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  • 301.
    Karlén, Jerker
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Primary Health Care in Central County.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Hedmark, Max
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Olsen Faresjö, Åshild
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Faresjö, Tomas
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
    Impact of prenatal psychosocial exposures on hair cortisol levels and child health: cohort study2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Background Early psychosocial exposures are increasingly recognized as crucial for health throughout life. A possible mechanism could be physiologic dysregulation due to stress. Cortisol in hair is a new biomarker, assessing long-term HPA axis activity. The objective was to investigate whether prenatal adverse psychosocial circumstances influence infant cortisol levels in hair and health outcome in children prospectively until age 10.

    Methods True prospective cohort study in the general community with a questionnaire covering 11 psychosocial items in the family during pregnancy formed a composite scale of prenatal psychosocial vulnerability, and cumulative incidence of diseases through diagnoses until age 10 in n=1876 children. At age 1, cortisol levels in hair were measured using a competitive radioimmunoassay on a subsample of n=209.

    Results Children with added prenatal psychosocial exposures had higher infant cortisol levels in hair (B=0.40, p<0.0001, adjusted for gender and size for gestational age) in a cumulative manner and were more often (p≤0.05) affected by 12 of the 14 most common childhood diagnoses with a general pattern of rising ORs.

    Conclusions These findings support the model of physiologic dysregulation as a plausible mechanism in how the duration and number of early detrimental psychosocial exposures determine health outcome. It indicates that the multiplicity of adversities should be targeted in future interventions and could help to identify children who are at high risk of poor health. Furthermore, given the prolonged nature of exposure to a stressful social environment, the novel biomarker of cortisol in hair could be of major importance.

  • 302.
    Kawa, Lizan
    et al.
    Karolinska Institute, Sweden.
    Barde, Swapnali
    Karolinska Institute, Sweden.
    Arborelius, Ulf P.
    Karolinska Institute, Sweden.
    Theodorsson, Elvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Agoston, Denes
    Karolinska Institute, Sweden; Uniformed Serv University of Health Science, MD 20814 USA.
    Risling, Marten
    Karolinska Institute, Sweden.
    Hokfelt, Tomas
    Karolinska Institute, Sweden.
    Expression of galanin and its receptors are perturbed in a rodent model of mild, blast-induced traumatic brain injury2016In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 279, p. 159-167Article in journal (Refereed)
    Abstract [en]

    The symptomatology, mood and cognitive disturbances seen in post-traumatic stress disorder (PTSD) and mild blast-induced traumatic brain injury (mbTBI) overlap considerably. However the pathological mechanisms underlying the two conditions are currently unknown. The neuropeptide galanin has been suggested to play a role in the development of stress and mood disorders. Here we applied bio- and histochemical methods with the aim to elucidate the nature of any changes in the expression of galanin and its receptors in a rodent model of mbTBI. In situ hybridization and quantitative polymerase chain reaction studies revealed significant, injury induced changes, in some cases lasting at least for one week, in the mRNA levels of galanin and/or its three receptors, galanin receptor 1-3 (GalR1-3). Such changes were seen in several forebrain regions, and the locus coeruleus. In the ventral periaqueductal gray GalR1 mRNA levels were increased, while GalR2 were decreased. Analysis of galanin peptide levels using radioimmunoassay demonstrated an increase in several brain regions including the locus coeruleus, dorsal hippocampal formation and amygdala. These findings suggest a role for the galanin system in the endogenous response to mbTBI, and that pharmacological studies of the effects of activation or inhibition of different galanin receptors in combination with functional assays of behavioral recovery may reveal promising targets for new therapeutic strategies in mbTBI. (C) 2016 Elsevier Inc. All rights reserved.

  • 303.
    Kechagias, Stergios
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Dernroth, Dženeta Nezirević
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgren, Anders
    Skåne University Hospital, Lund.
    Hansson, Therese
    Skåne University Hospital, Lund.
    Isaksson, Anders
    Skåne University Hospital, Lund.
    Walther, Lisa
    Skåne University Hospital, Lund.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Nystrom, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Phosphatidylethanol Compared with Other Blood Tests as a Biomarker of Moderate Alcohol Consumption in Healthy Volunteers: A Prospective Randomized Study.2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50, no 4, p. 399-406Article in journal (Refereed)
    Abstract [en]

    AIM: It is generally agreed that traditional alcohol biomarkers lack in sensitivity to detect hazardous alcohol consumption. The present study was undertaken to evaluate the ability of phosphatidylethanol (PEth) and traditional alcohol markers to detect moderate alcohol consumption and to distinguish between moderate alcohol consumption and abstinence.

    METHODS: Forty-four subjects, 32 females and 12 males, were included in the study. They were randomized to alcohol abstention or to alcohol consumption. Female participants consumed 150 ml of red wine (equivalent to 16 g of alcohol) per 24 h and the male participants double the amount. The study lasted for 3 months. Blood samples were drawn at the start and at the end of the study period. Blood samples were analysed for PEth, carbohydrate-deficient transferrin (CDT), mean corpuscular volume (MCV), γ-glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

    RESULTS: ROC curves for the various biochemical markers were plotted in order to assess their ability to discriminate between abstention and moderate daily consumption of alcohol. PEth and CDT were the only markers with AUROCs significantly higher than 0.5, and PEth was detected in all participants randomized to alcohol consumption.

    CONCLUSION: PEth was the only marker that could detect moderate intake and the present results also indicate that PEth probably can distinguish moderate alcohol consumption from abstinence.

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  • 304.
    Keller, Baerbel
    et al.
    University of Medical Centre, Germany; University of Freiburg, Germany.
    Zaidman, Irina
    Ruth Rappaport Childrens Hospital, Israel.
    Sascha Yousefi, O.
    University of Medical Centre, Germany; University of Freiburg, Germany; University of Freiburg, Germany; University of Freiburg, Germany.
    Hershkovitz, Dov
    Rambam Health Care Campus, Israel.
    Stein, Jerry
    Schneider Childrens Medical Centre Israel, Israel; Schneider Childrens Medical Centre Israel, Israel.
    Unger, Susanne
    University of Medical Centre, Germany; University of Freiburg, Germany.
    Schachtrup, Kristina
    University of Medical Centre, Germany; University of Freiburg, Germany.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kuperman, Amir A.
    Galilee Medical Centre, Israel; Galilee Medical Centre, Israel; Bar Ilan University, Israel.
    Shaag, Avraham
    Hebrew University of Jerusalem, Israel.
    Schamel, Wolfgang W.
    University of Medical Centre, Germany; University of Freiburg, Germany; University of Freiburg, Germany.
    Elpeleg, Orly
    Hebrew University of Jerusalem, Israel.
    Warnatz, Klaus
    University of Medical Centre, Germany; University of Freiburg, Germany.
    Stepensky, Polina
    Hebrew University of Jerusalem, Israel; Hebrew University of Jerusalem, Israel.
    Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT2016In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 213, no 7, p. 1185-1199Article in journal (Refereed)
    Abstract [en]

    The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca2+ mobilization, residual T cells were able to induce Ca2+ influx and nuclear factor (NF) kappa B signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease.

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  • 305.
    Khassebaf, Jasmine
    et al.
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Hellmark, Bengt
    Örebro University Hospital, Sweden.
    Davidsson, Sabina
    Örebro University, Sweden; Örebro University Hospital, Sweden.
    Unemo, Magnus
    Örebro University Hospital, Sweden.
    Nilsdotter-Augustinsson, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Söderquist, Bo
    Örebro University, Sweden.
    Antibiotic susceptibility of Propionibacterium acnes isolated from orthopaedic implant-associated infections.2015In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 32, p. 57-62Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Prosthetic joint infections (PJIs) caused by Propionibacterium acnes account for a larger proportion of the total number of PJIs than previously assumed and thus knowledge of the antimicrobial susceptibility patterns of P. acnes is of great value in everyday clinical practice.

    MATERIALS AND METHODS: Using Etest, the present study investigated the susceptibility of 55 clinical isolates of P. acnes, obtained from orthopaedic implant-associated infections of the knee joint (n = 5), hip joint (n = 17), and shoulder joint (n = 33), to eight antimicrobial agents: benzylpenicillin, clindamycin, metronidazole, fusidic acid, doxycycline, moxifloxacin, linezolid and rifampicin. Synergy testing was also conducted, in which rifampicin was combined with each of the remaining seven antibiotics.

    RESULTS: All isolates (n = 55) were susceptible to most of the antibiotics tested, with the exception of 100% resistance to metronidazole, five (9.1%) isolates displaying decreased susceptibility to clindamycin, and one (1.8%) to moxifloxacin. None of the antimicrobial agents investigated were synergistic with each other when combined and nine isolates were antagonistic for various antimicrobial combinations. The majority of the antimicrobial combinations had an indifferent effect on the isolates of P. acnes. However, the combination of rifampicin and benzylpenicillin showed an additive effect on nearly half of the isolates.

    CONCLUSION: Almost all P. acnes, isolated from orthopaedic implant-associated infections, predominantly PJIs, were susceptible to the antibiotics tested, with the exception of complete resistance to metronidazole. Synergy test could not demonstrate any synergistic effect but additive effects were found when combining various antibiotics. Antagonistic effects were rare.

  • 306.
    Kilebrant, Sophie
    et al.
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Braathen, Gunnar
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Emilsson, Roger
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Glansen, Ulla
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Soderpalm, Ann-Charlott
    University of Gothenburg, Sweden.
    Zetterlund, Bo
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Westerberg, Barbro
    Regional Vastra Gotaland Child and Youth Habilitat, Sweden.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Swolin-Eide, Diana
    University of Gothenburg, Sweden.
    WHOLE-BODY VIBRATION THERAPY IN CHILDREN WITH SEVERE MOTOR DISABILITIES2015In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 47, no 3, p. 223-228Article in journal (Refereed)
    Abstract [en]

    Objective: To study the effect of whole-body vibration therapy on bone mass, bone turnover and body composition in severely disabled children. Methods: Nineteen non-ambulatory children aged 5.1-16.3 years (6 males, 13 females) with severe motor disabilities participated in an intervention programme with standing exercise on a self-controlled dynamic platform, which included whole-body vibration therapy (vibration, jump and rotation movements). Whole-body vibration therapy was performed at 40-42 Hz, with an oscillation amplitude of 0.2 mm, 5-15 min/treatment, twice/week for 6 months. Bone mass parameters and bone markers were measured at the study start, and after 6 and 12 months. Results: Whole-body vibration therapy was appreciated by the children. Total-body bone mineral density increased during the study period (p less than0.05). Z-scores for total-body bone mineral density ranged from -5.10 to -0.60 at study start and remained unchanged throughout. Approximately 50% of the subjects had increased levels of carboxy-terminal telopeptides of type I collagen and decreased levels of osteocalcin at the start. Body mass index did not change during the intervention period, but had increased by the 12-month follow-up (pless than 0.05). Conclusion: Whole-body vibration therapy appeared to be well tolerated by children with severe motor disabilities. Total-body bone mineral density increased after 6 months of whole-body vibration therapy. Higher carboxy-terminal telopeptides of type I collagen and lower osteocalcin values indicated that severely disabled children have a reduced capacity for bone acquisition.

  • 307.
    Kissopoulou, Antheia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Next Generation Sequencing Analysis of Human Platelet PolyA plus mRNAs and rRNA-Depleted Total RNA2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 81809-Article in journal (Refereed)
    Abstract [en]

    Background: Platelets are small anucleate cells circulating in the blood vessels where they play a key role in hemostasis and thrombosis. Here, we compared platelet RNA-Seq results obtained from polyA+ mRNA and rRNA-depleted total RNA. Materials and Methods: We used purified, CD45 depleted, human blood platelets collected by apheresis from three male and one female healthy blood donors. The Illumina HiSeq 2000 platform was employed to sequence cDNA converted either from oligo(dT) isolated polyA+ RNA or from rRNA-depleted total RNA. The reads were aligned to the GRCh37 reference assembly with the TopHat/Cufflinks alignment package using Ensembl annotations. A de novo assembly of the platelet transcriptome using the Trinity software package and RSEM was also performed. The bioinformatic tools HTSeq and DESeq from Bioconductor were employed for further statistical analyses of read counts. Results: Consistent with previous findings our data suggests that mitochondrially expressed genes comprise a substantial fraction of the platelet transcriptome. We also identified high transcript levels for protein coding genes related to the cytoskeleton function, chemokine signaling, cell adhesion, aggregation, as well as receptor interaction between cells. Certain transcripts were particularly abundant in platelets compared with other cell and tissue types represented by RNA-Seq data from the Illumina Human Body Map 2.0 project. Irrespective of the different library preparation and sequencing protocols, there was good agreement between samples from the 4 individuals. Eighteen differentially expressed genes were identified in the two sexes at 10% false discovery rate using DESeq. Conclusion: The present data suggests that platelets may have a unique transcriptome profile characterized by a relative over-expression of mitochondrially encoded genes and also of genomic transcripts related to the cytoskeleton function, chemokine signaling and surface components compared with other cell and tissue types. The in vivo functional significance of the non-mitochondrial transcripts remains to be shown.

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  • 308.
    Kling, Daniel
    et al.
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science, Norway.
    DellAmico, Barbara
    National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden.
    Tillmar, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden.
    FamLinkX - implementation of a general model for likelihood computations for X-chromosomal marker data2015In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 17Article in journal (Refereed)
    Abstract [en]

    The use of genetic markers located on the X chromosome has seen a significant increase in the last years and their utility has been well studied. This paper describes the software FamLinkX, freely available at http://www.famlink.se, implementing a new algorithm for likelihood computations accounting for linkage, linkage disequilibrium and mutations. It is obvious that such software is sought for among forensic users as more and more X-chromosomal markers become available. We provide some simulated examples demonstrating the utility of the implementation as well as its application in forensic casework. Though algebraic derivations are generally unfeasible, the paper outlines some theoretical considerations and provides a discussion on the validation of the software. The focus of this paper is to compare the software to existing methods in a forensic setting, perform a validation study as well as to provide an idea of the discriminatory power for X-chromosomal markers. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

  • 309.
    Kling, Daniel
    et al.
    Department of Forensic Services, Oslo University Hospital, Oslo, Norway.
    Tillmar, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kinship inference for males with identical Y-STR profiles using whole genome SNP data provides a deeper understanding about the level of coancestry in the Swedish male population2017In: Forensic Science International: Genetics Supplement Series, ISSN 1875-1768, E-ISSN 1875-175X, Vol. 6, p. e393-e394Article in journal (Refereed)
    Abstract [en]

    Male individuals, from a Swedish reference population, with identical 17 loci Y-chromosomal STR haplotypes were analyzed with more than 900,000 autosomal SNPs in order to estimate their degree of genetic relatedness. This study shows that even though identical Y-STR profiles are shared, there is no evidence that these individuals are related to a higher degree compared with randomly unrelated male individuals in the Swedish population. Based on the results in this study, we conclude that the data do not show any signs of a biased sampling when it comes to the studied male individuals representing the Swedish reference population. © 2017 Elsevier B.V.

  • 310.
    Kling, Daniel
    et al.
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science, Norway.
    Tillmar, Andreas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Egeland, Thore
    Norwegian University of Life Science, Norway; Norwegian Institute Public Heatlh, Norway.
    Mostad, Petter
    Norwegian University of Life Science, Norway; University of Gothenburg, Sweden.
    A general model for likelihood computations of genetic marker data accounting for linkage, linkage disequilibrium, and mutations2015In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 129, no 5, p. 943-954Article in journal (Refereed)
    Abstract [en]

    Several applications necessitate an unbiased determination of relatedness, be it in linkage or association studies or in a forensic setting. An appropriate model to compute the joint probability of some genetic data for a set of persons given some hypothesis about the pedigree structure is then required. The increasing number of markers available through high-density SNP microarray typing and NGS technologies intensifies the demand, where using a large number of markers may lead to biased results due to strong dependencies between closely located loci, both within pedigrees (linkage) and in the population (allelic association or linkage disequilibrium (LD)). We present a new general model, based on a Markov chain for inheritance patterns and another Markov chain for founder allele patterns, the latter allowing us to account for LD. We also demonstrate a specific implementation for X chromosomal markers that allows for computation of likelihoods based on hypotheses of alleged relationships and genetic marker data. The algorithm can simultaneously account for linkage, LD, and mutations. We demonstrate its feasibility using simulated examples. The algorithm is implemented in the software FamLinkX, providing a user-friendly GUI for Windows systems (FamLinkX, as well as further usage instructions, is freely available at www.famlink.se). Our software provides the necessary means to solve cases where no previous implementation exists. In addition, the software has the possibility to perform simulations in order to further study the impact of linkage and LD on computed likelihoods for an arbitrary set of markers.

  • 311.
    Kling, Daniel
    et al.
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science, Norway.
    Tillmar, Andreas O.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Egeland, Thore
    Norwegian University of Life Science, Norway; Norwegian Institute Public Heatlh, Norway.
    Familias 3-Extensions and new functionality2014In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 13, p. 121-127Article in journal (Refereed)
    Abstract [en]

    In relationship testing the aim is to determine the most probable pedigree structure given genetic marker data for a set of persons. Disaster Victim Identification (DVI) based on DNA data from presumed relatives of the missing persons can be considered to be a collection of relationship problems. Forensic calculations in investigative mode address questions like "How many markers and reference persons are needed? Such questions can be answered by simulations. Mutations, deviations from Hardy-Weinberg Equilibrium (or more generally, accounting for population substructure) and silent alleles cannot be ignored when evaluating forensic evidence in case work. With the advent of new markers, so called microvariants have become more common. Previous mutation models are no longer appropriate and a new model is proposed. This paper describes methods designed to deal with DVI problems and a new simulation model to study distribution of likelihoods. There are softwares available, addressing similar problems. However, for some problems including DVI, we are not aware of freely available validated software. The Familias software has long been widely used by forensic laboratories worldwide to compute likelihoods in relationship scenarios, though previous versions have lacked desired functionality, such as the above mentioned. The extensions as well as some other novel features have been implemented in the new version, freely available at www.familias.no. The implementation and validation are briefly mentioned leaving complete details to Supplementary sections.

  • 312.
    Klingspor, Lena
    et al.
    Karolinska Inst, Sweden.
    Ullberg, Mans
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Rydberg, Johan
    Dept Clin Microbiol, Sweden.
    Kondori, Nahid
    Univ Gothenburg, Sweden.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Swanberg, Jonas
    Ryhov Hosp, Sweden.
    Nilsson, Kenneth
    Uppsala Univ, Sweden.
    Bengten, Cecilia Jendle
    Karlstad Cent Hosp, Sweden.
    Johansson, Marcus
    Kalmar Cty Hosp, Sweden.
    Granlund, Margareta
    Umea Univ, Sweden.
    Tornqvist, Eva
    Orebro Univ Hosp, Sweden.
    Nyberg, Anders
    Cty Hosp Sundsvall Harnosand, Sweden.
    Kindlund, Karin
    Hallands Hosp, Sweden.
    Ygge, Minna
    Sunderby Hosp, Sweden.
    Kartout-Boukdir, Dalila
    Unilabs AB, Sweden.
    Toepfer, Michael
    Unilabs AB, Sweden.
    Halldin, Eva
    Vasteras Hosp, Sweden.
    Kahlmeter, Gunnar
    Cent Hosp Vaxjo, Sweden.
    Ozenci, Volkan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Epidemiology of fungaemia in Sweden: A nationwide retrospective observational survey2018In: Mycoses (Berlin), ISSN 0933-7407, E-ISSN 1439-0507, Vol. 61, no 10, p. 777-785Article in journal (Refereed)
    Abstract [en]

    ObjectivesTo identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates to identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates in Sweden. MethodsThe study was a retrospective, observational nationwide laboratory-based surveillance for fungaemia and fungal meningitis and was conducted from September 2015 to August 2016. ResultsIn total, 488 Candida blood culture isolates were obtained from 471 patients (58% males). Compared to our previous study, the incidence of candidaemia has increased from 4.2/100000 (2005-2006) to 4.7/100000 population/year (2015-2016). The three most common Candida spp. isolated from blood cultures were Candida albicans (54.7%), Candida glabrata (19.7%) and species in the Candida parapsilosis complex (9.4%). Candida resistance to fluconazole was 2% in C.albicans and between 0% and 100%, in non-albicans species other than C.glabrata and C.krusei. Resistance to voriconazole was rare, except for C.glabrata, C.krusei and C.tropicalis. Resistance to anidulafungin was 3.8% while no Candida isolate was resistant to amphotericin B. ConclusionsWe report an overall increase in candidaemia but a minor decrease of C.albicans while C.glabrata and C.parapsilosis remain constant over this 10-year period.

  • 313.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Extrinsic control of Wnt signaling in the intestine2017In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 97, p. 1-8Article, review/survey (Refereed)
    Abstract [en]

    The canonical Wnt/beta-catenin signaling pathway is a central regulator of development and tissue homeostasis. In the intestine, Wnt signaling is primarily known as the principal organizer of epithelial stem cell identity and proliferation. Within the last decade, numerous scientific breakthroughs have shed light on epithelial self-organization in the gut, and organoids are now routinely used to study stem cell biology and intestinal pathophysiology. The contribution of non-epithelial cells to Wnt signaling in the gut has received less attention. However, there is mounting evidence that stromal cells are a rich source of Wnt pathway activators and inhibitors, which can dynamically shape Wnt signaling to control epithelial proliferation and restitution. Elucidating the extent and mechanisms of paracrine Wnt signaling in the intestine has the potential to broaden our understanding of epithelial homeostasis, and may be of particular relevance for disorders such as inflammatory bowel diseases and colitis-associated cancers.

  • 314.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Parkos, Charles A.
    Department of Pathology and Laboratory Medicine, Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, USA.
    The Epithelial Barrier2013In: Molecular Genetics of Inflammatory Bowel Disease / [ed] D'Amato M., Rioux J., Springer Science+Business Media B.V., 2013, p. 265-280Chapter in book (Refereed)
  • 315.
    Koeser, Claudio U.
    et al.
    Univ Cambridge, England; Res Ctr Borstel, Germany.
    Heyckendorf, Jan
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Andres, Sonke
    Res Ctr Borstel, Germany.
    Olaru, Ioana D.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Sturegard, Erik
    Lund Univ, Sweden.
    Beckert, Patrick
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Schleusener, Viola
    Res Ctr Borstel, Germany.
    Kohl, Thomas A.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Hillemann, Doris
    Res Ctr Borstel, Germany.
    Moradigaravand, Danesh
    Wellcome Trust Sanger Inst, England.
    Parkhill, Julian
    Wellcome Trust Sanger Inst, England.
    Peacock, Sharon J.
    Univ Cambridge, England; Wellcome Trust Sanger Inst, England; London Sch Hyg and Trop Med, England.
    Niemann, Stefan
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Lange, Christoph
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany; Karolinska Inst, Sweden.
    Merker, Matthias
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
    Reply to Dookie et al., "Whole-Genome Sequencing To Guide the Selection of Treatment for Drug-Resistant Tuberculosis"2018In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 8, article id e00616-18Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 316.
    Kumar, Arun
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. GSK, Italy.
    Meldgaard, Trine Sundebo
    GSK, Italy; Tech Univ Denmark, Denmark.
    Bertholet, Sylvie
    GSK, Italy; GSK, MD 20850 USA.
    Novel Platforms for the Development of a Universal influenza vaccine2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 600Article, review/survey (Refereed)
    Abstract [en]

    Despite advancements in immunotherapeutic approaches, influenza continues to cause severe illness, particularly among immunocompromised individuals, young children, and elderly adults. Vaccination is the most effective way to reduce rates of morbidity and mortality caused by influenza viruses. Frequent genetic shift and drift among influenzavirus strains with the resultant disparity between circulating and vaccine virus strains limits the effectiveness of the available conventional influenza vaccines. One approach to overcome this limitation is to develop a universal influenza vaccine that could provide protection against all subtypes of influenza viruses. Moreover, the development of a novel or improved universal influenza vaccines may be greatly facilitated by new technologies including virus-like particles, T-cell-inducing peptides and recombinant proteins, synthetic viruses, broadly neutralizing antibodies, and nucleic acid-based vaccines. This review discusses recent scientific advances in the development of next-generation universal influenza vaccines.

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  • 317.
    Kumar Jeengar, Manish
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. National Institute Pharmaceut Educ and Research Institute, India.
    Thummuri, Dinesh
    National Institute Pharmaceut Educ and Research Institute, India.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Naidu, V. G. M.
    National Institute Pharmaceut Educ and Research Institute, India; National Institute Pharmaceut Educ and Research Institute, India.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3924Article in journal (Refereed)
    Abstract [en]

    Uridine, one of the four components that comprise RNA, has attracted attention as a novel therapeutic modulator of inflammation. However, very little is known about its effect on intestinal inflammation. The aim of the present study was to investigate the potential protective effect of intracolonic administered uridine against DSS induced colitis in male C57BL/6 mice. Intracolonic instillation of 3 doses of uridine 1 mg/Kg (lower dose), 5 mg/Kg (medium dose), and 10 mg/Kg (higher dose) in saline was performed daily. Uridine at medium and high dose significantly reduced the severity of colitis (DAI score) and alleviated the macroscopic and microscopic signs of the disease. The levels of proinflammatory cytokines IL-6, IL-1 beta and TNF in serum as well as mRNA expression in colon were significantly reduced in the uridine treated groups. Moreover, colon tissue myloperoxidase activities, protein expression of IL-6, TNF-alpha, COX-2, P-NFkB and P-Ikk-alpha beta in the colon tissues were significantly reduced in medium and high dose groups. These findings demonstrated that local administration of uridine alleviated experimental colitis in male C57BL/6 mice accompanied by the inhibition of neutrophil infiltration and NF-kappa B signaling. Thus, Uridine may be a promising candidate for future use in the treatment of inflammatory bowel disease.

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  • 318.
    Kumar, Manish
    et al.
    Department of Chemistry, Bose Institute, Kolkata 700009, India.
    Sahu, Sanjaya Kumar
    Department of Chemistry, Bose Institute, Kolkata 700009, India.
    Kumar, Ranjeet
    Department of Chemistry, Bose Institute, Kolkata 700009, India.
    Subuddhi, Arijita
    Department of Chemistry, Bose Institute, Kolkata 700009, India.
    Maji, Ranjan Kumar
    Bioinformatics Centre, Bose Institute, Kolkata 700054, India.
    Jana, Kuladip
    Division of Molecular Medicine, Bose Institute, Kolkata 700054, India.
    Gupta, Pushpa
    National Jalma Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra 282006, India.
    Raffetseder, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ghosh, Zhumur
    Bioinformatics Centre, Bose Institute, Kolkata 700054, India.
    van Loo, Geert
    VIB Inflammation Research Center, Ghent University, 9052 Ghent / Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
    Beyaert, Rudi
    VIB Inflammation Research Center, Ghent University, 9052 Ghent / Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
    Gupta, Umesh D
    National Jalma Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra 282006, India.
    Kundu, Manikuntala
    Bioinformatics Centre, Bose Institute, Kolkata 700054, India.
    Basu, Joyoti
    Bioinformatics Centre, Bose Institute, Kolkata 700054, India.
    MicroRNA let-7 Modulates the Immune Response to Mycobacterium tuberculosis Infection via Control of A20, an Inhibitor of the NF-κB Pathway.2015In: Cell host & microbe, ISSN 1934-6069, Vol. 17, no 3, p. 345-56Article in journal (Refereed)
    Abstract [en]

    The outcome of the interaction between Mycobacterium tuberculosis (Mtb) and a macrophage depends on the interplay between host defense and bacterial immune subversion mechanisms. MicroRNAs critically regulate several host defense mechanisms, but their role in the Mtb-macrophage interplay remains unclear. MicroRNA profiling of Mtb-infected macrophages revealed the downregulation of miR-let-7f in a manner dependent on the Mtb secreted effector ESAT-6. We establish that let-7f targets A20, a feedback inhibitor of the NF-κB pathway. Expression of let-7f decreases and A20 increases with progression of Mtb infection in mice. Mtb survival is attenuated in A20-deficient macrophages, and the production of TNF, IL-1β, and nitrite, which are mediators of immunity to Mtb, is correspondingly increased. Further, let-7f overexpression diminishes Mtb survival and augments the production of cytokines including TNF and IL-1β. These results uncover a role for let-7f and its target A20 in regulating immune responses to Mtb and controlling bacterial burden.

  • 319.
    Kuninty, Praneeth R.
    et al.
    Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, The Netherlands.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Tjomsland, Vegard
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Storm, Gert
    Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, The Netherlands / Department of Pharmaceutics, Utrecht University, The Netherlands.
    Östman, Arne
    Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Sweden.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Prakash, Jai
    Department of Biomaterials, Science and Technology, Section: Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, The Netherlands / Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Sweden.
    MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 13, p. 16396-16408Article in journal (Refereed)
    Abstract [en]

    Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. Although depletion of tumor stroma is debatable, attenuation of PSC activity is still an interesting strategy to treat pancreatic cancer. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs as well as in TGF-β-activated human PSCs (hPSCs). Inhibition of miR-199a or miR-214 using their hairpin inhibitors in hPSCs significantly inhibited their TGFβ-induced differentiation (gene and protein levels of α-SMA, Collagen, PDGFβR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs were prepared, which attained smaller size when hPSCs were transfected with anti-miR-199a or -214 than those transfected with control anti-miR. The conditioned medium obtained from TGFβ-activated hPSCs induced tumor cell proliferation and endothelial cell tube formation, but these effects were abrogated when hPSCs were transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in PSCs in pancreatic cancer.

  • 320.
    Labbe Sandelin, Lisa
    et al.
    Uppsala University, Sweden; Kalmar County Hospital, Sweden.
    Tolf, Conny
    Linnaeus University, Sweden.
    Larsson, Sara
    Linnaeus University, Sweden.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Salaneck, Erik
    Uppsala University, Sweden.
    Jaenson, Thomas G. T.
    Uppsala University, Sweden.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Olsen, Bjorn
    Uppsala University, Sweden.
    Waldenstrom, Jonas
    Linnaeus University, Sweden.
    Candidatus Neoehrlichia mikurensis in Ticks from Migrating Birds in Sweden2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, p. e0133250-Article in journal (Refereed)
    Abstract [en]

    Candidatus Neoehrlichia mikurensis (CNM; family Anaplasmataceae) was recently recognized as a potential tick-borne human pathogen. The presence of CNM in mammals, in host-seeking Ixodes ticks and in ticks attached to mammals and birds has been reported recently. We investigated the presence of CNM in ornithophagous ticks from migrating birds. A total of 1,150 ticks (582 nymphs, 548 larvae, 18 undetermined ticks and two adult females) collected from 5,365 birds captured in south-eastern Sweden was screened for CNM by molecular methods. The birds represented 65 different species, of which 35 species were infested with one or more ticks. Based on a combination of morphological and molecular species identification, the majority of the ticks were identified as Ixodes ricinus. Samples were initially screened by real-time PCR targeting the CNM 16S rRNA gene, and confirmed by a second real-time PCR targeting the groEL gene. For positive samples, a 1260 base pair fragment of the 16S rRNA gene was sequenced. Based upon bacterial gene sequence identification, 2.1% (24/1150) of the analysed samples were CNM-positive. Twenty-two out of 24 CNM-positive ticks were molecularly identified as I. ricinus nymphs, and the remaining two were identified as I. ricinus based on morphology. The overall CNM prevalence in I. ricinus nymphs was 4.2%. None of the 548 tested larvae was positive. CNM-positive ticks were collected from 10 different bird species. The highest CNM-prevalences were recorded in nymphs collected from common redpoll (Carduelis flammea, 3/7), thrush nightingale (Luscinia luscinia, 2/29) and dunnock (Prunella modularis, 1/17). The 16S rRNA sequences obtained in this study were all identical to each other and to three previously reported European strains, two of which were obtained from humans. It is concluded that ornithophagous ticks may be infected with CNM and that birds most likely can disperse CNM-infected ticks over large geographical areas.

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  • 321.
    Lager, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
    Faller, Maximilian
    German National Reference Centre Borrelia, Germany.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
    Kjelland, Vivian
    University of Agder, Norway; Hospital Southern Norway Trust, Norway.
    Andreassen, Ashild
    Norwegian Institute Public Heatlh, Norway.
    Dargis, Rimtas
    Slagelse Hospital, Denmark.
    Quarsten, Hanne
    Hospital Southern Norway Trust, Norway.
    Dessau, Ram
    Slagelse Hospital, Denmark.
    Fingerle, Volker
    German National Reference Centre Borrelia, Germany.
    Margos, Gabriele
    German National Reference Centre Borrelia, Germany.
    Noraas, Solvi
    Hospital Southern Norway Trust, Norway.
    Ornstein, Katharina
    Skånevard Kryh, Sweden.
    Petersson, Ann-Cathrine
    Department Clin Microbiol, Sweden.
    Matussek, Andreas
    Regional Jonköping County, Sweden; Karolinska University of Lab, Sweden; Karolinska Institute, Sweden.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
    Henningsson, Anna
    Regional Jonköping County, Sweden.
    Molecular detection of Borrelia burgdorferi sensu lato - An analytical comparison of real-time PCR protocols from five different Scandinavian laboratories2017In: PLoS ONE, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185434Article in journal (Refereed)
    Abstract [en]

    Introduction Lyme borreliosis (LB) is the most common tick transmitted disease in Europe. The diagnosis of LB today is based on the patient A s medical history, clinical presentation and laboratory findings. The laboratory diagnostics are mainly based on antibody detection, but in certain conditions molecular detection by polymerase chain reaction (PCR) may serve as a complement. Aim The purpose of this study was to evaluate the analytical sensitivity, analytical specificity and concordance of eight different real-time PCR methods at five laboratories in Sweden, Norway and Denmark. Method Each participating laboratory was asked to analyse three different sets of samples (reference panels; all blinded) i) cDNA extracted and transcribed from water spiked with cultured Borrelia strains, ii) cerebrospinal fluid spiked with cultured Borrelia strains, and iii) DNA dilution series extracted from cultured Borrelia and relapsing fever strains. The results and the method descriptions of each laboratory were systematically evaluated. Results and conclusions The analytical sensitivities and the concordance between the eight protocols were in general high. The concordance was especially high between the protocols using 16S rRNA as the target gene, however, this concordance was mainly related to cDNA as the type of template. When comparing cDNA and DNA as the type of template the analytical sensitivity was in general higher for the protocols using DNA as template regardless of the use of target gene. The analytical specificity for all eight protocols was high. However, some protocols were not able to detect Borrelia spielmanii, Borrelia lusitaniae or Borrelia japonica.

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  • 322.
    Lange, C.
    et al.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany; Karolinska Inst, Sweden.
    Alghamdi, W. A.
    Univ Florida, FL USA.
    Al-Shaer, M. H.
    Univ Florida, FL USA.
    Brighenti, S.
    Karolinska Univ Hosp Huddinge, Sweden.
    Diacon, A. H.
    Task Appl Sci, South Africa; Stellenbosch Univ, South Africa.
    DiNardo, A. R.
    Baylor Coll Med, TX 77030 USA.
    Grobbel, H. P.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Groschel, M. I.
    Univ Groningen, Netherlands; Natl Reference Ctr Mycobacteria, Germany.
    von Groote-Bidlingmaier, F.
    Task Appl Sci, South Africa.
    Hauptmann, M.
    German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany.
    Heyckendorf, J.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Kohler, N.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Kohl, T. A.
    Natl Reference Ctr Mycobacteria, Germany.
    Merker, M.
    Natl Reference Ctr Mycobacteria, Germany.
    Niemann, S.
    German Ctr Infect Res DZIF, Germany; Natl Reference Ctr Mycobacteria, Germany.
    Peloquin, C. A.
    Univ Florida, FL USA.
    Reimann, M.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Schaible, U. E.
    German Ctr Infect Res DZIF, Germany; Res Ctr Borstel, Germany; Univ Lubeck, Germany; LRA INFECTIONS 21, Germany.
    Schaub, D.
    Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
    Schleusener, V.
    Natl Reference Ctr Mycobacteria, Germany.
    Thye, T.
    Bernhard Nocht Inst Trop Med, Germany.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital.
    Perspectives for personalized therapy for patients with multidrug-resistant tuberculosis2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 284, no 2, p. 163-188Article, review/survey (Refereed)
    Abstract [en]

    According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.

  • 323.
    Lao, O.
    et al.
    Department of Forensic Molecular Biology, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, Netherlands.
    Lu, T.T.
    Institut für Medizinische Informatik und Statistik, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Nothnagel, M.
    Institut für Medizinische Informatik und Statistik, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Junge, O.
    Institut für Medizinische Informatik und Statistik, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Freitag-Wolf, S.
    Institut für Medizinische Informatik und Statistik, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Caliebe, A.
    Institut für Medizinische Informatik und Statistik, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Balascakova, M.
    Institute of Biology and Medical Genetics, University Hospital Motol, 2nd School of Medicine, CZ 150 06 Prague 5, Czech Republic.
    Bertranpetit, J.
    Unitat de Biologia Evolutiva, Pompeu Fabra University, 08003 Barcelona, Catalonia, Spain.
    Bindoff, L.A.
    Department of Neurology, Haukeland University Hospital, Institute of Clinical Medicine, 5021 Bergen, Norway.
    Comas, D.
    Unitat de Biologia Evolutiva, Pompeu Fabra University, 08003 Barcelona, Catalonia, Spain.
    Holmlund, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Linköping, Sweden.
    Kouvatsi, A.
    Department of Genetics, Development, and Molecular Biology, Aristotle University of Thessaloniki, GR-540 06 Thessaloniki, Greece.
    Macek, M.
    Institute of Biology and Medical Genetics, University Hospital Motol, 2nd School of Medicine, CZ 150 06 Prague 5, Czech Republic.
    Mollet, I.
    Laboratoire d'Empreintes Génétiques, EFS-RA site de Lyon, 69007 Lyon, France.
    Parson, W.
    Institute of Legal Medicine, Medical University Innsbruck, A-6020 Innsbruck, Austria.
    Palo, J.
    Department of Forensic Medicine, University of Helsinki, Helsinki, FIN-00014, Finland.
    Ploski, R.
    Department of Medical Genetics, Medical University Warsaw, 02-007 Warsaw, Poland.
    Sajantila, A.
    Department of Forensic Medicine, University of Helsinki, Helsinki, FIN-00014, Finland.
    Tagliabracci, A.
    Istituto di Medicina Legale, University of Ancona, I-60020 Ancona, Italy.
    Gether, U.
    Molecular Neuropharmacology Group, Center for Pharmacogenomics Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark.
    Werge, T.
    Research Institute of Biological Psychiatry, Center for Pharmacogenomics, Mental Health Center Sct. Hans, DK-4000 Roskilde, Denmark.
    Rivadeneira, F.
    Department of Internal Medicine, Genetics Laboratory, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, Netherlands, Department of Epidemiology, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, Netherlands.
    Hofman, A.
    Department of Epidemiology, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, Netherlands.
    Uitterlinden, A.G.
    Department of Internal Medicine, Genetics Laboratory, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, Netherlands, Department of Epidemiology, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, Netherlands.
    Gieger, C.
    Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians University, D-81377 Munich, Germany.
    Wichmann, H.-E.
    Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians University, D-81377 Munich, Germany.
    Ruther, A.
    Rüther, A., Institut für Medizinische Molekularbiologie, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Schreiber, S.
    Institut für Medizinische Molekularbiologie, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Becker, C.
    Cologne Center for Genomics, Institut für Genetik, University of Cologne, D-50674 Cologne, Germany.
    Nurnberg, P.
    Nürnberg, P., Cologne Center for Genomics, Institut für Genetik, University of Cologne, D-50674 Cologne, Germany.
    Nelson, M.R.
    Genetics, GlaxoSmithKline, Research Triangle Park, NC 27709, United States.
    Krawczak, M.
    Institut für Medizinische Informatik und Statistik, Christian-Albrechts University Kiel, D-24105 Kiel, Germany.
    Kayser, M.
    Department of Forensic Molecular Biology, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, Netherlands.
    Correlation between Genetic and Geographic Structure in Europe2008In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 18, no 16, p. 1241-1248Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry. © 2008 Elsevier Ltd. All rights reserved.

  • 324.
    Larsson, A.
    et al.
    Lund University, Sweden.
    Tynngård, Nahreen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Kander, T.
    Lund University, Sweden; Skåne University Hospital Lund, Sweden.
    Bonnevier, J.
    Lund University, Sweden; Skåne University Hospital Lund, Sweden.
    Schott, U.
    Lund University, Sweden; Skåne University Hospital Lund, Sweden.
    Comparison of point-of-care hemostatic assays, routine coagulation tests, and outcome scores in critically ill patients2015In: Journal of critical care, ISSN 0883-9441, E-ISSN 1557-8615, Vol. 30, no 5, p. 1032-1038Article in journal (Refereed)
    Abstract [en]

    Purpose: The purposes of the study are to compare point-of-care (POC) hemostatic devices in critically ill patients with routine laboratory tests and intensive care unit (ICU) outcome scoring assessments and to describe the time course of these variables in relation to mortality rate. Materials and methods: Patients admitted to the ICU with a prognosis of more than 3 days of stay were included. The POC devices, Multiplate platelet aggregometry, rotational thromboelastometry, and ReoRox viscoelastic tests, were used. All variables were compared between survivors and nonsurvivors. Point-of-care results were compared to prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen concentration, and Sequential Organ Failure Assessment score and Simplified Acute Physiology Score 3. Results: Blood was sampled on days 0 to 1, 2 to 3, and 4 to 10 from 114 patients with mixed diagnoses during 237 sampling events. Nonsurvivors showed POC and laboratory signs of hypocoagulation and decreased fibrinolysis over time compared to survivors. ReoRox detected differences between survivors and nonsurvivors better than ROTEM and Multiplate. Conclusions: All POC and routine laboratory tests showed a hypocoagulative response in nonsurvivors compared to survivors. ReoRox was better than ROTEM and Multiplate at detecting differences between surviving and nonsurviving ICU patients. However, Simplified Acute Physiology Score 3 showed the best association to mortality outcome.

  • 325.
    Larsson, Clarinda
    et al.
    Linköping University, Faculty of Medicine and Health Sciences.
    Hvidsten, Dag
    Univ Hosp North Norway, Norway; Nordland Hosp, Norway.
    Stuen, Snorre
    Norwegian Univ Life Sci, Norway.
    Jonsson Henningsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Candidatus Neoehrlichia mikurensis” in Ixodes ricinus ticks collected near the Arctic Circle in Norway2018In: Parasites & Vectors, ISSN 1756-3305, E-ISSN 1756-3305, Vol. 11, article id 620Article in journal (Refereed)
    Abstract [en]

    Background: "Candidatus Neoehrlichia mikurensis" is a gram-negative bacterium belonging to the family Anaplasmataceae that, in Europe, is transmitted by Ixodes ricinus ticks. Candidatus N. mikurensis can cause a severe systemic inflammatory syndrome, neoehrlichiosis, mostly in persons with other underlying diseases. To date, "Ca. N. mikurensis "has been found in ticks in different countries in Asia and Europe, but never as far north as at the Arctic Circle. Methods: A total of 1104 I. ricinus ticks collected from vegetation and from animals in northern Norway (64-68 degrees N) were analysed for the prevalence of "Ca. N. mikurensis". Of them, 495 ticks were collected from vegetation by flagging and 609 ticks were collected from dogs and cats. Total nucleic acid extracted from the ticks were converted to cDNA and analyzed with real-time PCR targeting the 16S rRNA gene of "Ca. N. mikurensis". Positive samples were further analysed by nested PCR and sequencing. Results: "Candidatus N. mikurensis" was detected in 11.2% of all collected I. ricinus ticks in northern Norway. The prevalence differed between ticks collected from vegetation (18.2%; 90/495) compared to ticks collected from dogs and cats (5.6%; 34/609). The ticks from dogs and cats were collected in Bronnoy area and seven additional districts further north. The prevalence of "Ca. N. mikurensis" in these ticks differed between geographical localities, with the highest prevalence in the Bronnoy area. Conclusions: The detection of "Ca. N. mikurensis" in I. ricinus ticks from the Arctic Circle in northern Norway indicates potential risk for tick-bitten humans at this latitude to be infected with "Ca. N. mikurensis".

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  • 326.
    Larsson, Marie C.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Ewa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Woksepp, Hanna
    Kalmar County Hospital, Sweden .
    Frolander, Kerstin
    Kalmar County Hospital, Sweden .
    Mårtensson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Rashed, Foad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Annika, Wistedt
    Kalmar County Hospital, Sweden .
    Schön, Thomas
    Kalmar County Hospital, Sweden .
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Rapid identification of pneumococci, enterococci, beta-haemolytic streptococci and S. aureus from positive blood cultures enabling early reports2014In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 14, no 146Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The aim of this study was to evaluate diagnostic tests in order to introduce a diagnostic strategy to identify the most common gram-positive bacteria (pneumococci, enterococci, β-haemolytic streptococci and S. aureus) found in blood cultures within 6 hours after signalling growth.

    METHODS:

    The tube coagulase test was optimized and several latex agglutination tests were compared and evaluated before a validation period of 11 months was performed on consecutive positive blood culture patient samples from Kalmar County Hospital, Sweden.

    RESULTS:

    During the validation period 150 (91%) of a total of 166 gram-positive cocci (119 in clusters, 45 in chains or pairs and 2 undefined morphology) were correctly identified as S. aureus, CoNS, Pneumococci, Enterococci or group A streptococci (GAS), group B streptococci (GBS), group G streptococci (GGS) within 6 hours with a minimal increase in work-load and costs. The remaining samples (9%) were correctly identified during the next day. No samples were incorrectly grouped with this diagnostic strategy and no patient came to risk by early reporting.

    CONCLUSION:

    A simple strategy gives reliable and cost-effective reporting of >90% of the most common gram-positive cocci within 6 hours after a blood cultures become positive. The high specificity of the tests used makes preliminary reports reliable. The reports can be used to indicate the focus of infection and not the least, support faster administration of proper antimicrobial treatment for patients with serious bacterial infections.

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  • 327.
    Larsson, Marie C
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Microbiology.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ängeby, Kristian
    Karolinska University Hospital, Hospital, Stockholm, Sweden; University of the West Indies, Kingston, Jamaica.
    Nordvall, Michaela
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Microbiology.
    Jureen, Pontus
    Public Health Agency of Sweden, Stockholm, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences. Kalmar County Hospital, Sweden; Linnaeus University, Kalmar, Sweden.
    A luciferase-based assay for rapid assessment of drug activity against Mycobacterium tuberculosis including monitoring of macrophage viability2014In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 106, p. 146-150Article in journal (Refereed)
    Abstract [en]

    The intracellular (IC) effect of drugs against Mycobacterium tuberculosis (Mtb) is not well established but increasingly important to consider when combining current and future multidrug regimens into the best possible treatment strategies. For this purpose, we developed an IC model based on a genetically modified Mtb H37Rv strain, expressing the Vibrio harvei luciferase (H37Rv-lux) infecting the human macrophage like cell line THP-1. Cells were infected at a low multiplicity of infection (1:1) and subsequently exposed to isoniazid (INH), ethambutol (EMB), amikacin (AMI) or levofloxacin (LEV) for 5 days in a 96-well format. Cell viability was evaluated by Calcein AM and was maintained throughout the experiment. The number of viable H37Rv-lux was determined by luminescence and verified by a colony forming unit analysis. The results were compared to the effects of the same drugs in broth cultures. AMI, EMB and LEV were significantly less effective intracellularly (MIC90: greater than4 mg/L, 8 mg/L and 2 mg/L, respectively) compared to extracellularly (MIC90: 0.5 mg/L for AMI and EMB; 0.25 mg/L for LEV). The reverse was the case for INH (IC: 0.064 mg/L vs EC: 0.25 mg/L). In conclusion, this luciferase based method, in which monitoring of cell viability is included, has the potential to become a useful tool while evaluating the intracellular effects of anti-mycobacterial drugs.

  • 328.
    Latanova, A. A.
    et al.
    Russian Acad Sci, Russia; Karolinska Inst, Sweden; Gamaleja Res Ctr Epidemiol and Microbiol, Russia.
    Petkov, S.
    Karolinska Inst, Sweden.
    Kilpelainen, A.
    Karolinska Inst, Sweden.
    Jansons, J.
    Riga Stradins Univ, Latvia.
    Latyshev, O. E.
    Gamaleja Res Ctr Epidemiol and Microbiol, Russia; Russian Acad Sci, Russia.
    Kuzmenko, Y. V.
    Russian Acad Sci, Russia.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Abakumov, M. A.
    Pirogov Russian Natl Res Med Univ, Russia; Natl Univ Sci and Technol MISIS, Russia.
    Valuev-Elliston, V. T.
    Russian Acad Sci, Russia.
    Gomelsky, M.
    Univ Wyoming, WY 82071 USA.
    Karpov, V. L.
    Russian Acad Sci, Russia.
    Chiodi, F.
    Karolinska Inst, Sweden.
    Wahren, B.
    Karolinska Inst, Sweden.
    Logunov, D. Y.
    Gamaleja Res Ctr Epidemiol and Microbiol, Russia; Russian Acad Sci, Russia.
    Starodubova, E. S.
    Russian Acad Sci, Russia.
    Isaguliants, M. G.
    Gamaleja Res Ctr Epidemiol and Microbiol, Russia; Russian Acad Sci, Russia; Riga Stradins Univ, Latvia.
    Codon optimization and improved delivery/immunization regimen enhance the immune response against wild-type and drug-resistant HIV-1 reverse transcriptase, preserving its Th2-polarity2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8078Article in journal (Refereed)
    Abstract [en]

    DNA vaccines require a considerable enhancement of immunogenicity. Here, we optimized a prototype DNA vaccine against drug-resistant HIV-1 based on a weak Th2-immunogen, HIV-1 reverse transcriptase (RT). We designed expression-optimized genes encoding inactivated wild-type and drug-resistant RTs (RT-DNAs) and introduced them into mice by intradermal injections followed by electroporation. RT-DNAs were administered as single or double primes with or without cyclic-di-GMP, or as a prime followed by boost with RT-DNA mixed with a luciferase-encoding plasmid ("surrogate challenge"). Repeated primes improved cellular responses and broadened epitope specificity. Addition of cyclic-di-GMP induced a transient increase in IFN-gamma production. The strongest anti-RT immune response was achieved in a prime-boost protocol with electroporation by short 100V pulses done using penetrating electrodes. The RT-specific response, dominated by CD4+T-cells, targeted epitopes at aa 199-220 and aa 528-543. Drug-resistance mutations disrupted the epitope at aa 205-220, while the CTL epitope at aa 202-210 was not affected. Overall, multiparametric optimization of RT strengthened its Th2- performance. A rapid loss of RT/luciferase-expressing cells in the surrogate challenge experiment revealed a lytic potential of anti-RT response. Such lytic CD4+ response would be beneficial for an HIV vaccine due to its comparative insensitivity to immune escape.

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  • 329.
    Latanova, Anastasia
    et al.
    Russian Academic Science, Russia; Gamaleja Research Centre Epidemiol and Microbiol, Russia; Karolinska Institute, Sweden.
    Petkov, Stefan
    Karolinska Institute, Sweden.
    Kuzmenko, Yulia
    Russian Academic Science, Russia.
    Kilpelainen, Athina
    Karolinska Institute, Sweden.
    Ivanov, Alexander
    Russian Academic Science, Russia.
    Smirnova, Olga
    Russian Academic Science, Russia.
    Krotova, Olga
    Russian Academic Science, Russia; Gamaleja Research Centre Epidemiol and Microbiol, Russia.
    Korolev, Sergey
    Lomonosov Moscow State University, Russia.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Karpov, Vadim
    Russian Academic Science, Russia.
    Isaguliants, Maria
    Gamaleja Research Centre Epidemiol and Microbiol, Russia; Riga Stradins University, Latvia; Russian Academic Science, Russia.
    Starodubova, Elizaveta
    Russian Academic Science, Russia; Karolinska Institute, Sweden; Russian Academic Science, Russia.
    Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice2017In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 7407136Article in journal (Refereed)
    Abstract [en]

    Reverse transcriptase (RT) is a key enzyme in viral replication and susceptibility to ART and a crucial target of immunotherapy against drug-resistant HIV-1. RT induces oxidative stress which undermines the attempts to make it immunogenic. We hypothesized that artificial secretion may reduce the stress and make RT more immunogenic. Inactivated multidrug-resistant RT (RT1.14opt-in) was N-terminally fused to the signal providing secretion of NS1 protein of TBEV (Ld) generating optimized inactivated Ld-carrying enzyme RT1.14oil. Promotion of secretion prohibited proteasomal degradation increasing the half-life and content of RT1.14oil in cells and cell culture medium, drastically reduced the residual polymerase activity, and downmodulated oxidative stress. BALB/c mice were DNA-immunized with RT1.14opt-in or parental RT1.14oil by intradermal injections with electroporation. Fluorospot and ELISA tests revealed that RT1.14opt-in and RT1.14oil induced IFN-gamma/IL-2, RT1.14opt-in induced granzyme B, and RT1.14oil induced perforin production. Perforin secretion correlated with coproduction of IFN-gamma and IL-2 (R = 0,97). Both DNA immunogens induced strong anti-RT antibody response. Ld peptide was not immunogenic. Thus, Ld-driven secretion inferred little change to RT performance in DNA immunization. Positive outcome was the abrogation of polymerase activity increasing safety of RT-based DNA vaccines. Identification of the molecular determinants of low cellular immunogenicity of RT requires further studies.

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  • 330.
    Le, Ngai Kien
    et al.
    Natl Hosp Pediat, Hanoi, Vietnam.
    Wertheim, HF
    Univ Oxford, Clin Res Unit, Hanoi, Vietnam; Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford, England; Radboudumc, RCI, Dept Med Microbiol, Nijmegen, Netherlands.
    Vu, Phu Dinh
    Natl Hosp Trop Dis, Hanoi, Vietnam.
    Khu, Dung Thi Khanh
    Natl Hosp Pediat, Hanoi, Vietnam.
    Le, Hai Tanh
    Natl Hosp Pediat, Hanoi, Vietnam.
    Hoang, Bich Thi Ngoc
    Natl Hosp Pediat, Hanoi, Vietnam.
    Vo, Vu Thanh
    HCMC, Childrens Hosp 1, Hanoi, Vietnam.
    Lam, YM
    HCMC, Hosp Trop Dis, Hanoi, Vietnam.
    Vu, DTV
    Univ Oxford, Clin Res Unit, Hanoi, Vietnam; Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford OX1 2JD, England.
    Nguyen, TH
    Natl Hosp Pediat, Hanoi, Vietnam.
    Thai, TQ
    HCMC, Childrens Hosp 1, Hanoi, Vietnam.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rydell, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Van Nguyen, K
    HCMC, Hosp Trop Dis, Hanoi, Vietnam.
    Nadjm, Behzad
    Univ Oxford, Clin Res Unit, Hanoi, Vietnam; Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford OX1 2JD, England.
    Clarkson, Louise
    Karolinska Inst, Stockholm, Sweden.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Larsson, Mattias
    University of Oxford, Vietnam; University of Oxford, England; Karolinska Institute, Sweden.
    High prevalence of hospital-acquired infections caused by gram-negative carbapenem resistant strains in Vietnamese pediatric ICUs A multi-centre point prevalence survey2016In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 95, no 27, article id e4099Article in journal (Refereed)
    Abstract [en]

    There is scarce information regarding hospital-acquired infections (HAIs) among children in resource-constrained settings. This study aims to measure prevalence of HAIs in Vietnamese pediatric hospitals. Monthly point prevalence surveys (PPSs) in 6 pediatric intensive care units (ICUs) in 3 referral hospitals during 1 year. A total of 1363 cases (1143 children) were surveyed, 59.9% male, average age 11 months. Admission sources were: other hospital 49.3%, current hospital 36.5%, and community 15.3%. Reasons for admission were: infectious disease (66%), noninfectious (20.8%), and surgery/trauma (11.3%). Intubation rate was 47.8%, central venous catheter 29.4%, peripheral venous catheter 86.2%, urinary catheter 14.6%, and hemodialysis/filtration 1.7%. HAI was diagnosed in 33.1% of the cases: pneumonia (52.2%), septicemia (26.4%), surgical site infection (2%), and necrotizing enterocolitis (2%). Significant risk factors for HAI included age under 7 months, intubation and infection at admission. Microbiological findings were reported in 212 cases (43%) with 276 isolates: 50 Klebsiella pneumoniae, 46 Pseudomonas aeruginosa, and 39 Acinetobacter baumannii, with carbapenem resistance detected in 55%, 71%, and 65%, respectively. Staphylococcus aureus was cultured in 18 cases, with 81% methicillin-resistant Staphylococcus aureus. Most children (87.6%) received antibiotics, with an average of 1.6 antibiotics per case. Colistin was administered to 96 patients, 93% with HAI and 49% with culture confirmed carbapenem resistance. The high prevalence of HAI with carbapenem resistant gram-negative strains and common treatment with broad-spectrum antibiotics and colistin suggests that interventions are needed to prevent HAI and to optimize antibiotic use.

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  • 331.
    Leander, Gunilla
    et al.
    Blekingesjukhuset, Karlskrona.
    Eliasson, Erik
    Institutionen för laboratoriemedicin, Karolinska institutet, Karolinska universitetssjukhuset, Sweden.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Giske, CG
    Klinisk mikrobiologi, Karolinska universitetssjukhuset, Sweden.
    Betalaktamantibiotika och frågan om dosregim vid svår infektion: Förlängd infusion teoretiskt tilltalande – Ännu saknas evidens för klinisk nytta2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 13, article id CW3PArticle in journal (Refereed)
    Abstract [sv]

    Betalaktamantibiotika är första­handsmedel vid svår sepsis/septisk chock.

    Djurstudier visar att den fria antibiotikakoncentrationen i blodet bör överstiga den koncentration som krävs för att hämma bakterietillväxt (MIC) under minst 50 procent av dygnet för maximal effekt av betalaktamantibiotika. 

    Infusion av betalaktamer under flera timmar eller kontinuerlig infusion kan teoretiskt öka tiden över MIC jämfört med dagens standardadministration av bolusdoser.

    Enligt denna litteraturgenomgång saknas evidens för säker skillnad i klinisk effekt mellan kontinuerlig infusion, förlängd infusion eller standardbolusdos av betalaktamantibiotika. Inkluderade studier är mycket heterogena avseende bl a patienturval, infektionsfokus, bakteriella agens och doseringsregimer.  

    I avvaktan på resultat från nya studier bör patienter med svår sepsis, framför allt vid septisk chock, ges höga och täta intermittenta betalaktamdoser alternativt förlängd infusion i syfte att nå fri antibiotikakoncentration i blodet, som överstiger MIC under minst halva dosintervallet.

  • 332.
    Lerm, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dockrell, H. M.
    London Sch Hyg and Trop Med, England.
    Addressing diversity in tuberculosis using multidimensional approaches2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 284, no 2, p. 116-124Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis is a complex disease, which can affect many organs other than the lungs. Initial infection may be cleared without inducing immunological memory, or progress directly to primary disease. Alternatively, the infection may be controlled as latent TB infection, that may progress to active tuberculosis at a later stage. There is now a greater understanding that these infection states are part of a continuum, and studies using PET/CT imaging have shown that individual lung granulomas may respond to infection independently, in an un-synchronized manner. In addition, the Mycobacterium tuberculosis organisms themselves can exist in different states: as nonculturable forms, as persisters, as rapidly growing bacteria and a biofilm-forming cording phenotype. The omics approaches of transcriptomics, metabolomics and proteomics can help reveal the mechanisms underlying these different infection states in the host, and identify biosignatures with diagnostic potential, that can predict the development of disease, in progressors as early as 12-18 months before it can be detected clinically, or that can monitor the success of anti-TB therapy. Further insights can be obtained from studies of BCG vaccination and new TB vaccines. For example, epigenetic changes associated with trained immunity and a stronger immune responses following BCG vaccination can be identified. These omics approaches may be particularly valuable when linked to studies of mycobacterial growth inhibition, as a direct read-out of the ability to control mycobacterial growth. The second generation of omics studies is identifying much smaller signatures based on as few as 3 or 4 genes. Thus, narrowing down omics-derived biosignatures to a manageable set of markers now opens the way to field-friendly point of care assays.

  • 333.
    Lerm, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Netea, M. G.
    Radboud University of Nijmegen, Netherlands.
    Trained immunity: a new avenue for tuberculosis vaccine development2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 4, p. 337-346Article, review/survey (Refereed)
    Abstract [en]

    Adaptive immunity towards tuberculosis (TB) has been extensively studied for many years. In addition, in recent years the profound contribution of innate immunity to host defence against this disease has become evident. The discovery of pattern recognition receptors, which allow innate immunity to tailor its response to different infectious agents, has challenged the view that this arm of immunity is nonspecific. Evidence is now accumulating that innate immunity can remember a previous exposure to a microorganism and respond differently during a second exposure. Although the specificity and memory of innate immunity cannot compete with the highly sophisticated adaptive immune response, its contribution to host defence against infection and to vaccine-induced immunity should not be underestimated and needs to be explored. Here, we present the concept of trained immunity and discuss how this may contribute to new avenues for control of TB.

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  • 334.
    Li, Jiyun
    et al.
    China Agr Univ, Peoples R China.
    Hulth, Anette
    Publ Hlth Agcy Sweden, Sweden.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Borjesson, Stefan
    Natl Vet Inst SVA, Sweden.
    Chen, Baoli
    Shandong Ctr Dis Control and Prevent, Peoples R China.
    Bi, Zhenwang
    Shandong Ctr Dis Control and Prevent, Peoples R China.
    Wang, Yang
    China Agr Univ, Peoples R China.
    Schwarz, Stefan
    China Agr Univ, Peoples R China; Free Univ Berlin, Germany.
    Wu, Congming
    China Agr Univ, Peoples R China.
    Letter: Occurrence of the mobile colistin resistance gene mcr-3 in Escherichia coli from household pigs in rural areas in JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol 73, issue 6, pp 1721-17232018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 6, p. 1721-1723Article in journal (Other academic)
    Abstract [en]

    n/a

  • 335.
    Lieberman, L.
    et al.
    University of Health Network, Canada.
    Devine, D. V.
    Canadian Blood Serv, Canada; University of British Columbia, Canada,.
    Reesink, H. W.
    University of Amsterdam, Netherlands.
    Panzer, S.
    Medical University of Vienna, Austria.
    Wong, J.
    Australian Red Cross Blood Serv, Australia.
    Raison, T.
    Australian Red Cross Blood Serv, Australia.
    Benson, S.
    Australian Red Cross Blood Serv, Australia.
    Pink, J.
    Australian Red Cross Blood Serv, Australia.
    Leitner, G. C.
    University of Vienna, Austria.
    Horvath, M.
    University of Vienna, Austria.
    Compernolle, V.
    Belgian Red Cross Flanders, Belgium.
    Prado Scuracchio, P. S.
    Blood Bank Hospital Sirio Libanes, Brazil.
    Wendel, S.
    Blood Bank Hospital Sirio Libanes, Brazil.
    Delage, G.
    Hema Quebec, Canada.
    Nahirniak, S.
    Alberta Health Serv, Canada.
    Dongfu, X.
    Shanghai Blood Centre, Peoples R China.
    Krusius, T.
    Finnish Red Cross Blood Serv, Finland.
    Juvonen, E.
    Finnish Red Cross Blood Serv, Finland.
    Sainio, S.
    Finnish Red Cross Blood Serv, Finland.
    Cazenave, J. -P.
    Etab Francais Sang EFS Alsace, France.
    Guntz, P.
    Etab Francais Sang EFS Alsace, France.
    Kientz, D.
    Etab Francais Sang EFS Alsace, France.
    Andreu, G.
    Institute National Transfus Sanguine INTS, France.
    Morel, P.
    EFS Bourgogne Franche Comte, France.
    Seifried, E.
    German Red Cross, Germany.
    Hourfar, K.
    German Red Cross, Germany.
    Lin, C. K.
    Hong Kong.
    O'Riordan, J.
    National Blood Centre, Ireland.
    Raspollini, E.
    Fdn Ca Granda Osped Maggiore Policlin, Italy.
    Villa, S.
    Fdn Ca Granda Osped Maggiore Policlin, Italy.
    Rebulla, P.
    Fdn Ca Granda Osped Maggiore Policlin, Italy; Fdn Ca Granda Osped Maggiore Policlin, Italy.
    Flanagan, P.
    New Zealand Blood Serv, New Zealand.
    Teo, D.
    Health Science Author, Singapore.
    Lam, S.
    Health Science Author, Singapore.
    Ang, A. L.
    Health Science Author, Singapore.
    Lozano, M.
    University of Clin Hospital, Spain.
    Sauleda, S.
    Blood and Tissue Bank Catalonia, Spain.
    Cid, J.
    University of Clin Hospital, Spain.
    Pereira, A.
    University of Clin Hospital, Spain.
    Ekermo, Bengt
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Niederhauser, C.
    Blood Transfus Serv SRC Berne, Switzerland.
    Waldvogel, S.
    Blood Transfus Serv SRC, Switzerland.
    Fontana, S.
    Blood Transfus Serv SRC Berne, Switzerland.
    Desborough, M. J.
    John Radcliffe Hospital, England.
    Pawson, R.
    John Radcliffe Hospital, England.
    Li, M.
    Blood Syst Inc, AZ, USA.
    Kamel, H.
    Blood Syst Inc, AZ, USA.
    Busch, M.
    Blood Syst Inc, AZ, USA.
    Qu, L.
    University of Pittsburgh, PA, USA; Institute Transfus Med, PA, USA.
    Triulzi, D.
    University of Pittsburgh, PA, USA; Institute Transfus Med, PA, USA.
    Prevention of transfusion-transmitted cytomegalovirus (CMV) infection: Standards of care2014In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 107, no 3, p. 276-311Article in journal (Refereed)
    Abstract [en]

    n/a

  • 336.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Arbring, Kerstin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Wallstedt, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rånby, Mats
    Zafena AB, Borensberg, Sweden.
    A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs)2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 171-176Article in journal (Refereed)
    Abstract [en]

    Background: There is a clinical need for point-of-care (POC) methods for non-vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena’s Simple Simon™ PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type.

    Methods: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10 µL end-to-end capillary used to add the citrated plasma sample to 200 µL of prothrombin time (PT) reagent by either a 20 µL or a 5 µL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons.

    Results: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20 µL variant showed markedly higher PT results than the 5 µL. The effects were even more pronounced at room temperature than at +37 °C. In plasmas from patients treated with NOACs (n = 30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20 µL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1–2.1 for dabigatran and apixaban, and INR 1.1–5.0 for rivaroxaban. Using an INR ratio between the 20 µL and 5 µL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80 µg/L for apixaban, 60 µg/L for dabigatran, and 20 µg/L for rivaroxaban.

    Conclusions: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent.

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  • 337.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Stable solution2015Patent (Other (popular science, discussion, etc.))
  • 338.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Macwan, Ankit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Protease-activated receptor 4 is more important than protease-activated receptor 1 for the thrombin-induced procoagulant effect on platelets in JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol 14, issue 8, pp 1639-16412016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 8, p. 1639-1641Article in journal (Other academic)
    Abstract [en]

    n/a

  • 339.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Faxälv, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Caveats in studies of the physiological role of polyphosphates in coagulation2016In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 44, p. 35-39Article, review/survey (Refereed)
    Abstract [en]

    Platelet-derived polyphosphates (polyP), stored in dense granule and released upon platelet activation, have been claimed to enhance thrombin activation of coagulation factor XI (FXI) and to activate FXII directly. The latter claim is controversial and principal results leading to these conclusions are probably influenced by methodological problems. It is important to consider that low-grade contact activation is initiated by all surfaces and is greatly amplified by the presence of phospholipids simulating the procoagulant membranes of activated platelets. Thus, proper use of inhibitors of the contact pathway and a careful choice of materials for plates and tubes is important to avoid artefacts. The use of phosphatases used to degrade polyP has an important drawback as it also degrades the secondary activators ADP and ATP, which are released from activated platelets. In addition, the use of positively charged inhibitors, such as polymyxin B, to inhibit polyP in platelet-rich plasma and blood is problematic, as polymyxin B also slows coagulation in the absence of polyP. In conclusion we hope awareness of the above caveats may improve research on the physiological roles of polyP in coagulation. © 2016 Authors; published by Portland Press Limited.

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  • 340.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Wallstedt, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Gustafsson, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Persson, Egon
    Novo Nordisk AS, Denmark.
    Hillarp, Andreas
    Halmstad County Hospital, Sweden.
    More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 135, no 3, p. 544-547Article in journal (Refereed)
    Abstract [en]

    The number of patients on antithrombotic treatment due to atrial fibrillation and venous thromboembolism is increasing fast due to an aging population. A growing proportion will be treated with novel oral anticoagulants, the first in clinical use was the direct oral thrombin inhibitor dabigatran (Pradaxa (R)). A small percentage of the patients on dabigatran will experience serious bleeding or be in need of urgent surgery. The aim of this study was to test the effects of different hemostatic agents in potentially reversing the anticoagulant effects in vitro in blood or platelet-rich plasma (PRP) spiked with dabigatran. Whole blood or PRP was spiked with the active substance dabigatran, 200 mu g/L. We measured clotting time being induced by 1.4 pmol/L tissue factor using the instrument ReoRox2 (TM) and initial clot growth velocity from a tissue factor covered surface using the instrument Thrombodynamics Analyzer T-2 (TM). Dabigatran prolonged clotting time 5-fold but reduced clot growth velocity only slightly. The reversing effects of prothrombin complex concentrates (PCC), activated PCC (APCC) and recombinant activated factor VII (rFVIIa) were then tested. APCC (1.8 U/mL) reduced the prolonged clotting time by 1/3, rFVIIa (2 mu g/L) only slightly (n = 10-20). The reduction was not significant using Mann-Whitney test but significant using t-test with Bonferronis correction for multiple comparisons, whereas PCC (0.56 U/mL) had no effect on clotting time. APCC doubled initial clot growth velocity, although even more in the absence of dabigatran. In conclusion, APCC and rFVIIa, but not PCC, seem to reverse, at least partially, some effects of dabigatran on coagulation parameters. Systematic evaluation of case reports, registries and, ultimately, randomized clinical trials are needed to elucidate potential benefit for patients. (C) 2014 Elsevier Ltd. All rights reserved.

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  • 341.
    Lindblom, Anders
    et al.
    Uppsala University, Sweden; Clin Research Centre, Sweden.
    Wallmenius, Katarina
    Uppsala University, Sweden.
    Sjöwall, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Fryland, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Ryhov, Sweden.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Ryhov, Sweden.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Nilsson, Kenneth
    Uppsala University, Sweden; Clin Research Centre, Sweden.
    Prevalence of Rickettsia spp. in Ticks and Serological and Clinical Outcomes in Tick-Bitten Individuals in Sweden and on the Aland Island2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0166653Article in journal (Refereed)
    Abstract [en]

    Tick-transmitted diseases are an emerging health problem, and the hard tick Ixodes ricinus is the main vector for Borrelia spp., tick-borne encephalitis virus and most of the spotted fever Rickettsiae in Europe. The aim of the present study was to examine the incidence of rickettsial infection in the southernmost and south central parts of Sweden and the Aland Islands in Finland the risk of infection in humans and its correlation with a bite of a Rickettsia-infected tick, the self-reported symptoms of rickettsial disease, and the prevalence of co-infection between Rickettsia spp. and Borrelia spp. Persons with a recent tick bite were enrolled through public media and asked to answer a questionnaire, provide a blood sample and bring detached ticks at enlistment and at follow-up three months later. Blood samples were previously analysed for Borrelia spp. antibodies and, for this report, analysed for antibodies to Rickettsia spp. by immunofluorescence and in 16 cases also using Western Blot. Ninety-six (44.0%) of the 218 participants were seropositive for IgG antibodies to Rickettsia spp. Forty (18.3%) of the seropositive participants had increased titres at the follow-up, indicating recent/current infection, while four (1.8%) had titres indicating probable recent/current infection (amp;gt;= 1: 256). Of 472 ticks, 39 (8.3%) were Rickettsia sp. positive. Five (31.3%) of 16 participants bitten by a Rickettsia-infected tick seroconverted. Experience of the selfreported symptoms nausea (p = 0.006) and radiating pain (p = 0.041) was more common among those with recent, current or probable infection compared to those who did not seroconvert. Participants who showed seroreactivity or seroconversion to Rickettsia spp. had more symptoms than those who were seronegative. Seven (3.2%) participants showed seroconversion to Borrelia spp., and three (1.4%) of these showed seroconversion to both Rickettsia spp. and Borrelia spp., in accordance with previous studies in Sweden. Symptoms of rickettsial disease were in most of the cases vague and general that were difficult to differentiate from other tick-borne diseases.

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  • 342. Order onlineBuy this publication >>
    Lindblom, Pontus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Epidemiological and Ecological Studies of Tick-borne Encephalitis Virus2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ticks are blood-sucking parasites that are an inconvenience for both humans and animals. The tick by itself is normally harmless unless they attack in excessive numbers. The harm from ticks stems from them being excellent vectors for other parasites, in the form of bacteria and virus that via the ticks are provided a bridge to move across the blood streams of different animals, including humans.

    One of the most pathogenic tick-borne disease for humans is caused by a flavivirus, the tick-borne encephalitis virus (TBEV). Each year approximately 10 000 individuals on the Eurasian continent develop neurological disease, in the form of meningitis, encephalitis, myelitis and radiculitis, following a bite by a TBEV infected tick.

    To evaluate the risk of TBEV infection after a tick-bite, we have developed a study to investigate ticks that have bitten humans and to follow up the tick-bitten humans to investigate if they get infected, and if they develop symptoms, and further trace the virus back to the tick that is infected with TBEV. Ticks, blood samples, and questionnaires were collected in collaboration with 34 primary health care centers in Sweden and on the Åland Islands during 2008 and 2009.

    Several demographical and biological factors were investigated regarding the interaction between ticks and humans. The main finding was that men removed the ticks later than women, and that both older men and older women removed the ticks later than younger individuals. This could in part explain why older individuals in general, and men in particular, are at greater risk of acquiring tick-borne encephalitis (TBE).

    Furthermore, the prevalence of TBEV in ticks that have bitten humans were investigated, in order to correlate the copy number of TBEV in the tick and the tick feeding-time to the risk of developing symptomatic and asymptomatic infection. This entailed the development of new methodology for tick analysis and TBEV real-time PCR. The result showed a very low risk of TBEV infection in the studied areas, only 5 of 2167 investigated ticks contained TBEV. Three of the individuals bitten by TBEV infected ticks were vaccinated and did not develop symptoms of TBEV infection. One unvaccinated individual got bitten by a tick containing 1800 virus copies, with a feeding-time of 12-24h, and interestingly showed no signs of infection. Another unvaccinated individual got bitten by a tick containing 7.7 million virus copies, with a feedingtime of >60h. This individual developed symptoms consistent with a 1st phase of TBE, including fever and headache, but did not develop the 2nd neurological phase of TBEV infection. Despite only  finding 5 ticks infected with TBEV, a correlation between the virus load in the tick and the tick feeding-time was observed. In 2 other individuals, TBEV antibody seroconversion was detected during the 3 month study period, one without symptoms, while the other experienced symptoms consistent with the 1st phase of TBE. These observations support the hypothesis that a higher virus amount in the tick and a longer feeding time increases the risk of TBEV infection.

    To further examine TBEV in ticks that have bitten humans and find factors that may predict the risk of human infection and development of TBE, we characterized several TBEV strains genetically. Including TBEV strains isolated from ticks that have bitten human, from questing field-collected ticks, and TBEV strains isolated from patients with TBE. In one of the ticks detached from a human after >60h of feeding, there was a heterogeneous population of TBEV quasispecies with varying poly(A) length in the 3’ untranslated region of the genome was observed. These variations might have implications for differences in virulence between TBEV strains, and the heterogeneous quasispecies population observed could be the virus adapting from replication in tick cells to mammalian cells.

    We also investigated the response to TBEV vaccination in relation to 14 health-related factors in a population of older individuals on the Åland Islands. Blood samples, questionnaires, and vaccination records were collected from 533 individuals. Three different serological assays to characterize antibody response to TBEV vaccination were used. The main finding was that the number of vaccine doses in relation to age was the most important factor determining successful vaccination. The response to each vaccination dose declined linearly with age, and as much as 47%  of individuals 50 years or older that had taken 3 vaccine doses were seronegative, compared to 23% that had taken 4 doses and 6% with 5 doses. Comparison between the serological assays revealed that the cutoffs determining the balance between sensitivity and specificity differed, but not the overall accuracy.

    Taken together, these results contribute to a better understanding of the TBEV epidemiology and can provide tools in the prevention of TBE.

    List of papers
    1. Ixodes ricinus ticks removed from humans in Northern Europe: seasonal pattern of infestation, attachment sites and duration of feeding
    Open this publication in new window or tab >>Ixodes ricinus ticks removed from humans in Northern Europe: seasonal pattern of infestation, attachment sites and duration of feeding
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    2013 (English)In: Parasites & Vectors, ISSN 1756-3305, E-ISSN 1756-3305, Vol. 6, no 362Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    The common tick Ixodes ricinus is the main vector in Europe of the tick-borne encephalitis virus and of several species of the Borrelia burgdorferi sensu lato complex, which are the etiological agents of Lyme borreliosis. The risk to contract bites of I. ricinus is dependent on many factors including the behaviour of both ticks and people. The tick's site of attachment on the human body and the duration of tick attachment may be of clinical importance. Data on I. ricinus ticks, which were found attached to the skin of people, were analysed regarding potentially stage-specific differences in location of attachment sites, duration of tick attachment (= feeding duration), seasonal and geographical distribution of tick infestation in relation to age and gender of the tick-infested hosts.

    METHODS:

    During 2008-2009, 1770 tick-bitten persons from Sweden and the Åland Islands removed 2110 I. ricinus ticks. Participants provided information about the date of tick detection and location on their body of each attached tick. Ticks were identified to species and developmental stage. The feeding duration of each nymph and adult female tick was microscopically estimated based on the scutal and the coxal index.

    RESULTS:

    In 2008, participants were tick-bitten from mid-May to mid-October and in 2009 from early April to early November. The infestation pattern of the nymphs was bimodal whereas that of the adult female ticks was unimodal with a peak in late summer. Tick attachment site on the human body was associated with stage of the tick and gender of the human host. Site of attachment seemed to influence the duration of tick feeding. Overall, 63% of nymphs and adult female ticks were detected and removed more than 24 hours after attachment. Older persons, compared to younger ones, and men, compared to women, removed "their" ticks after a longer period of tick attachment.

    CONCLUSIONS:

    The infestation behaviour of the different tick stages concerning where on the host's body the ticks generally will attach and when such ticks generally will be detected and removed in relation to host age and gender, should be of value for the development of prophylactic methods against tick infestation and to provide relevant advice to people on how to avoid or reduce the risk of tick infestation.

    Place, publisher, year, edition, pages
    BioMed Central, 2013
    Keywords
    Ixodes ricinus; Tick infestation; Tick bite; Attachment site; Feeding behaviour; Feeding duration; Host-seeking behaviour; Seasonal activity; Sweden; Åland
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-103499 (URN)10.1186/1756-3305-6-362 (DOI)000330064200001 ()24360096 (PubMedID)
    Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2017-12-06Bibliographically approved
    2. Tick-borne encephalitis virus in ticks detached from humans and follow-up of serological and clinical response.
    Open this publication in new window or tab >>Tick-borne encephalitis virus in ticks detached from humans and follow-up of serological and clinical response.
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    2014 (English)In: Ticks and Tick Borne Diseases, ISSN 1877-959X, Vol. 5, no 1, p. 21-28Article in journal (Refereed) Published
    Abstract [en]

    The risk of tick-borne encephalitis virus (TBEV) infection after a tick bite remains largely unknown. To address this, we investigated the presence of TBEV in ticks detached from humans in an attempt to relate viral copy number, TBEV subtype, and tick feeding time with the serological and clinical response of the tick-bitten participants. Ticks, blood samples, and questionnaires were collected from tick-bitten humans at 34 primary health care centers in Sweden and in the Aland Islands (Finland). A total of 2167 ticks was received from 1886 persons in 2008-2009. Using a multiplex quantitative real-time PCR, 5 TBEV-infected ticks were found (overall prevalence 0.23%, copy range <4 X 10(2)-7.7 X 10(6) per tick). One unvaccinated person bitten by a tick containing 7.7 x 10(6) TBEV copies experienced symptoms. Another unvaccinated person bitten by a tick containing 1.8 x 10(3) TBEV copies developed neither symptoms nor TBEV antibodies. The remaining 3 persons were protected by vaccination. In contrast, despite lack of TBEV in the detached ticks, 2 persons developed antibodies against TBEV, one of whom reported symptoms. Overall, a low risk of TBEV infection was observed, and too few persons got bitten by TBEV-infected ticks to draw certain conclusions regarding the clinical outcome in relation to the duration of the blood meal and virus copy number. However, this study indicates that an antibody response may develop without clinical symptoms, that a bite by an infected tick not always leads to an antibody response or clinical symptoms, and a possible correlation between virus load and tick feeding time. (C) 2013 Elsevier GmbH. All rights reserved.

    Place, publisher, year, edition, pages
    Jena, Germany: Elsevier, 2014
    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-103491 (URN)10.1016/j.ttbdis.2013.07.009 (DOI)000329007300004 ()24275477 (PubMedID)
    Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2020-01-16Bibliographically approved
    3. Determining factors for successful vaccination against tick-borne encephalitis virus in older individuals
    Open this publication in new window or tab >>Determining factors for successful vaccination against tick-borne encephalitis virus in older individuals
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    2014 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We performed a cross-sectional study including 533 persons (median age 61) from the highly TBE endemic Åland Islands in the archipelago between Sweden and Finland. Blood samples, questionnaires and vaccination records were obtained from all study participants. The aim was to investigate if there was any association between TBEV antibody titer and 14 healthrelated factors: [age, gender, number of vaccine doses (0-5), time since last vaccine dose, previous TBE disease, vaccination against other flaviviruses, ≥2 tick-bites during the previous 3 months, pet-ownership, asthma, smoking, allergy, diabetes, medication, and previous tumor]. Measurement of TBEV IgG antibodies was performed using two commercial ELISA assays (Enzygnost and Immunozym), and a third in-house rapid fluorescent focus inhibition test was used to measure TBEV neutralizing antibodies. The age of the person and the number of vaccine doses were the two most important factors determining successful vaccination. The response to each vaccine dose declined linearly with increased age. A 35 year age difference corresponds to a vaccine dose increment from 3 to 4 to achieve the same response. Participants receiving medication and participants previously vaccinated against other flaviviruses had lower TBEV antibody titers on average, while those with self-reported asthma had higher titers. By comparing the 3 serological assays we show that the Enzygnost and Immunozym assay differ due to choice of cutoffs, but not in overall accuracy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-105919 (URN)
    Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2014-04-14Bibliographically approved
    4. Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance
    Open this publication in new window or tab >>Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance
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    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103264-Article in journal (Refereed) Published
    Abstract [en]

    The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3´ non-coding region (3´NCR). A different genomic structure was found in the 3´NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3´NCRs of additional Scandinavian TBEV strains and controls, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A)3C(A)6 poly(A)  tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A)3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the re-sequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.

    Place, publisher, year, edition, pages
    Public Library of Science, 2014
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-105920 (URN)10.1371/journal.pone.0103264 (DOI)000341354800074 ()25058476 (PubMedID)
    Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2017-12-05Bibliographically approved
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    Epidemiological and Ecological Studies of Tick-borne Encephalitis Virus
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  • 343.
    Lindblom, Pontus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Fryland, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Matussek, Andreas
    County Hospital Ryhov, Sweden .
    Haglund, Mats
    County Hospital Kalmar, Sweden .
    Sjöwall, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Vene, Sirkka
    Public Health Agency Sweden, Stockholm.
    Nyman, Dag
    Aland Central Hospital, Finland .
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Factors Determining Immunological Response to Vaccination against Tick-Borne Encephalitis Virus in Older Individuals2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e0100860-Article in journal (Refereed)
    Abstract [en]

    We performed a cross-sectional study including 533 individuals (median age 61) from the highly TBE endemic A land Islands in the archipelago between Sweden and Finland. Blood samples, questionnaires and vaccination records were obtained from all study participants. The aim was to investigate if there was any association between TBEV antibody titer and 12 health-related factors. Measurement of TBEV IgG antibodies was performed using two commercial ELISA assays (Enzygnost and Immunozym), and a third in-house rapid fluorescent focus inhibition test was used to measure TBEV neutralizing antibodies. The age of the individual and the number of vaccine doses were the two most important factors determining the immunological response to vaccination. The response to each vaccine dose declined linearly with increased age. A 35 year age difference corresponds to a vaccine dose increment from 3 to 4 to achieve the same immunological response. Participants previously vaccinated against other flaviviruses had lower odds of being seropositive for neutralizing TBEV antibodies on average, while participants with self-reported asthma had higher odds of being seropositive. By comparing the 3 serological assays we show that the Enzygnost and Immunozym assay differ due to choice of cutoffs, but not in overall accuracy.

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  • 344.
    Lindblom, Pontus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Fryland, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Sjowall, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Haglund, Mats
    Kalmar County hospital.
    Matussek, Andreas
    County Hospital Ryhov, Jönköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Vene, Sirkka
    Swedish Institute for Communicable Disease Control, Stockholm.
    Nyman, Dag
    Åland Central Hospital, Åland, Finland.
    Andreassen, Åshild
    Norwegian Institute of Public Health, Olso, Norway.
    Forsberg, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Tick-borne encephalitis virus in ticks detached from humans and follow-up of serological and clinical response.2014In: Ticks and Tick Borne Diseases, ISSN 1877-959X, Vol. 5, no 1, p. 21-28Article in journal (Refereed)
    Abstract [en]

    The risk of tick-borne encephalitis virus (TBEV) infection after a tick bite remains largely unknown. To address this, we investigated the presence of TBEV in ticks detached from humans in an attempt to relate viral copy number, TBEV subtype, and tick feeding time with the serological and clinical response of the tick-bitten participants. Ticks, blood samples, and questionnaires were collected from tick-bitten humans at 34 primary health care centers in Sweden and in the Aland Islands (Finland). A total of 2167 ticks was received from 1886 persons in 2008-2009. Using a multiplex quantitative real-time PCR, 5 TBEV-infected ticks were found (overall prevalence 0.23%, copy range <4 X 10(2)-7.7 X 10(6) per tick). One unvaccinated person bitten by a tick containing 7.7 x 10(6) TBEV copies experienced symptoms. Another unvaccinated person bitten by a tick containing 1.8 x 10(3) TBEV copies developed neither symptoms nor TBEV antibodies. The remaining 3 persons were protected by vaccination. In contrast, despite lack of TBEV in the detached ticks, 2 persons developed antibodies against TBEV, one of whom reported symptoms. Overall, a low risk of TBEV infection was observed, and too few persons got bitten by TBEV-infected ticks to draw certain conclusions regarding the clinical outcome in relation to the duration of the blood meal and virus copy number. However, this study indicates that an antibody response may develop without clinical symptoms, that a bite by an infected tick not always leads to an antibody response or clinical symptoms, and a possible correlation between virus load and tick feeding time. (C) 2013 Elsevier GmbH. All rights reserved.

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  • 345.
    Lindeborg, Mats
    et al.
    Uppsala University, Sweden .
    Barboutis, Christos
    Hellenic Ornithological Society and Natural History Museum of Crete, Greece.
    Ehrenborg, Christian
    Uppsala University, Sweden .
    Fransson, Thord
    Swedish Museum of Natural History, Stockholm, Sweden.
    Jaenson, Thomas G. T.
    Uppsala University, Sweden .
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control, Solna, Sweden .
    Nyström, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Salaneck, Erik
    Uppsala University, Sweden .
    Waldenström, Jonas
    Linnaeus University, Kalmar, Sweden .
    Olsen, Björn
    Uppsala University, Sweden .
    Migratory Birds, Ticks, and Crimean-Congo Hemorrhagic Fever Virus2012In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 18, no 12, p. 2095-2097Article in journal (Other academic)
  • 346.
    Lindh Falk, Annika
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlberg, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Heslyk, Annika
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Creating spaces for interprofessional learning: Strategic revision of a common IPL curriculum in undergraduate programs2015In: Interprofessional Education in Europe: Policy and Practice / [ed] Andre Vyt, Majda Pahor, Tiina Tervaskanto-Maentausta, Antwerpen: Garant Publishers Limited , 2015, p. 49-66Chapter in book (Refereed)
  • 347. Order onlineBuy this publication >>
    Lindqvist, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Department of Infection Control.
    Epidemiological and molecular biological studies of multi-resistant methicillin-susceptible Staphylococcus aureus2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Antibiotic resistance is increasingly recognised as a major problem and threat. During the last decades Gram-positive bacteria in general, and methicillin-resistant Staphylococcus aureus (MRSA) in particular, have been in focus both concerning matters of antibiotic resistance and as pathogens causing health care-associated (nosocomial) infections. In contrast to MRSA, studies on clonal distribution of methicillin-susceptible S. aureus (MSSA) are scarce. However, interest in MSSA has increased since it was shown that MRSA emerges from susceptible backgrounds by acquisition of a staphylococcal cassette chromosome element, carrying the mecA gene encoding methicillin-resistance (SCCmec).

    In an outbreak investigation of MRSA in Östergötland County, Sweden, in 2005, a high incidence of MSSA isolates with concomitant resistance to erythromycin, clindamycin and tobramycin (ECT-R) was detected. Analysis showed that 91 % of the investigated isolates were genetically related (clonal). The ECT-R clone was divided into four different but closely related patterns with pulsed-field gel electrophoresis (PFGE), and was designated spa type t002. Whole genome sequencing revealed that the ECT-R clone carried a pseudo-SCC element estimated to be 12 kb in size, showing a resemblance of more than 99 % with the SCCmec type II element of MRSA strain N315 (New York/Japan clone). This suggested a probable derivation from a highly successful MRSA strain, which had partially excised its SCCmec. The clonal outbreak was concentrated in eight hospital departments and two primary care centres, all located in the city of Linköping. Despite a high exchange of patients with the hospitals in the neighbouring counties in southeast Sweden (Jönköping- and Kalmar County), the ECT-R clone seemed to be limited to Östergötland County. However, a tobramycin-resistant clone predominated by isolates of spa type t084 was found in all three counties in southeast Sweden, and in particular among newborns, suggesting inter-hospital transmission.

    The ECT-R clone has survived as an abundant MSSA clone for a decade in Östergötland County, which indicates an insufficiency in the maintenance of basic hygiene guidelines, and that the clone probably possesses mechanisms of virulence and transmission that are yet to be discovered.

    List of papers
    1. A clonal outbreak of methicillin-susceptible Staphylococcus aureus with concomitant resistance to erythromycin, clindamycin and tobramycin in a Swedish county
    Open this publication in new window or tab >>A clonal outbreak of methicillin-susceptible Staphylococcus aureus with concomitant resistance to erythromycin, clindamycin and tobramycin in a Swedish county
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    2009 (English)In: SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES, ISSN 0036-5548, Vol. 41, no 5, p. 324-333Article in journal (Refereed) Published
    Abstract [en]

    In contrast to methicillin-resistant Staphylococcus aureus (MRSA), studies on clonal distribution of methicillin-susceptible S. aureus (MSSA) are scarce. Since 2004, an increasing incidence of concomitant resistance to erythromycin, clindamycin and tobramycin (ECT) among MSSA has been detected in Ostergotland County, Sweden. The objectives of this study were to investigate the genetic relatedness among these isolates with 2 genotyping methods, pulsed-field gel electrophoresis (PFGE), and sequence-based typing of the polymorphic region X of the staphylococcal protein A gene (spa typing), and to determine the incidence of the Panton-Valentine leukocidin (PVL) gene. When genotyping 54 ECT-resistant MSSA isolates from 49 patients (1 isolate per patient per y), 91% were shown to be part of a clonal outbreak with both methods used (spa type t002). The clonal outbreak was concentrated in 8 hospital departments and 2 primary care centres, all located in the city of Linkoping. All isolates were negative for the PVL gene. In conclusion, this study demonstrates an ongoing clonal outbreak of PVL-negative ECT-resistant MSSA. This stresses the need to continuously maintain basic hygiene rules, since nosocomial transmission of pathogens is not limited to known resistant bacteria such as MRSA.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-18138 (URN)10.1080/00365540902801202 (DOI)
    Available from: 2009-05-09 Created: 2009-05-08 Last updated: 2014-01-22
    2. Detection and characterisation of SCCmec remnants in multiresistant methicillin-susceptible Staphylococcus aureus causing a clonal outbreak in a Swedish county
    Open this publication in new window or tab >>Detection and characterisation of SCCmec remnants in multiresistant methicillin-susceptible Staphylococcus aureus causing a clonal outbreak in a Swedish county
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    2012 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 31, no 2, p. 141-147Article in journal (Refereed) Published
    Abstract [en]

    The purpose of this study was to investigate if multiresistant methicillin-susceptible Staphylococcus aureus (MR-MSSA) causing a clonal outbreak in A-stergotland County, Sweden, were derived from methicillin-resistant S. aureus (MRSA) by carrying remnants of SCCmec, and, if so, to characterise this element. A total of 54 MSSA isolates with concomitant resistance to erythromycin, clindamycin and tobramycin from 49 patients (91% clonally related, spa type t002) were investigated with the BD GeneOhm MRSA assay and real-time polymerase chain reaction (PCR) targeting the SCCmec integration site/SCCmec right extremity junction. DNA sequencing of one isolate representing the MR-MSSA outbreak clone was performed by massive parallel 454 pyrosequencing. All isolates that were part of the clonal outbreak carried SCCmec remnants. The DNA sequencing revealed the carriage of a pseudo-SCC element 12 kb in size, with a genomic organisation identical to an SCCmec type I (TM) I (TM) element, except for a 41-kb gap. This study demonstrates the presence of a pseudo-SCC element resembling SCCmec type II among MR-MSSA, suggesting possible derivation from MRSA. The presence of SCCmec remnants should always be considered when SCCmec typing is used for MRSA detection, and may not be suitable in locations with a high prevalence of MR-MSSA, since this might give a high number of false-positive results.

    Place, publisher, year, edition, pages
    Springer Verlag (Germany), 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-74635 (URN)10.1007/s10096-011-1286-y (DOI)000298855900006 ()
    Note

    Funding Agencies|Ostergotland County Council||Scandinavian Society for Antimicrobial Chemotherapy (SSAC)|2009-22495|

    Available from: 2012-02-03 Created: 2012-02-03 Last updated: 2017-12-08
    3. Genetic relatedness of multi-resistant methicillin-susceptible Staphylococcus aureus in southeast Sweden
    Open this publication in new window or tab >>Genetic relatedness of multi-resistant methicillin-susceptible Staphylococcus aureus in southeast Sweden
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    2014 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: A high exchange of patients occurs between the hospitals in southeast Sweden, resulting in a possible transmission of nosocomial pathogens. The objective of this study was to investigate the incidence and possible genetic relatedness of multi-resistant methicillinsusceptible Staphylococcus aureus (MSSA) in the region in general, and in particular the possible persistence and transmission of the ECT-R clone (t002) showing resistance to erythromycin, clindamycin and tobramycin previously found in Östergötland County.

    Methods: Three groups of S. aureus isolates with different antibiotic resistance profiles, including the ECT-R profile, were collected from the three County Councils in southeast Sweden and investigated with spa typing, real-time PCR targeting the staphylococcal cassette chromosome (SCC) mec right extremity junction (MREJ), and microarray.

    Results: All isolates with the ECT-R resistance profile (n = 12) from Östergötland County and two additional isolates with another antibiotic resistance profile were designated spa type t002, MREJ type ii, and were clustered in the same clonal cluster (CC) (i.e. CC5) by the microarray result, indicating the persistence of the ECT-R clone. In addition, 60 % of the isolates belonged to CC15 from newborns, with 94 % sharing spa type t084, indicating interhospital transmission.

    Conclusions: The persistence of the ECT-R clone and the possible transmission of the t084 strain indicate that there is still an insufficiency in the maintenance of basic hygiene guidelines. The ECT-R clone probably possesses mechanisms of virulence and transmission that make it so successful.

    Keywords
    MSSA, multi-resistance, genetic relatedness, t002, t084
    National Category
    Clinical Medicine Medical Genetics
    Identifiers
    urn:nbn:se:liu:diva-103678 (URN)
    Available from: 2014-01-22 Created: 2014-01-22 Last updated: 2018-01-11Bibliographically approved
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    Epidemiological and molecular biological studies of multi-resistant methicillin-susceptible Staphylococcus aureus
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  • 348.
    Lindqvist, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Department of Infection Control.
    Isaksson, Barbro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Department of Infection Control. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Microbiology.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Wistedt, Annika
    Department of Clinical Microbiology and Infection Control, Kalmar County Hospital, Kalmar, Sweden.
    Swanberg, Jonas
    Clinical Microbiology Laboratory, Ryhov Hospital, Jönköping, Sweden.
    Skov, Robert
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Rhod Larsen, Anders
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Larsen, Jesper
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Petersen, Andreas
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Genetic relatedness of multi-resistant methicillin-susceptible Staphylococcus aureus in southeast Sweden2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: A high exchange of patients occurs between the hospitals in southeast Sweden, resulting in a possible transmission of nosocomial pathogens. The objective of this study was to investigate the incidence and possible genetic relatedness of multi-resistant methicillinsusceptible Staphylococcus aureus (MSSA) in the region in general, and in particular the possible persistence and transmission of the ECT-R clone (t002) showing resistance to erythromycin, clindamycin and tobramycin previously found in Östergötland County.

    Methods: Three groups of S. aureus isolates with different antibiotic resistance profiles, including the ECT-R profile, were collected from the three County Councils in southeast Sweden and investigated with spa typing, real-time PCR targeting the staphylococcal cassette chromosome (SCC) mec right extremity junction (MREJ), and microarray.

    Results: All isolates with the ECT-R resistance profile (n = 12) from Östergötland County and two additional isolates with another antibiotic resistance profile were designated spa type t002, MREJ type ii, and were clustered in the same clonal cluster (CC) (i.e. CC5) by the microarray result, indicating the persistence of the ECT-R clone. In addition, 60 % of the isolates belonged to CC15 from newborns, with 94 % sharing spa type t084, indicating interhospital transmission.

    Conclusions: The persistence of the ECT-R clone and the possible transmission of the t084 strain indicate that there is still an insufficiency in the maintenance of basic hygiene guidelines. The ECT-R clone probably possesses mechanisms of virulence and transmission that make it so successful.

  • 349.
    Lindqvist, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Health and Developmental Care, Department of Infection Control.
    Isaksson, Barbro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Health and Developmental Care, Department of Infection Control.
    Swanberg, J.
    Ryhov Hospital, Sweden.
    Skov, R.
    Statens Serum Institute, Denmark.
    Larsen, A. R.
    Statens Serum Institute, Denmark.
    Larsen, J.
    Statens Serum Institute, Denmark.
    Petersen, A.
    Statens Serum Institute, Denmark.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases. Linköping University, Faculty of Medicine and Health Sciences.
    Long-term persistence of a multi-resistant methicillin-susceptible Staphylococcus aureus (MR-MSSA) clone at a university hospital in southeast Sweden, without further transmission within the region2015In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 34, no 7, p. 1415-1422Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to characterise isolates of methicillin-susceptible Staphylococcus aureus (MSSA) with resistance to clindamycin and/or tobramycin in southeast Sweden, including the previously described ECT-R clone (t002) found in Östergotland County, focusing on clonal relatedness, virulence determinants and existence of staphylococcal cassette chromosome (SCC) mec remnants. MSSA isolates with resistance to clindamycin and/or tobramycin were collected from the three county councils in southeast Sweden and investigated with spa typing, polymerase chain reaction (PCR) targeting the SCCmec right extremity junction (MREJ) and DNA microarray technology. The 98 isolates were divided into 40 spa types, and by microarray clustered in 17 multi-locus sequence typing (MLST) clonal complexes (MLST-CCs). All isolates with combined resistance to clindamycin and tobramycin (n = 12) from Östergotland County and two additional isolates (clindamycin-R) were designated as spa type t002, MREJ type ii and were clustered in CC5, together with a representative isolate of the ECT-R clone, indicating the clones persistence. These isolates also carried several genes encoding exotoxins, Q9XB68-dcs and qacC. Of the isolates in CC15, 83 % (25/30) were tobramycin-resistant and were designated spa type t084. Of these, 68 % (17/25) were isolated from new-borns in all three counties. The persistence of the ECT-R clone in Östergotland County, although not found in any other county in the region, carrying certain virulence factors that possibly enhance its survival in the hospital environment, highlights the fact that basic hygiene guidelines must be maintained even when MRSA prevalence is low.

  • 350.
    Littorin, C
    et al.
    Örebro University, Örebro, Sweden.