosity and possible confounders were collected from parental questionnaires at 9 or 12 years on 20 072 twins through the Swedish Twin Register, linked to the Swedish Medical Birth Register, the National Patient Register and the Prescribed Drug Register. The association between asthma and ADHD, the impact of asthma severity and medication, was assessed by generalized estimating equations. Cross-twin-cross-trait correlations (CTCT) were estimated to explore the relative importance of genes and environment for the association.

    RESULTS: Asthmatic children had a higher risk of also having ADHD [odds ratio (OR) 1.53, 95% confidence interval (CI): 1.16-2.02]. The association was not restricted to either of the two dimensions of ADHD. The magnitude of the association increased with asthma severity (OR 2.84, 95% CI: 1.86-4.35) for ≥ 4 asthma attacks in the last 12 months and was not affected by asthma treatment. The CTCTs possibly indicate that the genetic component in overlap of the disorders is weak.

    CONCLUSIONS AND CLINICAL RELEVANCE: Childhood asthma, especially severe asthma, is associated with ADHD. Asthma medication seems not to increase the risk of ADHD. Clinicians should be aware of the potential of ADHD in asthma. Optimal asthma care needs to be integrated with effective evaluation and treatment of ADHD in children with co-existing disorders.

  • 55.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Medicine, Örebro University, Sweden.
    The mucosal immune system in microscopic colitis2012In: Microscopic colitis / [ed] S. Miehlke, A. Münich, Basel: S. Karger, 2012, p. 33-39Conference paper (Other academic)
  • 56.
    Hylén, Ulrika
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Center.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Humble, Mats B.
    Örebro University, School of Medical Sciences. University Health Care Research Center.
    Bartoszek, Jakub
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Bejerot, Susanne
    Örebro University, School of Medical Sciences. University Health Care Research Center.
    Increased inflammasome activity in markedly ill psychiatric patients: An explorative study2020In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 339, article id 577119Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate inflammatory perturbations in 40 patients with severe and complex psychiatric disorders by studying the activity of the NLRP3 inflammasome, with a trans-diagnostic approach. Gene expression of CASP1, NLRP3, PYCARD, IL1B, IL1RN, TNF showed a significant increase in the patient group compared to a matched control group. Plasma levels of IL1Ra, IL-18, TNF, IL-6 and CRP were increased in the patient group. Within the patient group, increased gene expression of inflammatory markers correlated with increased disease severity. The findings support the inflammation hypothesis for markedly ill psychiatric patients across diagnostic groups.

  • 57.
    Isaksson, Helena S.
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Farkas, Sanja A.
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Müller, Patrick
    Affymetrix core facility at Novum, BEA, Karolinska Institute, Huddinge, Sweden.
    Gustafsson, Dan
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nilsson, Torbjörn, K.
    Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
    Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, no 2, p. 240-251Article in journal (Refereed)
    Abstract [en]

    A child, 2 years with the "hypercalprotectinemia with hyperzincemia" clinical syndrome presented with atypical symptoms and signs, notably persistent fever of around 38°C, thrombocythaemia of >700 x 10(9) /L, and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analyzed whole-genome mRNA expression by the Affymetrix HG U133 PLUS 2.0 array on three occasions 3 to 5 months apart. Major upregulation was demonstrated for the JAK/STAT pathway including in particular CD177, S100A8, S100A9, and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors, and activators, accounting for the febrile apathic state; and the HMBG1 gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic workup of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.

  • 58.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Boiko, Iryna
    Clinical Laboratory Department, Ternopil Regional Clinical Dermatovenerologic Dispensary, Ternopil, Ukraine.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Blondeel, Karel
    Department of Reproductive Health and Research, World Health Organization (WHO), Geneva, Switzerland.
    Kiarie, James
    Department of Reproductive Health and Research, World Health Organization (WHO), Geneva, Switzerland.
    Toskin, Igor
    Department of Reproductive Health and Research, World Health Organization (WHO), Geneva, Switzerland.
    Peeling, Rosanna W.
    London School of Hygiene and Tropical Medicine (LSHTM), London, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    WHO laboratory validation of Xpert((R)) CT/NG and Xpert((R)) TV on the GeneXpert system verifies high performances2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 12, p. 907-912Article in journal (Refereed)
    Abstract [en]

    Effective tests for diagnosis of sexually transmitted infections (STIs), used point of care to inform treatment and management decisions, are urgently needed. We evaluated the analytical sensitivity and specificity of the Xpert((R)) CT/NG and Xpert((R)) TV tests, examining 339 samples spiked with phenotypically and/or genetically diverse strains of Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, and other related species that may cross-react. The APTIMA Combo 2 test and APTIMA TV test were used as reference tests. The analytical sensitivity for all three agents in the Xpert((R)) CT/NG and Xpert((R)) TV tests was <= 10(2) genome equivalents/reaction. The analytical specificity of both tests was high. False-positive results were identified in the Xpert((R)) TV test when challenging with high concentrations of Trichomonas tenax, Trichomonas gallinae, Trichomonas stableri, and Trichomonas aotus. However, the clinical relevance of these cross-reactions can likely be neglected, because these species have not been identified in urogenital samples from humans. In conclusion, the analytical sensitivity and specificity of the user-friendly Xpert((R)) CT/NG and Xpert((R)) TV tests on the GeneXpert system were high. The results support the use of specimens from also extra-genital sites, for example, pharynx and rectum. However, appropriate clinical validations are additionally required.

  • 59.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Neisseria meningitidis, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Neisseria meningitidis, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Hedberg, Sara Thulin
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Neisseria meningitidis carriage in Swedish teenagers associated with the serogroup W outbreak at the World Scout Jamboree, Japan 20152018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 4, p. 337-341Article in journal (Refereed)
    Abstract [en]

    The aims of the study were to estimate the carrier state of Neisseria meningitidis in Swedish teenagers and its association with an outbreak at the World Scout Jamboree in 2015 as well as to compare sensitivity of throat versus nasopharyngeal swab for optimal detection of carriage. In total, 1 705 samples (cultures n = 32, throat swabs n = 715, nasopharyngeal swabs n = 958) from 1 020 Jamboree participants were collected and sent to the National Reference Laboratory for Neisseria meningitidis for culture and molecular analysis. The overall positivity for N. meningitidis was 8% (83/1 020), whereas 2% (n = 22) belonged to a known sero/genogroup while the majority (n = 61) were non-groupable. Throat sample is clearly the sampling method of choice, in 56 individuals where both throat and nasopharynx samples were taken, N. meningitidis was detected in both throat and nasopharynx in eight individuals, in 46 individuals N. meningitidis was only detected in the throat and in two individuals only in the nasopharynx. Carriage studies are important to provide knowledge of the current epidemiology and association between carrier isolates and disease-causing isolates in a given population. Therefore, planning for a carriage study in Sweden is in progress.

  • 60.
    Jayaprakash, Kartheyaene
    et al.
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Gunaltay, Sezin
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    PKC, ERK/p38 MAP kinases and NF-B targeted signalling play a role in the expression and release of IL-1β  and CXCL8 in Porphyromonas gingivalis-infected THP1 cells2017In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 125, no 7, p. 623-633Article in journal (Refereed)
    Abstract [en]

    Porphyromonas gingivalis is a keystone pathogen in periodontitis and is gaining importance in cardiovascular pathogenesis. Protease-activated receptors (PARs), toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) on monocytes recognize the structural components on P. gingivalis, inducing inflammatory intermediates. Here, we elucidate the modulation of PARs, TLRs, NODs, and the role of MAPK and NF-B in IL-1 and CXCL8 release. THP1 cells were stimulated with P. gingivalis wild-type W50 and its isogenic gingipain mutants: Rgp mutant E8 and Kgp mutant K1A. We observed modulation of PARs, TLRs, NOD, IL-1 and CXCL8 expression by P. gingivalis. Gingipains hydrolyse IL-1 and CXCL8, which is more evident for IL-1 accumulation at 24 h. Inhibition of PKC (protein kinase C), p38 and ERK (extracellular signal-regulated kinases) partially reduced P. gingivalis-induced IL-1 at 6 h, whereas PKC and ERK reduced CXCL8 at both 6 and 24 h. Following NF-B inhibition, P. gingivalis-induced IL-1 and CXCL8 were completely suppressed to basal levels. Overall, TLRs, PARs and NOD possibly act in synergy with PKC, MAPK ERK/p38 and NF-B in P. gingivalis-induced IL-1 and CXCL8 release from THP1 cells. These pro-inflammatory cytokines could affect leucocytes in circulation and exacerbate other vascular inflammatory conditions such as atherosclerosis.

  • 61.
    Jayaprakash, Kartheyaene
    et al.
    Department of Medical Sciences, Örebro University, Örebro, Sweden.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Porphyromonas gingivalis-induced inflammatory responses in THP1 cells are altered by native and modified low-density lipoproteins in a strain-dependent manner2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 8, p. 667-677Article in journal (Refereed)
    Abstract [en]

    Strong epidemiological evidence supports an association between cardiovascular and periodontal disease and furthermore, the periodontopathogen Porphyromonas gingivalis has been identified in blood and from atheromatous plaques. Blood exposed to P.gingivalis shows an increased protein modification of low-density lipoprotein (LDL). In this study, we investigate the inflammatory responses of THP1 cells incubated with P.gingivalis and the effects of native or modified LDL on these responses. Reactive oxygen species (ROS) and IL-1 were observed in THP1 cells following infection with P.gingivalis ATCC33277 and W50. Caspase 1 activity was quantified in THP1 cells and correlated with IL-1 accumulation. Oxidized LDL (oxLDL) induced IL-1 release and CD36 expression on THP1 cells. Modified LDL co-stimulated with ATCC33277 exhibited regulatory effects on caspase 1 activity, IL-1 release and CD36 expression in THP1 cells, whereas W50 induced more modest responses in THP1 cells. In summary, we show that P.gingivalis is capable of inducing pro-inflammatory responses in THP1 cells, and native and modified LDL could alter these responses in a dose- and strain-dependent manner. Strain-dependent differences in THP1 cell responses could be due to the effect of P.gingivalis proteases, presence or absence of capsule and proteolytic transformation of native and modified LDL.

  • 62.
    Johansson, Karin
    et al.
    Department of Laboratory Medicine, Molecular Diagnostics, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Hanna
    Department of Laboratory Medicine, Molecular Diagnostics, Örebro University Hospital, Örebro, Sweden.
    Norén, Torbjörn
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Clostridium difficile infection diagnostics: evaluation of the C. DIFF Quik Chek Complete assay, a rapid enzyme immunoassay for detection of toxigenic C. difficile in clinical stool samples2016In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, no 11, p. 1016-1020Article in journal (Refereed)
    Abstract [en]

    Diagnostic testing for Clostridium difficile infection (CDI) has, in recent years, seen the introduction of rapid dual-EIA (enzyme immunoassay) tests combining species-specific glutamate dehydrogenase (GDH) with toxin A/B. In a prospective study, we compared the C. DIFF Quik Chek Complete test to a combination of selective culture (SC) and loop-mediated isothermal amplification (LAMP) of the toxin A gene. Of 419 specimens, 68 were positive in SC including 62 positive in LAMP (14.7%). The combined EIA yielded 82 GDH positives of which 47 were confirmed toxin A/B positive (11%) corresponding to a sensitivity and specificity of 94% for GDH EIA compared to SC and for toxin A/B EIA a sensitivity of 71% and a specificity of 99% compared to LAMP. Twenty different PCR ribotypes were evenly distributed except for UK 081 where only 25% were toxin A/B positive compared to LAMP. We propose a primary use of a combined GDH toxin A/B EIA permitting a sensitive 1-h result of 379 of 419 (90%, all negatives plus GDH and toxin EIA positives) referred specimens. The remaining 10% being GDH positive should be tested for toxin A/B gene on the same day and positive results left to a final decision by the physician.

  • 63.
    Jönsson, Agnez
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Foerster, Sunniva
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden; Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hamasuna, Ryoichi
    Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Lindberg, Magnus
    Örebro University, School of Medical Sciences. Department of Dermatovenerology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Jensen, Jörgen Skov
    Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark.
    Ohnishi, Makoto
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 29-37Article in journal (Refereed)
    Abstract [en]

    Treatment of gonorrhoea is a challenge worldwide because of emergence of resistance in N. gonorrhoeae to all therapeutic antimicrobials available and novel antimicrobials are imperative. The newer-generation fluoroquinolone sitafloxacin, mostly used for respiratory tract infections in Japan, can have a high in vitro activity against gonococci. However, only a limited number of recent antimicrobial-resistant isolates from Japan have been examined. We investigated the sitafloxacin activity against a global gonococcal panel (250 isolates cultured in 1991-2013), including multidrug-resistant geographically, temporally and genetically diverse isolates, and performed time-kill curve analysis for sitafloxacin. The susceptibility to sitafloxacin (agar dilution) and seven additional therapeutic antimicrobials (Etest) was determined. Sitafloxacin was rapidly bactericidal, and the MIC range, MIC50 and MIC90 was ≤0.001-1, 0.125 and 0.25 mg/L, respectively. There was a high correlation between the MICs of sitafloxacin and ciprofloxacin; however, the MIC50 and MIC90 of sitafloxacin were 6-fold and >6-fold lower, respectively. Sitafloxacin might be an option for particularly dual antimicrobial therapy of gonorrhoea and for cases with ceftriaxone resistance or allergy. However, further in vitro and particularly in vivo evaluations of potential resistance, pharmacokinetics/pharmacodynamics and ideal dosing for gonorrhoea, as well as performance of randomized controlled clinical, trials are crucial.

  • 64.
    Kalbina, Irina
    et al.
    Örebro University, School of Science and Technology. Orebro Life Science Center.
    Lagerqvist, Nina
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Moiane, Bélisario
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Eduardo Mondlane University, Maputo, Mozambique.
    Ahlm, Clas
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Andersson, Sören
    Örebro University, School of Medical Sciences. Örebro Life Science Center, Department of Science and Technology, Örebro University, Örebro, Sweden; Department of Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Falk, Kerstin I.
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Arabidopsis thaliana plants expressing Rift Valley fever virus antigens: Mice exhibit systemic immune responses as the result of oraladministration of the transgenic plants2016In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 127, p. 61-67Article in journal (Refereed)
    Abstract [en]

    The zoonotic Rift Valley fever virus affects livestock and humans in Africa and on the Arabian Peninsula.The economic impact of this pathogen due to livestock losses, as well as its relevance to public health,underscores the importance of developing effective and easily distributed vaccines. Vaccines that can bedelivered orally are of particular interest.

    Here, we report the expression in transformed plants (Arabidopsis thaliana) of Rift Valley fever virusantigens. The antigens used in this study were the N protein and a deletion mutant of the Gn glycoprotein.Transformed lines were analysed for specific mRNA and protein content by RT-PCR and Westernblotting, respectively. Furthermore, the plant-expressed antigens were evaluated for their immunogenicityin mice fed the transgenic plants. After oral intake of fresh transgenic plant material, a proportionof the mice elicited specific IgG antibody responses, as compared to the control animals that were fedwild-type plants and of which none sero-converted.

    Thus, we show that transgenic plants can be readily used to express and produce Rift Valley Fever virusproteins, and that the plants are immunogenic when given orally to mice. These are promising findingsand provide a basis for further studies on edible plant vaccines against the Rift Valley fever virus.

  • 65.
    Karefylaki, Styliani
    et al.
    Department of Pediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Gustafsson, Dan
    Örebro University, School of Health Sciences. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Recovery from food protein-induced enterocolitis syndrome caused by fish2016In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 27, no 1, p. 105-106Article in journal (Refereed)
  • 66.
    Kelly, Anne
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Hussain, Shahida
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Olcen, Per
    Mölling, Paula
    Örebro University Hospital.
    Gene variability and degree of expression of vaccine candidate factor H binding protein in clinical isolates of Neisseria meningitidis2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 1, p. 56-63Article in journal (Refereed)
    Abstract [en]

    The factor H binding protein (fHbp) is currently being evaluated in clinical trials as a vaccine candidate for a meningococcal group B vaccine. We have previously described the prevalence and sequence variation of fHbp (Jacobsson et al., 2009) and here we investigate the expression of the antigen. The present study includes isolates from carriers (n = 62) and patients with invasive Neisseria meningitidis infections (n = 146), of which 62 had a fatal outcome. Among the invasive isolates from patients with fatal and non-fatal infections fHbp allele 1 was most common (42% and 29% respectively), but it was only identified in 3% of the carrier isolates, where allele 16 was most frequent (13%). The Fluorescence-activated cell sorting analysis identified fHbp expression in all except seven isolates and further analysis by Western blot showed that five of these seven samples were indeed negative using a polyclonal anti-fHbp serum. The negative isolates belonged to serogroup B fHbp allele 24, Y allele 104, and W-135 allele 16 (all invasive). Two were non-serogroupable carrier isolates (allele 21 and 101). An interesting finding is that isolates from invasive infections with fatal outcome had lower expression of fHbp or lower affinity for the fHbp antibody compared to isolates from non-fatal invasive infections and carriers.

  • 67.
    Kempe, Per
    et al.
    Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Obstetrics & Gynaecology, County Hospital Sundsvall, Sundsvall, Sweden.
    Eklund, Daniel
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hallin, Agnes
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hammar, Mats
    Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Brynhildsen, Jan
    Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ernerudh, Jan
    Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Immune profile in relation to sex steroid cyclicity in healthy women and women with multiple sclerosis2018In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 1, no 26, p. 53-59Article in journal (Refereed)
    Abstract [en]

    To prospectively study systemic in vivo immunological effects of sex hormones, using different phases of oral combined hormonal contraceptives (CHC), and the natural menstrual cycles in both healthy women and in women with multiple sclerosis (MS), blood samples from sixty female MS patients and healthy controls with and without CHC were drawn in high and low estrogenic/progestogenic phases. Expression of Th-associated genes in blood cells was determined by qPCR and a panel of cytokines and chemokines was measured in plasma. High hormone level phases were associated with increases in Th1 (TBX21) and Th2 (GATA3) associated markers, as well as the B cell-associated chemokine CXCL13, while the inhibitory regulator CTLA-4 was decreased. These changes were not observed in MS patients, of whom most were treated with immunomodulatory drugs. Our data indicate immune activating properties in vivo of high steroid sex hormone levels during both CHC and normal menstrual cyclicity.

  • 68.
    Khairullin, Rafil
    et al.
    Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia; The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Vorobyev, Denis
    The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Obukhov, Andrey
    Tuvan Republican Skin and Venereal Diseases Dispensary, Tuva, Russia.
    Kuular, Ural-Herel
    Tuvan Republican Skin and Venereal Diseases Dispensary, Tuva, Russia.
    Kubanova, Anna
    The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Kubanov, Alexey
    The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Syphilis epidemiology in 1994-2013, molecular epidemiological strain typing and determination of macrolide resistance in Treponema pallidum in 2013-2014 in Tuva Republic, Russia2016In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, no 7, p. 595-602Article in journal (Refereed)
    Abstract [en]

    The incidence of syphilis in the Tuva Republic (geographical centre of Asia), Russia has been exceedingly high historically. No detailed examinations and no molecular investigations of Treponema pallidum strains transmitted in the Tuva Republic, or in general, in Russia, were published internationally. We examined the syphilis epidemiology in 1994-2013, and the molecular epidemiology and macrolide resistance in T. pallidum strains in 2013-2014 in the Tuva Republic. Among 95 mainly primary or secondary syphilis patients, the arp, tpr, tp0548 and 23S rRNA genes in 85 polA gene-positive genital ulcer specimens were characterized. The syphilis incidence in Tuva Republic peaked in 1998 (1562), however declined to 177 in 2013. Among the 70 (82%) completely genotyped specimens, six molecular strain types were found. Strain type 14d/f accounted for 91%, but also 14c/f, 14d/g, 14b/f, 14i/f, 9d/f, and 4d/f were identified. Two (2.4%) specimens contained the 23S rRNA A2058G macrolide resistance mutation. This is the first internationally published typing study regarding T. pallidum in Russia, performed in the Tuva Republic with the highest syphilis incidence in Russia. The two molecular strain types 4d/f and 9d/f have previously been described only in Eastern and Northern China and for the first time, macrolide-resistant syphilis was described in Russia.

  • 69. Kumawat, A. K.
    et al.
    Strid, H.
    Elgbratt, K.
    Nyhlin, N.
    Tysk, Curt
    Bohr, Johan
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Ökat uttryck av Th1/CTL-associerade gener samt högre frekvens CD8+ och CD4+8+, Ki67+ prolifererande, CD45RO+ aktiverade/minnes-T-celler i tarmslemhinnan hos patienter med kollagen kolit2011In: Gastrokuriren, ISSN 1651-0453, Vol. 16Article in journal (Other academic)
  • 70.
    Kumawat, Ashok
    et al.
    Örebro University, School of Health and Medical Sciences.
    Elgbratt, Kristina
    Örebro University, School of Health and Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Increased frequencies of Ki67+ proliferating and CD45RO+ memory CD8+ and CD4+8+ T lymphocytes in the intestinal mucosa of collagenous colitis patients2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 73, no 4, p. 374-374Article in journal (Refereed)
  • 71. Kumawat, Ashok
    et al.
    Götlind, Yu-Yuan
    Fritsch Fredin, Maria
    Willén, Roger
    Chazot, Paul
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Modulation of histamine 4 receptor mRNA and protein expression in Gai2-deficient mice during colitis progression2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 73, no 4, p. 373-373Article in journal (Refereed)
  • 72. Kumawat, Ashok Kumar
    et al.
    Götlind, Y. Y.
    Fritsch Fredin, M.
    Willén, R.
    Strid, H.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Expression patterns of histamine receptors in the Gai2-deficient mouse model of colitis2010In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 59, no Suppl 4, p. S358-S359Article in journal (Refereed)
  • 73.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Wickbom, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Hultgren, Olof
    Örebro University Hospital. Department of Microbiology and Immunology, Örebro University Hospital, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    An In Vitro Model to Evaluate the Impact of the Soluble Factors from the Colonic Mucosa of Collagenous Colitis Patients on T Cells: Enhanced Production of IL-17A and IL-10 from Peripheral CD4(+) T Cells2014In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 879843Article in journal (Refereed)
    Abstract [en]

    Soluble factors from intestinal mucosal cells contribute to immune homeostasis in the gut. We have established an in vitro model to investigate the regulatory role of soluble factors from inflamed intestinal mucosa of collagenous colitis (CC) patients in the differentiation of T cells. Peripheral blood CD4(+) T cells from healthy donors were polyclonally activated in the presence of conditioned medium (CM) generated from denuded biopsies (DNB) or isolated lamina propria mononuclear cells (LPMCs) from mucosal biopsies from CC patients compared to noninflamed controls, to determine proliferation and secretion of cytokines involved in T-cell differentiation. Compared to controls, we observed significantly increased production of the proinflammatory cytokines IFN-gamma, IL-17A, IL-6, and IL-1 beta and the anti-inflammatory cytokines IL-4 and IL-10 in the presence of CC-DNB-CM. The most pronounced effect of CC-LPMC-CM on peripheral CD4(+) T cells was a trend towards increased production of IL-17A and IL-10. A trend towards reduced inhibition of T-cell proliferation was noted in the presence of CC-DNB-CM. In conclusion, our in vitro model reveals implications of soluble factors from CC colonic mucosa on peripheral T cells, enhancing their production of both pro-and anti-inflammatory cytokines.

  • 74. Kumawat, Ashok Kumar
    et al.
    Strid, H.
    Elgbratt, K.
    Nyhlin, Nils
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Bohr, J.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Collagenous colitis patients demonstrate a Th1/CTL-associated gene expression profile with increased frequencies of Ki67+ proliferating and CD45RO+ activated/ memory CD8+ and CD4+8+ mucosal T cells2011Conference paper (Other academic)
  • 75. Kumawat, Ashok Kumar
    et al.
    Strid, H.
    Elgbratt, K.
    Nyhlin, Nils
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences.
    Bohr, J.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Health and Medical Sciences.
    Collagenous colitis patients demonstrate a Th1/CTL-associated gene expression profile with increased frequencies of Ki67+ proliferating and CD45RO+ activated/memory CD8+ and CD4+8+ mucosal T cells2011In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 60, no Suppl. 3, p. A318-Article in journal (Refereed)
  • 76. Kumawat, Ashok Kumar
    et al.
    Strid, H.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bohr, J.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Patienter med mikroskopisk kolit har blandad Th1/Th17 samt CTL-associerad cytokinprofil2012Conference paper (Other academic)
  • 77.
    Kumawat, Ashok Kumar
    et al.
    Örebro University, School of Health and Medical Sciences.
    Strid, Hilja
    Örebro University, School of Health and Medical Sciences.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital.
    Bohr, Johan
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Region Örebro County, Örebro, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 55, no 3-4, p. 355-364Article in journal (Refereed)
    Abstract [en]

    Background:

    Microscopic colitis (MC) is a chronic inflammatory bowel disorder of unknown aetiology comprising collagenous colitis (CC) and lymphocytic colitis (LC). Data on the local cytokine profile in MC is limited. This study investigated the T helper (Th) cell and cytotoxic T lymphocyte (CTL) mucosal cytokine profile at messenger and protein levels in MC patients.

    Methods:

    Mucosal biopsies from CC (n = 10), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 4), (LC-HR, n = 6), ulcerative colitis (UC, n = 3) and controls (n = 10) were analysed by real-time PCR and Luminex for expression/production of IL-1 beta, -4, -5, -6, -10, -12, -17, -21, -22, -23, IFN-gamma, TNF-alpha, T-bet and RORC2.

    Results:

    Mucosal mRNA but not protein levels of IFN-gamma and IL-12 were significantly up regulated in CC, LC as well as UC patients compared to controls. Transcription of the Th1 transcription factor T-bet was significantly enhanced in CC but not LC patients. mRNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients. Significantly enhanced IL-21 protein levels were noted in both CC and LC patients. IL-6 protein and IL-1 beta mRNA levels were increased in CC and UC but not LC patients. Increased mucosal mRNA levels of IFN-gamma, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients.

    Although at lower magnitude, IL-23A mRNA was upregulated in CC and LC, whereas TNF-alpha protein was increased in CC, LC as well as in UC patients.

    Neither mRNA nor protein levels of IL-4, IL-5 or IL-10 were significantly changed in any of the colitis groups. LC-HR and especially CC-HR patients had normalized mRNA and protein levels of the above cytokines compared to LC and CC patients. No significant differences were found between LC and CC in cytokine expression/production.

    Conclusion:

    LC and CC patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

  • 78.
    La Torre, Daria
    et al.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Larsson, Helena E.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Ivarsson, Sten A.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Lernmark, Åke
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 11, p. 3951-3956Article in journal (Refereed)
    Abstract [en]

    Children developing type 1 diabetes may have risk markers already in their umbilical cord blood. It is hypothesized that the risk for type 1 diabetes at an early age may be increased by a pathogenic pregnancy and be reflected in altered cord-blood composition. This study used metabolomics to test if the cord-blood lipidome was affected in children diagnosed with type 1 diabetes before 8 years of age. The present case-control study of 76 index children diagnosed with type 1 diabetes before 8 years of age and 76 healthy control subjects matched for HLA risk, sex, and date of birth, as well as the mother's age and gestational age, revealed that cord-blood phosphatidylcholines and phosphatidylethanolamines were significantly decreased in children diagnosed with type 1 diabetes before 4 years of age. Reduced levels of triglycerides correlated to gestational age in index and control children and to age at diagnosis only in the index children. Finally, gestational infection during the first trimester was associated with lower cord-blood total lysophosphatidylcholines in index and control children. In conclusion, metabolomics of umbilical cord blood may identify children at increased risk for type 1 diabetes. Low phospholipid levels at birth may represent key mediators of the immune system and contribute to early induction of islet autoimmunity.

  • 79.
    Lanjouw, E.
    et al.
    Department of Dermatology, Erasmus Medical Center, Rotterdam, The Netherlands.
    Ouburg, S.
    Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
    de Vries, H. J.
    Department of Dermatology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; STI Outpatient Clinic, Infectious Disease Cluster, Health Service Amsterdam, Amsterdam, The Netherlands; Center for Infection and Immunology Amsterdam (CINIMA), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands .
    Stary, A.
    Outpatients’ Centre for Infectious Venereodermatological Diseases, Vienna, Austria.
    Radcliffe, K.
    University Hospital Birmingham Foundation NHS Trust, Birmingham, United Kingdom.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Center for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    2015 European guideline on the management of Chlamydia trachomatis infections2016In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 27, no 5, p. 333-348Article in journal (Refereed)
    Abstract [en]

    Chlamydia trachomatis infections, which most frequently are asymptomatic, are major public health concerns globally. The 2015 European C. trachomatis guideline provides: up-to-date guidance regarding broader indications for testing and treatment of C. trachomatis infections; a clearer recommendation of using exclusively-validated nucleic acid amplification tests for diagnosis; advice on (repeated) C. trachomatis testing; the recommendation of increased testing to reduce the incidence of pelvic inflammatory disease and prevent exposure to infection; and recommendations to identify, verify and report C. trachomatis variants. Improvement of access to testing, test performance, diagnostics, antimicrobial treatment and follow-up of C. trachomatis patients are crucial to control its spread. For detailed background, evidence base and discussions, see the background review for the present 2015 European guideline on the management of Chlamydia trachomatis infections (Lanjouw E, etal. Int J STD AIDS. 2015).

  • 80.
    Lee, Hyukmin
    et al.
    Yonsei University College of Medicine, Seoul, South Korea.
    Suh, Young Hee
    Yonsei University College of Medicine, Seoul, South Korea.
    Lee, Sunhwa
    Seegene Medical Foundation, Seoul, South Korea.
    Kim, Yong-Kyun
    Samkwang Medical Laboratories, Seoul, South Korea.
    Han, Mi-Soon
    U2 Clinical Laboratories, Seoul, South Korea.
    Bae, Hye Gyung
    Green Cross Laboratories, Yongin, South Korea.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. World Health Organization Collaborating Centre for Gonorrhoea and other STIs, Örebro University, Örebro, Sweden.
    Lee, Kyungwon
    Yonsei University College of Medicine, Seoul, South Korea.
    Emergence and Spread of Cephalosporin-Resistant Neisseria gonorrhoeae with Mosaic penA Alleles, South Korea, 2012-20172019In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 25, no 3, p. 416-424Article in journal (Refereed)
    Abstract [en]

    In South Korea, surveillance of antimicrobial drug resistance in Neisseria gonorrhoeae is extremely limited. We describe the emergence and subsequent national spread of N. gonorrhoeae strains with mosaic penA alleles associated with decreased susceptibility and resistance to extended-spectrum cephalosporins. From 2012 through 2017, the proportion of mosaic penA alleles in gonococcal-positive nucleic acid amplification test (NAAT) specimens across South Korea increased from 1.1% to 23.9%. Gonococcal strains with mosaic penA alleles emerged in the international hubs of Seoul in Gyeonggi Province and Busan in South Gyeongsang Province and subsequently spread across South Korea. Most common was mosaic penA-10.001 (n = 572 isolates; 94.7%), which is associated with cefixime resistance. We also identified mosaic penA-34.001 and penA-60.001, both of which are associated with multidrug-resistant gonococcal strains and spread of cefixime and ceftriaxone resistance. Implementation of molecular resistance prediction from N. gonorrhoeae-positive nucleic acid amplification test specimens is imperative in South Korea and internationally.

  • 81.
    Lindh, Ingrid
    et al.
    Örebro University, School of Science and Technology. Örebro Life Sci Ctr, Univ Örebro, Örebro, Sweden; Sch Sci & Technol, Univ Örebro, Örebro, Sweden.
    Bråve, Andreas
    Swedish Institute for Communicable Disease Control (SMI), Stockholm, Sweden.
    Hallengärd, David
    Dept Microbiol Tumor & Cell Biol, Karolinska Inst, Stockholm, Sweden.
    Hadad, Ronza
    Örebro University, School of Science and Technology. Örebro Life Sci Ctr, Univ Örebro, Örebro, Sweden.
    Kalbina, Irina
    Örebro University, School of Science and Technology. Örebro Life Sci Ctr, Univ Örebro, Örebro, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology. Örebro Life Sci Ctr, Univ Örebro, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital. Örebro Life Sci Ctr, Univ Örebro, Örebro, Sweden; Örebro University Hospital, Örebro, Sweden.
    Oral delivery of plant-derived HIV-1 p24 antigen in low doses shows a superior priming effect in mice compared to high doses2014In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 32, no 20, p. 2288-2293Article in journal (Refereed)
    Abstract [en]

    During early infection with human immunodeficiency virus type 1 (HIV-1), there is a rapid depletion of CD4+ T-cells in the gut-associated lymphoid tissue (GALT) in the gastrointestinal tract. Therefore, immediate protection at these surfaces is of high priority for the development of an HIV-1 vaccine. Thus, transgenic plants expressing HIV-1 antigens, which are exposed to immune competent cells in the GALT during oral administration, can be interesting as potential vaccine candidates. In the present study, we used two HIV-1 p24 antigen-expressing transgenic plant systems, Arabidopsis thaliana and Daucus carota, in oral immunization experiments. Both transgenic plant systems showed a priming effect in mice and induced humoral immune responses, which could be detected as anti-p24-specific IgG in sera after an intramuscular p24 protein boost. Dose-dependent antigen analyses using transgenic Arabidopsis thaliana indicated that low p24 antigen doses were superior to high p24 antigen doses

  • 82.
    Lindh, Ingrid
    et al.
    Örebro University, School of Science and Technology.
    Bråve, Andreas
    Swedish Institute for Communicable Disease Control, The Public Health Agency of Sweden, Stockholm, Sweden.
    Hallengärd, David
    Swedish Institute for Communicable Disease Control, The Public Health Agency of Sweden, Stockholm, Sweden.
    Hadad, Ronza
    Örebro University, School of Science and Technology.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Andersson, Sören
    Örebro University Hospital, Örebro, Sweden.
    Oral delivery of transgenic plant-derived HIV-1 p24 antigen in low doses shows a superior priming effect in mice compared to higher doses2012In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 9, no Suppl. 2, article id P336Article in journal (Refereed)
    Abstract [en]

    Background

    The gut associated lymphoid tissue (GALT) includes around two thirds of the total lymphoid system. CD4+ T-cells in the GALT are a main target for HIV during primary infection. Thus, immunization targetting GALT is likely to be of importance for an effective vaccine strategy. Transgenic plants expressing HIV antigens can reach GALT conveniently. This system allows multiple boosts, has simple logistics (no cold chain, no injections) and large production capacity.

    Methods

    Three groups of mice were given extract from plant lines expressing HIV-1 p24 at (A) low level (20 ng/feeding); (B) high level (460 ng/feeding); (C) control (wild type, 0 ng). No adjuvant was included. The extracts were administered by gastric tube day 0, 14 and 28. On day 55 all mice were given an intramuscular (i.m.) boost with 10 micrograms of purified p24 antigen. Immune responses were determined by measurement of p24-antibodies in serum by ELISA.

    Results

    The mice immunized by the low dose plant line (A) showed a higher systemic immune response after i.m. boost compared to the high dose group (B). The w.t. controls (C) had undetectable p24-responses. The responses in group A were 3 to 10 times higher (ELISA OD values) than in group B. Pre-boost antibody responses were at background levels in all groups. Preliminary analyses indicate a predomninant Th1-type response (antigen-specific IgG2a higher than IgG1).

    Conclusion

    Simple and inexpensive means of vaccination are important in order to reach large numbers of people with effective vaccine regimens. The HIV-1 p24 low dose transgenic plant extracts given orally showed a superior priming effect in mice compared to the p24 high dose extracts. This could be an immunization method and route worth exploring further.

  • 83.
    Lindh, Ingrid
    et al.
    Örebro University, School of Science and Technology.
    Kalbina, Irina
    Örebro University, School of Science and Technology.
    Hedberg, Sara Thulin
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Bråve, Andreas
    Hinkula, Jorma
    Strid, Åke
    Örebro University, School of Science and Technology.
    Andersson, Sören
    Örebro University, School of Science and Technology.
    Feeding of mice with Arabidopsis thaliana expressing the HIV-1 subtype C p24 antigen gives rise to systemic immune responses2008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 11, p. 985-994Article in journal (Refereed)
    Abstract [en]

    Development of transgenic edible plants, to be used as production, storage and delivery systems for recombinant vaccine antigens, is a promising strategy to obtain cost effective vaccines against infectious diseases, not the least for use in developing countries. Therefore, we used Agrobacterium tumefaciens-mediated gene transfer to introduce the p24 gag gene encoding the nucleocapsid protein from HIV-1 subtype C into the Arabidopsis thaliana plant genome. Eighteen plant lines were confirmed positive for the p24 gene by PCR, four of these lines showed an apparent homozygous phenotype when grown on selective medium and these lines also showed transcription of the p24 gene into its corresponding mRNA. The mRNA in all four cases generated the p24 protein in plants, as verified by western blot analysis. The plants were shown to contain between 0.2 µg and 0.5 µg p24 protein per g of fresh tissue. Analysis of the localisation of the p24 protein showed that stem tissue contained the largest amount of protein, more than twice as much as leaf tissue, whereas no p24 protein was detected in roots. By using Southern blotting, we found that 4, 2-3, 2 and 1 T-DNA insertion events took place in the four lines 1, 2, 7, and 10, respectively. The genetic insertions of line 1 were stable from the T1 to the T4 generation and gave rise to the p24 protein in all cases, as verified by western blotting. In mice fed with fresh transgenic A. thaliana (line 10), anti-gag IgG was obtained in serum after a booster injection with recombinant p37Gag. No immune response was observed after equal booster injection of untreated mice or mice fed with A. thaliana WT plants.

  • 84.
    Ludvigsson, Jonas F.
    et al.
    Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden .
    Neovius, Martin
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Hammarström, Lennart
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Association Between IgA Deficiency & Other Autoimmune Conditions: A Population-Based Matched Cohort Study2014In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 34, no 4, p. 444-451Article in journal (Refereed)
    Abstract [en]

    Purpose: To examine autoimmune disorders in patients with IgA deficiency compared with the general population.

    Methods: Nationwide prospective population-based cohort study. Through six university hospitals in Sweden we identified 2100 individuals with IgA deficiency (IgA levels < .07 g/L) diagnosed between 1980 and 2011. Each patient with IgA deficiency was matched on age, sex, place of residence, and year of diagnosis with up to 10 general population controls (n = 18,653). Data on nine autoimmune disorders were retrieved from the Swedish National Patient Register (including inpatient and non-primary outpatient care). Autoimmune disorders were defined as having at least two visits listing the relevant international classification of disease (ICD) code as main diagnosis. Prevalences and prevalence ratios (PRs) were calculated.

    Results: Individuals with IgA deficiency more often had celiac disease (6.7 % vs. 0.19 % in controls) and type 1 diabetes (5.9 % vs. 0.57 %) corresponding to a 35-fold higher PR for celiac disease and 10-fold higher for type 1 diabetes. Also for the other autoimmune diseases did we see statistically significantly elevated prevalences and PRs (juvenile idiopathic arthritis (0.76 % vs. 0.09 % in controls, PR = 8.9), systemic lupus erythematosus (0.57 % vs. 0.06 %; PR = 8.9), inflammatory bowel disease (3.9 % vs. 0.81 %; PR = 5.0; specifically Crohn's disease (2.4 % vs. 0.42 %; PR = 5.7) and ulcerative colitis (1.7 % vs. 0.46 %; PR = 3.9)), hypothyreosis (0.76 % vs. 0.16 %; PR = 4.6), rheumatoid arthritis (2.2 % vs. 0.50 %; PR = 4.5), and hyperthyreosis (1.7 % vs. 0.43 %; PR = 3.9), but not with myasthenia gravis (0.05 % vs. 0.02 %; PR = 3.0).

    Conclusions: Individuals with IgA deficiency have a higher prevalence of several other autoimmune disorders.

  • 85.
    Ludvigsson, Jonas F.
    et al.
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.
    Neovius, Martin
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Hammarström, Lennart
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Risk of Infections Among 2100 Individuals with IgA Deficiency: a Nationwide Cohort Study2016In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 36, no 2, p. 134-140Article in journal (Refereed)
    Abstract [en]

    To explore the risk of infections in individuals with IgA deficiency compared to general population controls.

    In this nationwide prospective population-based cohort study, we used data on IgA levels (< 0.07 g/L) from six university hospitals in Sweden to identify 2100 individuals with IgA deficiency. Individuals were diagnosed between 1980 and 2010. For each patient with IgA deficiency we identified 10 controls from the general population, matched on age, sex, and place of residence (n = 18,653). Data on infections were obtained from the Swedish National Patient Register (including inpatient and hospital-based outpatient care) between 2001 and 2010. We defined infections as having a record of a relevant international classification of disease (ICD) code. Prevalences and prevalence ratios (PRs) were calculated.

    Individuals with IgA deficiency were more likely to have a record of any infection (36.1 vs. 18.8 % in controls) corresponding to a PR of 2.4 (95%CI 2.2-2.6). We also noted statistically significant associations with IgA deficiency (all P-values < 0.05) and respiratory tract infections (17.8 vs. 6.3 % in controls; PR = 3.2), gastrointestinal infections (6.0 vs. 1.8 % in controls; PR = 3.5), skin infections (4.1 vs. 2.2 % in controls; PR = 1.9), joint infections (0.48 vs. 0.24 % in controls; PR = 2.0; P = 0.052), sepsis (1.5 vs. 0.45 % in controls; PR = 3.4), meningitis (0.38 vs. 0.12 %, PR = 3.2), mastoiditis/otitis (2.1 vs. 1.1 % in controls; PR = 2.0), and urinary tract infections (6.1 vs. 3.4 % in controls; PR = 1.8).

    Individuals with IgA deficiency are at an increased risk of infections requiring hospital care.

  • 86.
    Ludvigsson, Jonas F.
    et al.
    Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Neovius, Martin
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Stephansson, Olof
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Women’ s and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Hammarström, Lennart
    Department of Laboratory Medicine, Karolinska Institutet, Solna, Sweden.
    IgA Deficiency, Autoimmunity & Pregnancy: A Population-Based Matched Cohort Study2014In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 34, no 7, p. 853-863Article in journal (Refereed)
    Abstract [en]

    Background: Several autoimmune disorders have been linked to adverse pregnancy outcome. IgA deficiency shares many autoimmune traits, but its association with pregnancy outcome is unknown.

    Methods: Prospective population-based cohort study in Sweden of 613 mothers with IgA deficiency (IgA levels < .07 g/L) diagnosed in 1980-2010 in six university hospitals. In 1973-2010, these women delivered 1,172 singleton infants registered in the Swedish Medical Birth Register. Each delivery to a woman with IgA deficiency was matched on maternal age, parity, early pregnancy smoking status, education level, and delivery year with up to 5 control births (n = 5,758).

    Results: Offspring to women with IgA deficiency had 79 g lower birth weight than controls (mean +/- SD: 3,457 +/- 559 vs 3,537 +/- 553 g, P < 0.001), and 1.4 days shorter gestational age (mean +/- SD: 278 +/- 13 vs 280 +/- 14 days, P = 0.001). No difference in preterm birth (< 37 weeks) could be detected in deliveries to women with IgA deficiency vs control deliveries (5.8 % vs 5.2 %; odds ratio (OR) = 1.13, 95%CI = 0.85-1.49), but small for gestational age birth was more common (4.3 % vs 2.8 %; OR = 1.48, 95%CI = 1.04-2.10). Women with IgA deficiency also delivered more often by caesarean section (16.9 % vs 11.9 %; OR = 1.51, 95%CI = 1.26-1.82), while no difference was observed regarding low Apgar score (< 7 at 5 min; 1.1 % vs 1.0 %; OR = 1.18; 95%CI = 0.62-2.27). When excluding women with autoimmune diseases, the excess risks of adverse pregnancy outcome diminished.

    Conclusion: There is a small excess risk of certain adverse delivery and perinatal outcomes among offspring to women with IgA deficiency. These excess risks are attenuated when considering the presence of autoimmune diseases.

  • 87.
    Ludvigsson, Jonas F.
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden .
    Neovius, Martin
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden .
    Ye, Weimin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Hammarström, Lennart
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden .
    IgA Deficiency and Risk of Cancer: A Population-Based Matched Cohort Study2015In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 35, no 2, p. 182-188Article in journal (Refereed)
    Abstract [en]

    To investigate the risk of cancer in individuals with IgA deficiency compared with the general population.

    Prospective nationwide population-based cohort study. We identified 2320 individuals with IgA deficiency (IgA levels < 0.07 g/L) diagnosed between 1980 and 2010 in six Swedish university hospitals. Individuals with IgA deficiency were then matched on age, sex, place of residence, and year of diagnosis with up to 10 general population controls (n = 23,130). Through linkage with the Swedish Cancer Register we calculated conditional hazard ratios (HRs) for cancer diagnosed after IgA deficiency diagnosis in patients without a previous cancer diagnosis.

    During follow-up, 125 individuals with IgA deficiency (61/10,000 person-years) and 984 controls (47/10,000 person-years) developed cancer (HR 1.31; 95%CI = 1.09-1.58). In cause-specific analyses, we found an increased risk of any gastrointestinal cancer (HR = 1.64; 95%CI = 1.07-2.50), but not for lymphoproliferative malignancy (HR 1.68; 95%CI = 0.89-3.19). Relative risk estimates for overall cancer were very high in the first year of follow-up (overall: HR = 2.80; 95%CI = 1.74-4.49), but failed to reach statistical significance thereafter. IgA deficiency diagnosed in childhood (n = 487) was not associated with overall cancer (HR = 3.26; 0.88-12.03).

    Individuals with IgA deficiency are at a moderately increased risk of cancer, with excess risks of gastrointestinal cancer. This excess risk is highest just after diagnosis suggesting a degree of surveillance bias. Children with IgA deficiency were at no increased risk of cancer but the statistical power was limited in subanalyses.

  • 88.
    Lundberg, Gunilla A.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    The role of the CXCL16-CXCR6 pathway in cell recruitment, activation and effector functions2007In: Chemokine research trends / [ed] Leah R. Grinwald, New York: Nova Science Publishers Inc , 2007, 1, p. 71-80Chapter in book (Other academic)
  • 89.
    Marinković, Tijana
    et al.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Sysi-Aho, Marko
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Integrated model of metabolism and autoimmune response in β-cell death and progression to type 1 diabetes2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, article id e51909Article in journal (Refereed)
    Abstract [en]

    Progression to type 1 diabetes is characterized by complex interactions of environmental, metabolic and immune system factors, involving both degenerative pathways leading to loss of pancreatic β-cells as well as protective pathways. The interplay between the degenerative and protective pathways may hold the key to disease outcomes, but no models have so far captured the two together. Here we propose a mathematical framework, an ordinary differential equation (ODE) model, which integrates metabolism and the immune system in early stages of disease process. We hypothesize that depending on the degree of regulation, autoimmunity may also play a protective role in the initial response to stressors. We assume that β-cell destruction follows two paths of loss: degenerative and autoimmune-induced loss. The two paths are mutually competing, leading to termination of the degenerative loss and further to elimination of the stress signal and the autoimmune response, and ultimately stopping the β-cell loss. The model describes well our observations from clinical and non-clinical studies and allows exploration of how the rate of β-cell loss depends on the amplitude and duration of autoimmune response.

  • 90.
    Matikas, Alexios
    et al.
    Department of Oncology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Lövrot, John
    Department of Oncology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Ramberg, Anna
    Department of Clinical Pathology and Cytology, Central Hospital Karlstad, Karlstad, Sweden.
    Eriksson, Margareta
    Department of Clinical Pathology and Cytology, Central Hospital Karlstad, Karlstad, Sweden.
    Lindsten, Therese
    Department of Clinical Pathology and Cytology, Central Hospital Karlstad, Karlstad, Sweden.
    Lekberg, Tobias
    Department of Oncology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Hedenfalk, Ingrid
    Department of Oncology/Pathology, Lund University, Lund, Sweden.
    Loman, Niklas
    Department of Oncology/Pathology, Lund University, Lund, Sweden.
    Bergh, Jonas
    Department of Oncology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Hatschek, Thomas
    Department of Oncology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Erlandsson, Ann
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Biology, Karlstad university, Karlstad, Sweden.
    Foukakis, Theodoros
    Department of Oncology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer2018In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, no 9, article id e1466017Article in journal (Refereed)
    Abstract [en]

    Gene expression (GE) signatures and Tumor Infiltrating Lymphocytes (TIL) enumeration are predictive for response to neoadjuvant chemotherapy in HR- and in HER2+ breast cancer, but data are conflicting in HR+/HER2- disease. This study aimed to explore their predictive value in this subset, measured both at baseline and after short exposure to chemotherapy. Specifically, the PROMIX phase 2 trial enrolled patients with locally advanced HER2- BC to receive six cycles of epirubicin and docetaxel, plus bevacizumab during cycles 3-6. Patients underwent tumor biopsies at baseline and after cycle 2 for GE profiling and enumeration of TIL, FOXP3+ T-cells and CD163+ macrophages. An immune related gene module and the quantification of the immune infiltrate were analyzed for association with pathologic complete response (pCR), decrease in tumor size and disease-free survival (DFS). Of the 150 patients enrolled in PROMIX, 113 were HR+/HER2-. Baseline GE and immune cell enumeration data were available from 71 patients, while data after 2 cycles of chemotherapy were available from 41. At baseline, only GE was statistically significantly associated with higher pCR rates (OR 2.29, 95% CI 1.05 - 5.38, p = 0.037) and decrease in tumor size (r = 0.25, p = 0.047). In contrast, longitudinal data indicate that both GE (r = 0.54, p<0.001) and TIL abundance (p = 0.009) are stronger predictors for the reduction of tumor size, while low FOXP3+ was statistically significantly associated with an improved DFS (p = 0.027). In conclusion, GE analysis, TIL and FOXP3+ enumeration after short-term exposure to chemotherapy carry important predictive information in HR+/HER2- breast cancer at the neoadjuvant setting.

  • 91.
    Mitselou, Niki
    et al.
    Örebro University, School of Medical Sciences. Department of Pediatrics.
    Hallberg, Jenny
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
    Stephansson, Olof
    Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Melen, Erik
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York NY, United States.
    Cesarean delivery, preterm birth, and risk of food allergy: Nationwide Swedish cohort study of more than 1 million children2018In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 142, no 5, p. 1510-1514e.2Article in journal (Refereed)
    Abstract [en]

    Background: Little is known about early-life risk factors for food allergy in children.

    Objectives: We examined the association between perinatal characteristics and future risk of food allergy in offspring.

    Methods: This nationwide Swedish cohort study of 1,086,378 children born in Sweden in 2001-2012 used prospectively recorded data from health care registers. Using Cox regression, we estimated hazard ratios (HRs) with 95% CIs for the association between perinatal characteristics (eg, cesarean delivery and preterm birth) and food allergy as defined by diagnoses in the National Patient Register, adjusting for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index, and asthma/pulmonary disease).

    Results: During the 13-year follow-up, 26,732 (2.5%) children were given a diagnosis of food allergy. Food allergy was positively associated with cesarean delivery (HR, 1.21; 95% CI, 1.18-1.25), large for gestational age (HR, 1.15; 95% CI, 1.10-1.19), and low 5-minute Apgar score (HR, 1.22; 95% CI, 1.10-1.36) but negatively associated with very preterm birth (<32 weeks of gestation: HR, 0.74; 95% CI, 0.56-0.98). No association was found between food allergy and moderately preterm birth, low birth weight, or small for gestational age. Risk estimates were similar when the outcome was restricted to 2 records of diagnosed food allergy. In 1,000 children undergoing cesarean delivery, an extra 5 developed food allergy compared with the reference group, suggesting that 17% of food allergy in children born by means of cesarean delivery can be explained by this exposure (attributable fraction).

    Conclusions: Cesarean delivery was associated with increased risk of food allergy, whereas very preterm birth decreased risk.

  • 92.
    Mitselou, Niki
    et al.
    Örebro University, School of Medical Sciences. Department of Pediatrics.
    Melén, Erik
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York NY, USA.
    The very preterm neonate's role in prevention of atopic disease: Reply2019In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 5, p. 1972-1973Article in journal (Refereed)
  • 93.
    Mohlin, Camilla
    et al.
    Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
    Johansson, Kjell
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ekdahl, Kristina N.
    Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Complement factor involvement during experimental AMD2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 163-163Article in journal (Other academic)
    Abstract [en]

    Background and aim: Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people over 60, occurring when the central part of the retina (macula) deterio-rates. Treatments of the neovascular form of AMD have progressed but not for the atrophic dry form, which is characterized by retinal pigment epithelial (RPE) cell dysfunction, retinal detachment and photoreceptor degeneration. The complement system has been acknowledged as a part of AMD-pathogenesis and suggested as a possible regulator of AMD progression. Different complement factors, both activating and inactivating elements, have been found in drusen; the clinical hallmark of AMD. The mechanism and underlying association of the complement system in AMD is incomplete and further investigations are needed. RPE cell and retinal tissue interactions, complement factor secretion and gene expressions were investigated.

    Methods: Post-confluent human RPE-cells were cultured with or without adult porcine retinas for three and five days in vitro. RPE-cell and retinal explant interactions were morphologically investigated by immunohistochemistry and lectin staining. The release of complement factors (C1q, C3, factor H, factor I and C4BP) was investigated by using Luminex xMAP technology and gene expression was investigated by real-time PCR, respectively.

    Results: Post-confluent RPE cells expressed zonula occludens-1 (ZO-1) immunoreactivity suggesting the presence of tight junctions in the cytoplasmic membrane. RPE-cells and retinal tissue showed preserved morphology and normal layering after co-culture. C1q, C3, factor H and factor I was secreted into the supernatants after the culturing process and RPE-cells were shown to express C1q, factor H and factor I.

    Conclusions: RPE-cell and retinal tissue integrity is preserved in the co-cultures. Complement system proteins appear to be locally produced and possibly a part of the pathogenesis during experimental AMD.

  • 94.
    Månsson, Emeli
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Centre for Clinical Research, Uppsala University, Uppsala, Sweden; County Hospital, Västerås, Sweden.
    Hellmark, Bengt
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Sundqvist, Martin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden.
    Sequence types of Staphylococcus epidermidis associated with prosthetic joint infections are not present in the laminar airflow during prosthetic joint surgery2015In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 123, no 7, p. 589-595Article in journal (Refereed)
    Abstract [en]

    Molecular characterization of Staphylococcus epidermidis isolates from prosthetic joint infections (PJIs) has demonstrated a predominance of healthcare-associated multi-drug resistant sequence types (ST2 and ST215). How, and when, patients acquire these nosocomial STs is not known. The aim was to investigate if sequence types of S. epidermidis associated with PJIs are found in the air during prosthetic joint surgery. Air sampling was undertaken during 17 hip/knee arthroplasties performed in operating theaters equipped with mobile laminar airflow units in a 500-bed hospital in central Sweden. Species identification was performed using MALDI-TOF MS and 16S rRNA gene analysis. Isolates identified as S. epidermidis were further characterized by MLST and antibiotic susceptibility testing. Seven hundred and thirty-five isolates were available for species identification. Micrococcus spp. (n = 303) and coagulase-negative staphylococci (n = 217) constituted the majority of the isolates. Thirty-two isolates of S. epidermidis were found. S. epidermidis isolates demonstrated a high level of allelic diversity with 18 different sequence types, but neither ST2 nor ST215 was found. Commensals with low pathogenic potential dominated among the airborne microorganisms in the operating field during prosthetic joint surgery. Nosocomial sequence types of S. epidermidis associated with PJIs were not found, and other routes of inoculation are therefore of interest in future studies.

  • 95.
    Månsson, Emeli
    et al.
    Örebro University, School of Medical Sciences. Centre for Clinical Research, Hospital of Västmanland, Region Västmanland, Västerås,Sweden; Centre for Clinical Research, Hospital of Västmanland, Uppsala University, Västerås, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Clinical Microbiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nilsdotter-Augustinsson, Åsa
    Department of Infectious Diseases, Department of Clinical and Experimental Medicine, Linköping University, Norrköping, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Staphylococcus epidermidis from prosthetic joint infections induces lower IL-1 release from human neutrophils than isolates from normal flora2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 8, p. 678-684Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to test the hypothesis that Staphylococcus epidermidis isolated from prosthetic joint infections (PJIs) differs from S.epidermidis isolated from normal flora in terms of its capacity to induce activation of caspase-1 and release of IL-1 in human neutrophils. The amount of active caspase-1 was determined over 6h by detecting Ac-YVAD-AMC fluorescence in human neutrophils incubated with S.epidermidis isolates from PJIs (ST2) or normal flora. The amount of IL-1 was detected by ELISA in neutrophil supernatants after 6h of incubation. Mean IL-1 release was lower after incubation with S.epidermidis from PJIs compared to isolates from normal flora, but no statistically significant difference was found in active caspase-1. Substantial inter-individual differences in both active caspase-1 and IL-1 were noted. These results suggest that evasion of innate immune response, measured as reduced capacity to induce release of IL-1 from human neutrophils, might be involved in the predominance of ST2 in S.epidermidis PJIs, but that other microbe-related factors are probably also important.

  • 96.
    Nestor, David
    et al.
    Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University Hospital, Örebro University, Örebro, Sweden; School of Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Malmvall, Bo-Eric
    Futurum - Academy for Health and Care, Jönköping County Council, Jönköping, Sweden.
    Masonda, Yohana Paul
    Department of Laboratory Medicine, Nkinga Referral Hospital Laboratory, Nkinga, Tanzania.
    Msafiri, John
    Department of Laboratory Medicine, Nkinga Referral Hospital Laboratory, Nkinga, Tanzania.
    Sundqvist, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology.
    Detection of extended-spectrum beta-lactamase production in Enterobacteriales from patients with suspected urinary tract infections, Tabora region, Rural Tanzania2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 8, p. 700-702Article in journal (Refereed)
  • 97. Nilsson, C
    et al.
    Larsson Sigfrinius, A.-K.
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Sverremark-Ekström, E.
    Linde, A.
    Lilja, G.
    Blomberg, M. T.
    Epstein-Barr virus and cytomegalovirus are differentially associated with numbers of cytokine-producing cells and early atopy2008In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 39, no 4, p. 509-517Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously shown that Epstein-Barr virus (EBV) seropositivity, at 2 years of age, was inversely related to IgE-sensitization and that this effect was enhanced when EBV is combined with cytomegalovirus (CMV) seropositivity. We hypothesize that early exposure to EBV or CMV will affect the cytokine balance in the individual.

    OBJECTIVE: The aim of this study was to relate the cytokine profile in peripheral blood mononuclear cells (PBMC) to the EBV and CMV serostatus and IgE-sensitization in children at 2 years of age.

    METHODS: Seventy-five children were followed prospectively from birth until 2 years of age. Their EBV and CMV serostatus was correlated to the numbers of IFN-gamma, IL-4, IL-10 and IL-12-producing PBMC following PHA stimulation in vitro. Skin prick tests and allergen-specific IgE antibodies were used to assess IgE-sensitization.

    RESULTS: In the study cohort, there was an inverse association between EBV seropositivity and IgE-sensitization but not with CMV seropositivity. Following linear regression analysis, we did not detect any statistically significant associations between children with IgG antibodies against EBV at 2 years of age and the investigated cytokines. However, there was a non-significant tendency to a positive association between high numbers of all individual cytokine-producing cells and EBV seropositivity. Children who were CMV seropositive had significantly higher numbers of IFN-gamma and lower numbers of IL-4-producing cells compared with CMV negative children. There was a significant, positive association between the number of IL-4-producing cells and IgE-sensitization.

    CONCLUSION: Taken together our results indicate that infections with EBV and CMV in different ways will interact with the immune system and may protect children from developing early atopy.

  • 98.
    Nixon Tangi, Tebeng
    et al.
    Department of Clinical Medicine, School of Health and Medical Science, Örebro University, Örebro, Sweden.
    Elmabsout, Ali Ateia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Role of NLRP3 and CARD8 in the regulation of TNF-α induced IL-1β release in vascular smooth muscle cells2012In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, no 3, p. 697-702Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-1β is known to be activated by the inflammasome. Inflammasome activities depend on a plethora of moieties including NLRP3 and CARD8, which have been reported to be associated with several inflammatory diseases. Aortic smooth muscle cells (AOSMCs) were transfected with siRNA targeting the NLRP3 and CARD8 genes, followed by tumor necrosis factor-α (TNF-α) treatment. We found that TNF-α induces IL-1β, IL-1Ra and NLRP3 genes but not CARD8. Silencing of the NLRP3 gene significantly decreased IL-1β expression and release, the IL-1Ra expression showed a borderline non-significant increment, while CARD8 knockdown did not affect the IL-1β and IL-1Ra mRNA expression or IL-1β protein release. Our results suggest that mainly NLRP3 plays a role in the regulation of IL-1β expression and release in AOSMC and could be a potential future target for the treatment of atherosclerosis and other inflammatory diseases.

  • 99.
    Norén, Torbjörn
    et al.
    Örebro University Hospital. Örebro University, School of Medical Sciences. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Magnusson, Cecilia
    Dept Infect Control, Ryhov Cty Hosp, Jönköping, Sweden; Dept Infect Dis, Ryhov Cty Hosp, Jönköping, Sweden.
    Eiserman, Maud
    Ryhov Cty Hosp, Jönköping, Sweden.
    Matussek, Andreas
    Div Med Serv, Dept Lab Med, Ryhov Cty Hosp, Jönköping, Sweden.
    Evaluation of the rapid loop-mediated isothermal amplification assay Illumigene for diagnosis of Clostridium difficile in an outbreak situation2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 2, p. 155-160Article in journal (Refereed)
    Abstract [en]

    An outbreak of Clostridium difficile infection (CDI) at Hoglandet Hospital Eksjo in southern Sweden in 2011 was mainly due to a multidrug-resistant PCR ribotype 046 (30% of all samples). Diagnostics used routinely was the Vidas CDAB assay, but to control the outbreak the rapid loop-mediated isothermal amplification (LAMP) assay Illumigene was introduced and both techniques were compared to Toxigenic culture (TC) prospectively. The LAMP assay had a superior sensitivity, that is, 98% compared to 79% for the Vidas CDAB assay. Most importantly, the mean turn-around-time from collecting sample to result was reduced from 59h to 2h enabling early isolation of patients and effective hygiene precautions. This may potentially decrease the morbidity and nosocomial transmissions of C. difficile.

  • 100.
    Ozolins, D.
    et al.
    Univ Latvia, Riga, Latvia.
    D'Elios, M. M.
    Univ Florence, Florence, Italy.
    Ripa, T.
    Cty Hosp Halland, Halmstad, Sweden.
    Bailey, R.
    London Sch Hyg & Trop Med, London, England.
    Timms, P.
    Queensland Univ Technol, Brisbane Qld, Australia.
    Spiteri, G.
    Haar, K.
    European Ctr Dis Prevent & Control ECDC, Stockholm, Sweden.
    Unemo, Magnus
    Örebro University Hospital, Örebro, Sweden.
    Second European multi-disciplinary conference of national strategies for Chlamydia trach. and human papillomavirus NSCP conf. in Berlin, 2013 enhanced detection, management and surveillance of sexually transmitted infections in Europe are essential!2013In: International journal of immunopathology and pharmacology, ISSN 0394-6320, Vol. 26, no 4, p. 839-845Article in journal (Refereed)
    Abstract [en]

    There is a need for updated guidance on detection, management and surveillance of sexually transmitted infections (STIs). Chlamydia, gonorrhoea and syphilis reporting needs to be mandatory in more European countries to aid collection of data. More widespread Chlamydia screening is needed in many countries as this is the only way to reduce complications. The role of Human Papillomavirus (HPV) screening in a situation where the prevalence of HPV infection has dropped significantly was also discussed in the context of the high cost of screening, the need for a relatively complex infrastructure, particularly in developing countries, and falling vaccination costs. An integrated HPV vaccination and screening policy could be the most appropriate with vaccination at 9-13 years as recommended by WHO and a single HPV screen at 35-39 years, possibly repeated thereafter every 10 years. Female and male HPV vaccination programmes could lead to near elimination of genital warts in both females and males. Surveillance of STIs should be intensified where needed; additional or better quality data should be collected including reasons for testing, denominator data to estimate positivity rates, diagnostic methods, concurrent STIs, sexual orientation and country of acquisition; more analytical rather than descriptive epidemiology is needed.

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