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  • 1.
    Ahlstrand, Erik
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Division of Hematology.
    Hellmark, Bengt
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology.
    Svensson, Karolina
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology.
    Long-term molecular epidemiology of staphylococcus epidermidis blood culture isolates from patients with hematological malignancies2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, e99045Article in journal (Refereed)
    Abstract [en]

    Staphylococcus epidermidis is an important cause of bloodstream infections in patients with hematological malignancies. Knowledge of the long-term epidemiology of these infections is limited. We surveyed all S. epidermidis blood culture isolates from patients treated for hematological malignancies at the University Hospital of Orebro, Sweden from 1980 to 2009. A total of 373 S. epidermidis isolates were identified and multilocus sequence typing, staphylococcal chromosome cassette mec (SCCmec) typing and standard antibiotic susceptibility testing were employed to characterize these isolates. The majority of the isolates 361/373 (97%) belonged to clonal complex 2, and the 373 isolates were divided into 45 sequence types (STs); Simpson's Diversity Index was 0.56. The most prevalent STs were ST2 (243/373, 65%) and ST215 (28/373, 8%). Ninety three percent (226/243) of the ST2 isolates displayed either SCCmec type III or IV. ST2 and 215 were isolated during the entire study period, and together these STs caused temporal peaks in the number of positive blood cultures of S. epidermidis. Methicillin resistance was detected in 213/273 (78%) of all isolates. In the two predominating STs, ST2 and ST215, methicillin resistance was detected in 256/271 isolates (95%), compared with 34/100 (34%) in other STs (p<0.001). In conclusion, in this long-term study of patients with hematological malignancies, we demonstrate a predominance of methicillin-resistant ST2 among S. epidermidis blood culture isolates.

  • 2.
    Ahmadi, Zainab
    et al.
    Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, Sweden.
    Sundh, Josefin
    Örebro University, School of Medical Sciences. Department of Respiratory Medicine.
    Bornefalk-Hermansson, Anna
    Department of Statistics, Uppsala University, Uppsala, Sweden.
    Ekström, Magnus
    Department of Clinical Sciences, Division of Respiratory Medicine & Allergology, Lund University, Lund, Sweden.
    Long-Term Oxygen Therapy 24 vs 15 h/day and Mortality in Chronic Obstructive Pulmonary Disease2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, e0163293Article in journal (Refereed)
    Abstract [en]

    Long-term oxygen therapy (LTOT) ≥ 15 h/day improves survival in hypoxemic chronic obstructive pulmonary disease (COPD). LTOT 24 h/day is often recommended but may pose an unnecessary burden with no clear survival benefit compared with LTOT 15 h/day. The aim was to test the hypothesis that LTOT 24 h/day decreases all-cause, respiratory, and cardiovascular mortality compared to LTOT 15 h/day in hypoxemic COPD. This was a prospective, observational, population-based study of COPD patients starting LTOT between October 1, 2005 and June 30, 2009 in Sweden. Overall and cause-specific mortality was analyzed using Cox and Fine-Gray regression, controlling for age, sex, prescribed oxygen dose, PaO2 (air), PaCO2 (air), Forced Expiratory Volume in one second (FEV1), WHO performance status, body mass index, comorbidity, and oral glucocorticoids. A total of 2,249 included patients were included with a median follow-up of 1.1 years (interquartile range, 0.6-2.1). 1,129 (50%) patients died and no patient was lost to follow-up. Higher LTOT duration analyzed as a continuous variable was not associated with any change in mortality rate (hazard ratio [HR] 1.00; (95% confidence interval [CI], 0.98 to 1.02) per 1 h/day increase above 15 h/day. LTOT exactly 24 h/day was prescribed in 539 (24%) patients and LTOT 15-16 h/day in 1,231 (55%) patients. Mortality was similar between the groups for all-cause, respiratory and cardiovascular mortality. In hypoxemic COPD, LTOT 24 h/day was not associated with a survival benefit compared with treatment 15-16 h/day. A design for a registry-based randomized trial (R-RCT) is proposed.

  • 3.
    Akhras, Michael S.
    et al.
    Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA..
    Pettersson, Erik
    Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA..
    Diamond, Lisa
    Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA..
    Unemo, Magnus
    Örebro University Hospital.
    Okamoto, Jennifer
    Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.;Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA..
    Davis, Ronald W.
    Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA..
    Pourmand, Nader
    Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA..
    The Sequencing Bead Array (SBA), a Next-Generation Digital Suspension Array2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, UNSP e76696Article in journal (Refereed)
    Abstract [en]

    Here we describe the novel Sequencing Bead Array (SBA), a complete assay for molecular diagnostics and typing applications. SBA is a digital suspension array using Next-Generation Sequencing (NGS), to replace conventional optical readout platforms. The technology allows for reducing the number of instruments required in a laboratory setting, where the same NGS instrument could be employed from whole-genome and targeted sequencing to SBA broad-range biomarker detection and genotyping. As proof-of-concept, a model assay was designed that could distinguish ten Human Papillomavirus (HPV) genotypes associated with cervical cancer progression. SBA was used to genotype 20 cervical tumor samples and, when compared with amplicon pyrosequencing, was able to detect two additional co-infections due to increased sensitivity. We also introduce in-house software Sphix, enabling easy accessibility and interpretation of results. The technology offers a multi-parallel, rapid, robust, and scalable system that is readily adaptable for a multitude of microarray diagnostic and typing applications, e. g. genetic signatures, single nucleotide polymorphisms (SNPs), structural variations, and immunoassays. SBA has the potential to dramatically change the way we perform probe-based applications, and allow for a smooth transition towards the technology offered by genomic sequencing.

  • 4.
    Almon, Ricardo
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Alvarez-Leon, Elisa Eva
    Preventive Medicine Service, Canary Health Service, Department of Clinical Sciences, Faculty of Health Sciences, University of Las Palmas de Gran Canaria, Canary Islands, Spain.
    Serra-Majem, Lluis
    Preventive Medicine Service, Canary Health Service, Department of Clinical Sciences, Faculty of Health Sciences, University of Las Palmas de Gran Canaria, Canary Islands, Spain.
    Association of the European lactase persistence variant (LCT-13910 C > T Polymorphism) with obesity in the Canary Islands2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, e43978Article in journal (Refereed)
    Abstract [en]

    Background: European lactose tolerance genotype (LCT -13910 C>T, rs4988234) has been positively associated to body mass indexes (BMI) in a meta-analysis of 31,720 individuals of northern and central European descent. A strong association of lactase persistence (LP) with BMI and obesity has also been traced in a Spanish Mediterranean population. The aim of this study was to analyze a potential association of LP compared to lactase non-persistence (LNP) with BMI in inhabitants of the Canary Islands of Spain using Mendelian randomization.

    Methods: A representative, randomly sampled population of adults belonging to the Canary Islands Nutrition Survey (ENCA) in Spain, aged 18-75 years (n = 551), was genotyped for the LCT - 13910 C>T polymorphism. Milk consumption was assessed by a validated questionnaire. Anthropometric variables were directly measured. WHO classification of BMI was used.

    Results: LP individuals were significantly more obese than LNP subjects (chi(2) = 10.59; p < 0.005). LP showed in a multivariate linear regression analysis showed a positive association of LP with BMI compared to LNP, (beta = 0.96; 95% CI: 0.08-1.85, p = 0.033). In a multinomial logistic regression analysis normal range weight LP subjects showed an odds ratio for obesity of 2.41; 95% CI 1.39-418, (p = 0.002) compared to LNP.

    Conclusions: The T-13910 of the allele LCT-13910 C>T polymorphism is positively associated with BMI. LP increases significantly the risk to develop obesity in the studied population. The LCT-13910 C>T polymorphism stands proxy for the lifetime exposure pattern, milk intake, that may increase susceptibility to obesity and to obesity related pathologies.

  • 5.
    Alpkvist, Helena
    et al.
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Athlin, Simon
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Infectious Diseases.
    Naucler, Pontus
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Herrmann, Björn
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Abdeldaim, Guma
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Department of Medical Microbiology and Parasitology, Faculty of Medicine, Benghazi University, Benghazi, Libya.
    Slotved, Hans-Christian
    Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Hedlund, Jonas
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Strålin, Kristoffer
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Clinical and Microbiological Factors Associated with High Nasopharyngeal Pneumococcal Density in Patients with Pneumococcal Pneumonia2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, e0140112Article in journal (Refereed)
    Abstract [en]

    Background: We aimed to study if certain clinical and/or microbiological factors are associated with a high nasopharyngeal (NP) density of Streptococcus pneumoniae in pneumococcal pneumonia. In addition, we aimed to study if a high NP pneumococcal density could be useful to detect severe pneumococcal pneumonia.

    Methods: Adult patients hospitalized for radiologically confirmed community-acquired pneumonia were included in a prospective study. NP aspirates were collected at admission and were subjected to quantitative PCR for pneumococcal DNA (Spn9802 DNA). Patients were considered to have pneumococcal etiology if S. pneumoniae was detected in blood culture and/ or culture of respiratory secretions and/or urinary antigen test.

    Results: Of 166 included patients, 68 patients had pneumococcal DNA detected in NP aspirate. Pneumococcal etiology was noted in 57 patients (84%) with positive and 8 patients (8.2%) with negative test for pneumococcal DNA (p<0.0001). The median NP pneumococcal density of DNA positive patients with pneumococcal etiology was 6.83 log(10) DNA copies/mL (range 1.79-9.50). In a multivariate analysis of patients with pneumococcal etiology, a high pneumococcal density was independently associated with severe pneumonia (Pneumonia Severity Index risk class IV-V), symptom duration >= 2 days prior to admission, and a medium/high serum immunoglobulin titer against the patient's own pneumococcal serotype. NP pneumococcal density was not associated with sex, age, smoking, co-morbidity, viral co-infection, pneumococcal serotype, or bacteremia. Severe pneumococcal pneumonia was noted in 28 study patients. When we studied the performance of PCR with different DNA cut-off levels for detection of severe pneumococcal pneumonia, we found sensitivities of 54-82% and positive predictive values of 37-56%, indicating suboptimal performance.

    Conclusions: Pneumonia severity, symptom duration similar to 2 days, and a medium/high serum immunoglobulin titer against the patient's own serotype were independently associated with a high NP pneumococcal density. NP pneumococcal density has limited value for detection of severe pneumococcal pneumonia.

  • 6.
    Andersson, Erik
    et al.
    Örebro University, School of Medical Sciences. School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bergemalm, Daniel
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Neumann, Gunter
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    D'Amato, Mauro
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; BioDonostia Health Research Institute, San Sebastian, Spain; IKERBA SQUE Basque Foundation for Science, Bilbao, Spain.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Subphenotypes of inflammatory bowel disease are characterized by specific serum protein profiles2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 10, e0186142Article in journal (Refereed)
    Abstract [en]

    Objective: Genetic and immunological data indicate that inflammatory bowel disease (IBD) are characterized by specific inflammatory protein profiles. However, the serum proteome of IBD is still to be defined. We aimed to characterize the inflammatory serum protein profiles of Crohn's disease (CD) and ulcerative colitis (UC), using the novel proximity extension assay.

    Methods: A panel of 91 inflammatory proteins were quantified in a discovery cohort of CD (n = 54), UC patients (n = 54), and healthy controls (HCs; n = 54). We performed univariate analyses by t-test, with false discovery rate correction. A sparse partial least-squares (sPLS) approach was used to identify additional discriminative proteins. The results were validated in a replication cohort.

    Results: By univariate analysis, 17 proteins were identified with significantly different abundances in CD and HCs, and 12 when comparing UC and HCs. Additionally, 64 and 45 discriminant candidate proteins, respectively, were identified with the multivariate approach. Correspondingly, significant cross-validation error rates of 0.12 and 0.19 were observed in the discovery cohort. Only FGF-19 was identified from univariate comparisons of CD and UC, but 37 additional discriminant candidates were identified using the multivariate approach. The observed cross-validation error rate for CD vs. UC remained significant when restricting the analyses to patients in clinical remission. Using univariate comparisons, 16 of 17 CD-associated proteins and 8 of 12 UC-associated proteins were validated in the replication cohort. The area under the curve for CD and UC was 0.96 and 0.92, respectively, when the sPLS model from the discovery cohort was applied to the replication cohort.

    Conclusions: By using the novel PEA method and a panel of inflammatory proteins, we identified proteins with significantly different quantities in CD patients and UC patients compared to HCs. Our data highlight the potential of the serum IBD proteome as a source for identification of future diagnostic biomarkers.

  • 7.
    Andersson, Tommy
    et al.
    Örebro University, School of Medical Sciences. Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Magnuson, Anders
    Örebro University Hospital. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Bryngelsson, Ing-Liss
    Örebro University Hospital. Department of Occupational and Environmental Medicine, Örebro University, Örebro, Sweden.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Henriksson, Karin M.
    Department of Medical Science, Uppsala University, Uppsala, Sweden.
    Edvardsson, Nils
    Sahlgrenska Academy at Sahlgrenska University Hospital, Göteborg, Sweden.
    Poci, Dritan
    Örebro University, School of Medical Sciences. Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Patients with atrial fibrillation and outcomes of cerebral infarction in those with treatment of warfarin versus no warfarin with references to CHA(2)DS(2)-VASc score, age and sex: A Swedish nationwide observational study with 48 433 patients2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, e0176846Article in journal (Refereed)
    Abstract [en]

    Aims: There is controversy in the guidelines as to whether patients with atrial fibrillation and a low risk of stroke should be treated with anticoagulation, especially those with a CHA(2)DS(2)-VASc score of 1 point.

    Methods: In a retrospective, nationwide cohort study, we used the Swedish National Patient Registry, the National Prescribed Drugs Registry, the Swedish Registry of Education and the Population and Housing Census Registry. 48 433 patients were identified between 1 January 2006 and 31 December 2008 with incident atrial fibrillation who were divided in age categories, sex and a CHA(2)DS(2)-VASc score of 0, 1, 2 and >= 3 and they were included in a time-varying analysis of warfarin treatment versus no treatment. The primary end-point was cerebral infarction and stroke, and patients were followed until 31 December 2009.

    Results: Patients with 1 point from the CHA(2)DS(2)-VASc score showed the following adjusted hazard ratios (HR) with a 95% confidence interval: men 65-74 years 0.46 (0.25-0.83), men < 65 years 1.11 (0.56-2.23) and women < 65 years 2.13 (0.94-4.82), where HR < 1 indicates protection with warfarin. In patients < 65 years and 2 points, HR in men was 0.35 (0.18-0.69) and in women 1.84 (0.86-3.94) while, in women with at least 3 points, HR was 0.31 (0.16-0.59). In patients 65-74 years and 2 points, HR in men was 0.37 (0.23-0.59) and in women 0.39 ( 0.21-0.73). Categories including age >= 65 years or >= 3 points showed a statistically significant protection from warfarin.

    Conclusions: Our results support that treatment with anticoagulation may be considered in all patients with an incident atrial fibrillation diagnosis and an age of 65 years and older, i.e. also when the CHA(2)DS(2)-VASc score is 1.

  • 8.
    Andorf, Sandra
    et al.
    Department Genetics and Biometry, Bioinformatics and Biomathematics Group, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany; Department of Medicine, Institute for Biostatistics and Informatics in Medicine and Ageing Research, University of Rostock, Rostock, Germany.
    Meyer, Rhonda C
    Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Selbig, Joachim
    Bioinformatics Chair, Institute for Biochemistry and Biology, University of Potsdam, Potsdam, Germany.
    Altmann, Thomas
    Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
    Repsilber, Dirk
    Department Genetics and Biometry, Bioinformatics and Biomathematics Group, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Integration of a systems biological network analysis and QTL results for biomass heterosis in Arabidopsis thaliana2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, e49951Article in journal (Refereed)
    Abstract [en]

    To contribute to a further insight into heterosis we applied an integrative analysis to a systems biological network approach and a quantitative genetics analysis towards biomass heterosis in early Arabidopsis thaliana development. The study was performed on the parental accessions C24 and Col-0 and the reciprocal crosses. In an over-representation analysis it was tested if the overlap between the resulting gene lists of the two approaches is significantly larger than expected by chance. Top ranked genes in the results list of the systems biological analysis were significantly over-represented in the heterotic QTL candidate regions for either hybrid as well as regarding mid-parent and best-parent heterosis. This suggests that not only a few but rather several genes that influence biomass heterosis are located within each heterotic QTL region. Furthermore, the overlapping resulting genes of the two integrated approaches were particularly enriched in biomass related pathways. A chromosome-wise over-representation analysis gave rise to the hypothesis that chromosomes number 2 and 4 probably carry a majority of the genes involved in biomass heterosis in the early development of Arabidopsis thaliana.

  • 9. Anedda, Francesca
    et al.
    Zucchelli, Marco
    Schepis, Danika
    Hellquist, Anna
    Corrado, Lucia
    D'Alfonso, Sandra
    Achour, Adnane
    McInerney, Gerald
    Bertorello, Alejandro
    Lordal, Mikael
    Befrits, Ragnar
    Bjork, Jan
    Bresso, Francesca
    Torkvist, Leif
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences.
    Kere, Juha
    D'Amato, Mauro
    Multiple polymorphisms affect expression and function of the neuropeptide S receptor (NPSR1)2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, e29523- p.Article in journal (Refereed)
    Abstract [en]

    Background: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02). Principal Findings: we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk. Significance: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.

  • 10.
    Arnberg, Filip K.
    et al.
    Uppsala Univ, Dept Neurosci, Uppsala, Sweden.
    Linton, Steven J.
    Örebro University, School of Law, Psychology and Social Work.
    Hultcrantz, Monica
    Swedish Council Hlth Technol Assessment, Stockholm, Sweden.
    Heintz, Emelie
    Swedish Council Hlth Technol Assessment, Stockholm, Sweden; Linköping Univ, Dept Med & Hlth Sci, Ctr Med Technol Assessment CMT, Linköping, Sweden .
    Jonsson, Ulf
    Swedish Council Hlth Technol Assessment, Stockholm, Sweden; Karolinska Inst, Dept Clin Neurosci, Div Insurance Med, Stockholm, Sweden .
    Internet-delivered psychological treatments for mood and anxiety disorders: a systematic review of their efficacy, safety, and cost-effectiveness2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, e98118- p.Article in journal (Refereed)
    Abstract [en]

    Background: Greater access to evidence-based psychological treatments is needed. This review aimed to evaluate whether internet-delivered psychological treatments for mood and anxiety disorders are efficacious, noninferior to established treatments, safe, and cost-effective for children, adolescents and adults.

    Methods: We searched the literature for studies published until March 2013. Randomized controlled trials (RCTs) were considered for the assessment of short-term efficacy and safety and were pooled in meta-analyses. Other designs were also considered for long-term effect and cost-effectiveness. Comparisons against established treatments were evaluated for noninferiority. Two reviewers independently assessed the relevant studies for risk of bias. The quality of the evidence was graded using an international grading system.

    Results: A total of 52 relevant RCTs were identified whereof 12 were excluded due to high risk of bias. Five cost-effectiveness studies were identified and three were excluded due to high risk of bias. The included trials mainly evaluated internet-delivered cognitive behavioral therapy (I-CBT) against a waiting list in adult volunteers and 88% were conducted in Sweden or Australia. One trial involved children. For adults, the quality of evidence was graded as moderate for the short-term efficacy of I-CBT vs. waiting list for mild/moderate depression (d = 0.83; 95% CI 0.59, 1.07) and social phobia (d = 0.85; 95% CI 0.66, 1.05), and moderate for no efficacy of internet-delivered attention bias modification vs. sham treatment for social phobia (d = 20.04; 95% CI 20.24, 0.35). The quality of evidence was graded as low/very low for other disorders, interventions, children/adolescents, noninferiority, adverse events, and cost-effectiveness.

    Conclusions: I-CBT is a viable treatment option for adults with depression and some anxiety disorders who request this treatment modality. Important questions remain before broad implementation can be supported. Future research would benefit from prioritizing adapting treatments to children/adolescents and using noninferiority designs with established forms of treatment.

  • 11.
    Asghar, Naveed
    et al.
    School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden.
    Lindblom, Pontus
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Melik, Wessam
    School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden.
    Lindqvist, Richard
    Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden.
    Haglund, Mats
    Department of Infectious Diseases, County Hospital, Kalmar, Sweden.
    Forsberg, Pia
    Division of Infectious Diseases, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Clinic of Infectious Diseases, Linköping University Hospital, Linköping, Sweden.
    Överby, Anna K.
    Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden.
    Andreassen, Åshild
    Division of Infectious Disease Control, Department of Virology, Norwegian Institute of Public Health, Oslo, Norway.
    Lindgren, Per-Eric
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Division of Medical Services, Department of Microbiology, County Hospital Ryhov, Jönköping, Sweden.
    Johansson, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden; RiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Tick-Borne Encephalitis Virus Sequenced Directly from Questing and Blood-Feeding Ticks Reveals Quasispecies Variance2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, e103264Article in journal (Refereed)
    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 control strains, 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 resequenced 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.

  • 12.
    Assadi, Ghazaleh
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden .
    Vesterlund, Liselotte
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bonfiglio, Ferdinando
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Mazzurana, Luca
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Cordeddu, Lina
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Schepis, Danika
    Rheumatology unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden .
    Mjösberg, Jenny
    Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden .
    Ruhrmann, Sabrina
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Fabbri, Alessia
    Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy .
    Vukojevic, Vladana
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Percipalle, Piergiorgio
    Biology Program, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Salomons, Florian A.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Laurencikiene, Jurga
    Lipid laboratory, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Törkvist, Leif
    Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden .
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    D'Amato, Mauro
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain .
    Functional Analyses of the Crohn's Disease Risk Gene LACC12016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, e0168276Article in journal (Refereed)
    Abstract [en]

    Background: Genetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression.

    Methods: We implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function.

    Results: FAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems.

    Conclusion: FAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.

  • 13.
    Bang, Charlotte Sahlberg
    et al.
    Örebro University, School of Health Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Persson, Katarina
    Örebro University, School of Medical Sciences.
    Global gene expression profiling and antibiotic susceptibility after repeated exposure to the carbon monoxide-releasing molecule-2 (CORM-2) in multidrug-resistant ESBL-producing uropathogenic Escherichia coli2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, e0178541Article in journal (Refereed)
    Abstract [en]

    Treatment of urinary tract infections is today a challenge due to the increasing prevalence of multidrug-resistant ESBL-producing uropathogenic Escherichia coli (UPEC). There is an urgent need for new treatment strategies for multidrug-resistant UPEC and preferably with targets that have low potential for development of resistance. Carbon monoxide-releasing molecules (CORMs) are novel and potent antibacterial agents. The present study examines the transcriptomic targets of CORM-2 in a multidrug-resistant ESBL-producing UPEC isolate in response to a single exposure to CORM-2 and after repeated exposure to CORM-2. The bacterial viability and minimal inhibitory concentration (MIC) were also examined after repeated exposure to CORM-2. Microarray analysis revealed that a wide range of processes were affected by CORM-2, including a general trend of down-regulation in energy metabolism and biosynthesis pathways and up-regulation of the SOS response and DNA repair. Several genes involved in virulence (ibpB), antibiotic resistance (marAB, mdtABC) and biofilm formation (bhsA, yfgF) were up-regulated, while some genes involved in virulence (kpsC, fepCEG, entABE), antibiotic resistance (evgA) and biofilm formation (artIP) were down-regulated. Repeated exposure to CORM-2 did not alter the gene expression patterns, the growth inhibitory response to CORM-2 or the MIC values for CORM-2, cefotaxime, ciprofloxacin and trimethoprim. This study identifies several enriched gene ontologies, modified pathways and single genes that are targeted by CORM-2 in a multidrug-resistant UPEC isolate. Repeated exposure to CORM-2 did not change the gene expression patterns or fold changes and the susceptibility to CORM-2 remained after repeated exposure.

  • 14.
    Bejerot, Susanne
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Eriksson, Jonna M.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Sexuality and gender role in autism spectrum disorder: a case control study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, e87961Article in journal (Refereed)
    Abstract [en]

    The 'extreme male brain theory of autism' describes an extreme male pattern of cognitive traits defined as strong systemising abilities paired with empathising weaknesses in autism spectrum disorder. However, beyond these cognitive traits, clinical observations have suggested an ambiguous gender-typed pattern regarding several sexually dimorphic traits. The aim of the present study was to investigate if patterns of non-cognitive sexually dimorphic traits differed between the autism spectrum disorder and control groups. Fifty adults with autism spectrum disorder and intelligence within the normal range, and 53 neurotypical controls responded to questions on gender role, self-perceived gender typicality and gender identity, as well as sexuality. Measures used were a Swedish modification of the Bem Sex Role Inventory and questions on sexuality and gender designed for the purpose of this study. Our results showed that one common gender role emerged in the autism spectrum disorder group. Masculinity (e.g. assertiveness, leadership and competitiveness) was weaker in the autism spectrum disorder group than in the controls, across men and women. Self-perceived gender typicality did not differ between the groups but tomboyism and bisexuality were overrepresented amongst women with autism spectrum disorder. Lower libido was reported amongst both male and female participants with autism spectrum disorder compared with controls. We conclude that the extreme male patterns of cognitive functions in the autistic brain do not seem to extend to gender role and sexuality. A gender-atypical pattern for these types of characteristics is suggested in autism spectrum disorder.

  • 15.
    Bergemalm, Daniel
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Örebro University, School of Health Sciences. Department of Gastroenterology, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. School of Medical Sciences, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden.
    Sapnara, Maria
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden .
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden .
    Hultgren Hörnquist, Elisabeth
    Örebro University Hospital. Örebro University, School of Medical Sciences. School of Medical Sciences, Faculty of Medicine and Health, University of Örebro, Örebro, Sweden .
    Elevated fecal peptidase D at onset of colitis in Galphai2-/- mice, a mouse model of IBD.2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, e0174275Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The identification of novel fecal biomarkers in inflammatory bowel disease (IBD) is hampered by the complexity of the human fecal proteome. On the other hand, in experimental mouse models there is probably less variation. We investigated the fecal protein content in mice to identify possible biomarkers and pathogenic mechanisms.

    METHODS: Fecal samples were collected at onset of inflammation in Galphai2-/- mice, a well-described spontaneous model of chronic colitis, and from healthy littermates. The fecal proteome was analyzed by two-dimensional electrophoresis and quantitative mass spectrometry and results were then validated in a new cohort of mice.

    RESULTS: As a potential top marker of disease, peptidase D was found at a higher ratio in Galphai2-/- mouse feces relative to controls (fold change 27; p = 0.019). Other proteins found to be enriched in Gαi2-/- mice were mainly pancreatic proteases, and proteins from plasma and blood cells. A tendency of increased calprotectin, subunit S100-A8, was also observed (fold change 21; p = 0.058). Proteases are potential activators of inflammation in the gastrointestinal tract through their interaction with the proteinase-activated receptor 2 (PAR2). Accordingly, the level of PAR2 was found to be elevated in both the colon and the pancreas of Galphai2-/- mice at different stages of disease.

    CONCLUSIONS: These findings identify peptidase D, an ubiquitously expressed intracellular peptidase, as a potential novel marker of colitis. The elevated levels of fecal proteases may be involved in the pathogenesis of colitis and contribute to the clinical phenotype, possibly by activation of intestinal PAR2.

  • 16.
    Bergemalm, Daniel
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Sapnara, Maria
    Department of Microbiology and Immunology, University of Gothenburg, Institute of Biomedicine, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Institute of Medicine, Gothenburg, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Gastroenterology.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Elevated fecal peptidase D at onset of colitis in Galphai2(-/-) mice, a mouse model of IBD2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, e0174275Article in journal (Refereed)
    Abstract [en]

    Background: The identification of novel fecal biomarkers in inflammatory bowel disease (IBD) is hampered by the complexity of the human fecal proteome. On the other hand, in experimental mouse models there is probably less variation. We investigated the fecal protein content in mice to identify possible biomarkers and pathogenic mechanisms.

    Methods: Fecal samples were collected at onset of inflammation in Galphai2(-/-) mice, a well-described spontaneous model of chronic colitis, and from healthy littermates. The fecal proteome was analyzed by two-dimensional electrophoresis and quantitative mass spectrometry and results were then validated in a new cohort of mice.

    Results: As a potential top marker of disease, peptidase D was found at a higher ratio in Galphai24mouse feces relative to controls (fold change 27; p = 0.019). Other proteins found to be enriched in Gai2(-/-) mice were mainly pancreatic proteases, and proteins from plasma and blood cells. A tendency of increased calprotectin, subunit S100-A8, was also observed (fold change 21; p = 0.058). Proteases are potential activators of inflammation in the gastrointestinal tract through their interaction with the proteinase-activated receptor 2 (PAR2). Accordingly, the level of PAR2 was found to be elevated in both the colon and the pancreas of Galphai24- mice at different stages of disease.

    Conclusions: These findings identify peptidase D, an ubiquitously expressed intracellular peptidase, as a potential novel marker of colitis. The elevated levels of fecal proteases may be involved in the pathogenesis of colitis and contribute to the clinical phenotype, possibly by activation of intestinal PAR2.

  • 17.
    Bergström, Ida
    et al.
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden .
    Lundberg, Anna K
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Jönsson, Simon
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Clinical Medicine, School of Health and Medical Sciences, IRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ernerudh, Jan
    Department of Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Jonasson, Lena
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Annexin A1 in blood mononuclear cells from patients with coronary artery disease: Its association with inflammatory status and glucocorticoid sensitivity.2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, e0174177Article in journal (Refereed)
    Abstract [en]

    Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.

  • 18.
    Bergström, Ida
    et al.
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lundberg, Anna K.
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Jönsson, Simon
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. IRiSC - Inflammatory Response and Infection Susceptibility Centre.
    Ernerudh, Jan
    Department of Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Jonasson, Lena
    Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Annexin A1 in blood mononuclear cells from patients with coronary artery disease: Its association with inflammatory status and glucocorticoid sensitivity2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, e0174177Article in journal (Refereed)
    Abstract [en]

    Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.

  • 19.
    Bertrand, Yann J K
    et al.
    Science and Historical Investigations of Evolution Laboratory of Dubá, Dubá, Czech Republic.
    Johansson, Magnus
    Örebro University, School of Medical Sciences. School of Natural Science, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden; RiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Norberg, Peter
    Department of Clinical Microbiology, Sahlgrenska University, Gothenburg, Sweden.
    Revisiting Recombination Signal in the Tick-Borne Encephalitis Virus: A Simulation Approach2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, e0164435Article in journal (Refereed)
    Abstract [en]

    The hypothesis of wide spread reticulate evolution in Tick-Borne Encephalitis virus (TBEV) has recently gained momentum with several publications describing past recombination events involving various TBEV clades. Despite a large body of work, no consensus has yet emerged on TBEV evolutionary dynamics. Understanding the occurrence and frequency of recombination in TBEV bears significant impact on epidemiology, evolution, and vaccination with live vaccines. In this study, we investigated the possibility of detecting recombination events in TBEV by simulating recombinations at several locations on the virus' phylogenetic tree and for different lengths of recombining fragments. We derived estimations of rates of true and false positive for the detection of past recombination events for seven recombination detection algorithms. Our analytical framework can be applied to any investigation dealing with the difficult task of distinguishing genuine recombination signal from background noise. Our results suggest that the problem of false positives associated with low detection P-values in TBEV, is more insidious than generally acknowledged. We reappraised the recombination signals present in the empirical data, and showed that reliable signals could only be obtained in a few cases when highly genetically divergent strains were involved, whereas false positives were common among genetically similar strains. We thus conclude that recombination among wild-type TBEV strains may occur, which has potential implications for vaccination with live vaccines, but that these events are surprisingly rare.

  • 20.
    Bertrand, Yann
    et al.
    Univ Gothenburg, Dept Plant & Environm Sci, Gothenburg, Sweden.
    Töpel, Mats
    Univ Gothenburg, Dept Plant & Environm Sci, Gothenburg, Sweden.
    Elväng, Annelie
    Södertörn Univ, Sch Life Sci, Huddinge, Sweden.
    Melik, Wessam
    Södertörn Univ, Sch Life Sci, Huddinge, Sweden; Stockholm Univ, Dept Genet Microbiol & Toxicol, Stockholm, Sweden.
    Johansson, Magnus
    Södertörn Univ, Sch Life Sci, Huddinge, Sweden.
    First dating of a recombination event in mammalian tick-borne flaviviruses2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, e31981Article in journal (Refereed)
    Abstract [en]

    The mammalian tick-borne flavivirus group (MTBFG) contains viruses associated with important human and animal diseases such as encephalitis and hemorrhagic fever. In contrast to mosquito-borne flaviviruses where recombination events are frequent, the evolutionary dynamic within the MTBFG was believed to be essentially clonal. This assumption was challenged with the recent report of several homologous recombinations within the Tick-borne encephalitis virus (TBEV). We performed a thorough analysis of publicly available genomes in this group and found no compelling evidence for the previously identified recombinations. However, our results show for the first time that demonstrable recombination (i.e., with large statistical support and strong phylogenetic evidences) has occurred in the MTBFG, more specifically within the Louping ill virus lineage. Putative parents, recombinant strains and breakpoints were further tested for statistical significance using phylogenetic methods. We investigated the time of divergence between the recombinant and parental strains in a Bayesian framework. The recombination was estimated to have occurred during a window of 282 to 76 years before the present. By unravelling the temporal setting of the event, we adduce hypotheses about the ecological conditions that could account for the observed recombination.

  • 21.
    Bilbija, Dusan
    et al.
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Haugen, Fred
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Sagave, Julia
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Baysa, Anton
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Bastani, Nasser
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Levy, Finn Olav
    Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norwa.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Division of Biomedicine, Department of Clinical Medicine.
    Blomhoff, Rune
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway .
    Valen, Guro
    Department of Physiology, University of Oslo, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Retinoic acid signalling is activated in the postischemic heart and may influence remodelling2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, e44740Article in journal (Refereed)
    Abstract [en]

    Background: All-trans retinoic acid (atRA), an active derivative of vitamin A, regulates cell differentiation, proliferation and cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE).We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemic remodelling.

    Methods and Findings: Myocardial infarction was induced through ligating the left coronary artery in mice. In vivo cardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genes and proteins by real time RT-PCR and western blot. Endogenous retinoids in postinfarcted hearts were analysed by triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolated from infarcted and sham operated RARE luciferase reporter hearts and monitored for RAR activity and expression of target genes. The effect of atRA on CF proliferation was evaluated by EdU incorporation. Myocardial infarction increased thoracic RAR activity in vivo (p<0.001), which was ascribed to the heart through ex vivo imaging (p = 0.002) with the largest signal 1 week postinfarct. This was accompanied by increased cardiac gene and protein expression of the RAR target genes retinol binding protein 1 (p = 0.01 for RNA, p = 0,006 for protein) and aldehyde dehydrogenase 1A2 (p = 0.04 for RNA, p = 0,014 for protein), while gene expression of cytochrome P450 26B1 was downregulated (p = 0.007). Concomitantly, retinol accumulated in the infarcted zone (p = 0.02). CM and CF isolated from infarcted hearts had higher luminescence than those from sham operated hearts (p = 0.02 and p = 0.008). AtRA inhibited CF proliferation in vitro (p = 0.02).

    Conclusions: The RA signalling pathway is activated in postischemic hearts and may play a role in regulation of damage and repair during remodelling.

  • 22.
    Biswas, Animesh
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Centre for Injury Prevention and Research, Bangladesh (CIPRB), Dhaka.
    Rahman, Fazlur
    Centre for Injury Prevention and Research, Bangladesh (CIPRB), Dhaka.
    Eriksson, Charli
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Halim, Abdul
    Centre for Injury Prevention and Research, Bangladesh (CIPRB), Dhaka.
    Dalal, Koustuv
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Facility Death Review of Maternal and Neonatal Deaths in Bangladesh2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, e0141902Article in journal (Refereed)
    Abstract [en]

    Objectives: To explore the experiences, acceptance, and effects of conducting facility death review (FDR) of maternal and neonatal deaths and stillbirths at or below the district level in Bangladesh.

    Methods This was a qualitative study with healthcare providers involved in FDRs. Two districts were studied: Thakurgaon district (a pilot district) and Jamalpur district (randomly selected from three follow-on study districts). Data were collected between January and November 2011. Data were collected from focus group discussions, in-depth interviews, and document review. Hospital administrators, obstetrics and gynecology consultants, and pediatric consultants and nurses employed in the same departments of the respective facilities participated in the study. Content and thematic analyses were performed.

    Results: FDR for maternal and neonatal deaths and stillbirths can be performed in upazila health complexes at sub-district and district hospital levels. Senior staff nurses took responsibility for notifying each death and conducting death reviews with the support of doctors. Doctors reviewed the FDRs to assign causes of death. Review meetings with doctors, nurses, and health managers at the upazila and district levels supported the preparation of remedial action plans based on FDR findings, and interventions were planned accordingly. There were excellent examples of improved quality of care at facilities as a result of FDR. FDR also identified gaps and challenges to overcome in the near future to improve maternal and newborn health.

    Discussion: FDR of maternal and neonatal deaths is feasible in district and upazila health facilities. FDR not only identifies the medical causes of a maternal or neonatal death but also explores remediable gaps and challenges in the facility. FDR creates an enabled environment in the facility to explore medical causes of deaths, including the gaps and challenges that influence mortality. FDRs mobilize health managers at upazila and district levels to forward plan and improve healthcare delivery.

  • 23.
    Blomgran, Robert
    et al.
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Patcha Brodin, Veronika
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Verma, Deepti
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Bergström, Ida
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Söderkvist, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Sjöwall, Christopher
    Division of Rheumatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Eriksson, Per
    Division of Rheumatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Lerm, Maria
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Center for Infectious Medicine, Karolinska Institute Huddinge, Stockholm, Sweden .
    Stendahl, Olle
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden .
    Särndahl, Eva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Common genetic variations in the NALP3 inflammasome are associated with delayed apoptosis of human neutrophils2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, e31326Article in journal (Refereed)
    Abstract [en]

    Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1 beta production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages.

    Methods and Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients' neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response.

    Conclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.

  • 24.
    Bluhm, Kerstin
    et al.
    Department of Ecosystem Analysis, Institute for Environmental Research, Aachen Biology and Biotechnology, RWTH Aachen University, Aachen, Germany.
    Otte, Jens
    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
    Yang, Lee
    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
    Zinsmeister, Christian
    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
    Legradi, Jessica
    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute for Environmental Studies, VU University Amsterdam, Amsterdam, The Netherlands.
    Keiter, Steffen
    Department of Ecosystem Analysis, Institute for Environmental Research, Aachen Biology and Biotechnology, RWTH Aachen University, Aachen, Germany.
    Kosmehl, Thomas
    Aquatic Ecology and Toxicology Group, Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Braunbeck, Thomas
    Aquatic Ecology and Toxicology Group, Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Strähle, Uwe
    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
    Hollert, Henner
    Department of Ecosystem Analysis, Institute for Environmental Research, Aachen Biology and Biotechnology, RWTH Aachen University, Aachen, Germany; School of Environment, Nanjing University, Nanjing, China; Key Laboratory of Yangtze River Environment of Education Ministry of China, College of Environmental Science and Engineering, Tongji University, Shanghai, China; College of Resources and Environmental Science, Chongqing University, Chongqing, China.
    Impacts of Different Exposure Scenarios on Transcript Abundances in Danio rerio Embryos when Investigating the Toxicological Burden of Riverine Sediments2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, e106523Article in journal (Refereed)
    Abstract [en]

    Purpose: Recently, a proof-of-concept study revealed the suitability of transcriptome analyses to obtain and assess changes in the abundance of transcripts in zebrafish (Danio rerio) embryos after exposure to organic sediment extracts. The present study investigated changes in the transcript abundance in zebrafish embryos exposed to whole sediment samples and corresponding organic extracts in order to identify the impact of different exposure pathways on sediment toxicity.

    Materials and Methods: Danio rerio embryos were exposed to sublethal concentrations of three sediment samples from the Danube River, Germany. The sediment samples were investigated both as freeze-dried samples and as organic extracts. Silica dust and a process control of the extraction procedure were used as references. After exposure, mRNA was isolated and changes in profiles of gene expression levels were examined by an oligonucleotide microarray. The microarray results were compared with bioassays, chemical analysis of the sediments and profiles of gene expression levels induced by several single substances.

    Results and Discussion: The microarray approach elucidated significant changes in the abundance of transcripts in exposed zebrafish embryos compared to the references. Generally, results could be related to Ah-receptor-mediated effects asconfirmed by bioassays and chemical analysis of dioxin-like contaminants, as well as to exposure to stress-inducing compounds. Furthermore, the results indicated that mixtures of chemicals, as present in sediment and extract samples, result in complex changes of gene expression level profiles difficult to compare with profiles induced by single chemical substances. Specifically, patterns of transcript abundances were less influenced by the chemical composition at the sampling site compared t the method of exposure (sediment/extract). This effect might be related to different bioavailability of chemicals.

    Conclusions: The apparent difference between the exposure scenarios is an important aspect that needs to be addressed when conducting analyses of alterations in the expression level of mRNA.

  • 25.
    Boberg, Johanna B.
    et al.
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Forest Mycol & Plant Pathol, Uppsala, Sweden.
    Finlay, Roger D.
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Forest Mycol & Plant Pathol, Uppsala, Sweden.
    Stenlid, Jan
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Forest Mycol & Plant Pathol, Uppsala, Sweden.
    Ekblad, Alf
    Örebro University, School of Science and Technology.
    Lindahl, Björn D.
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Forest Mycol & Plant Pathol, Uppsala, Sweden.
    Nitrogen and Carbon Reallocation in Fungal Mycelia during Decomposition of Boreal Forest Litter2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, e92897- p.Article in journal (Refereed)
    Abstract [en]

    Boreal forests are characterized by spatially heterogeneous soils with low N availability. The decomposition of coniferous litter in these systems is primarily performed by basidiomycete fungi, which often form large mycelia with a well-developed capacity to reallocate resources spatially-an advantageous trait in heterogeneous environments. In axenic microcosm systems we tested whether fungi increase their biomass production by reallocating N between Pinus sylvestris (Scots pine) needles at different stages of decomposition. We estimated fungal biomass production by analysing the accumulation of the fungal cell wall compound chitin. Monospecific systems were compared with systems with interspecific interactions. We found that the fungi reallocated assimilated N and mycelial growth away from well-degraded litter towards fresh litter components. This redistribution was accompanied by reduced decomposition of older litter. Interconnection of substrates increased over-all fungal C use efficiency (i.e. the allocation of assimilated C to biomass rather than respiration), presumably by enabling fungal translocation of growth-limiting N to litter with higher C quality. Fungal connection between different substrates also restricted N-mineralization and production of dissolved organic N, suggesting that litter saprotrophs in boreal forest ecosystems primarily act to redistribute rather than release N. This spatial integration of different resource qualities was hindered by interspecific interactions, in which litters of contrasting quality were colonised by two different basidiomycete species. The experiments provide a detailed picture of how resource reallocation in two decomposer fungi leads to a more efficient utilisation of spatially separated resources under N-limitation. From an ecosystem point of view, such economic fungal behaviour could potentially contribute to organic matter accumulation in the litter layers of boreal forests.

  • 26.
    Cajander, Sara
    et al.
    Örebro University, School of Health Sciences. Department of Infectious Diseases.
    Tina, Elisabet
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Bäckman, Anders
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Strålin, Kristoffer
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden .
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Källman, Jan
    Örebro University, School of Medical Sciences. Department of Infectious Diseases.
    Quantitative Real-Time Polymerase Chain Reaction Measurement of HLA-DRA Gene Expression in Whole Blood Is Highly Reproducible and Shows Changes That Reflect Dynamic Shifts in Monocyte Surface HLA-DR Expression during the Course of Sepsis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, e0154690Article in journal (Refereed)
    Abstract [en]

    Introduction: A decrease in the expression of monocyte surface protein HLA-DR (mHLA-DR), measured by flow cytometry (FCM), has been suggested as a marker of immunosuppression and negative outcome in severe sepsis. However, FCM is not always available due to sample preparation that limits its use to laboratory operational hours. In this prospective study we evaluated dynamic changes in mHLA-DR expression during sepsis in relation to changes in HLA-DRA gene expression and Class II transactivator (CIITA), measured by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR).

    Aims: The aims of this study were: 1. to validate the robustness of qRT-PCR measurement of HLA-DRA- and CIITA-mRNA expression, in terms of reproducibility; and 2. to see if changes in expression of these genes reflect changes in mHLA-DR expression during the course of severe and non-severe bacteraemic sepsis.

    Methods and Findings: Blood samples were collected from 60 patients with bacteraemic sepsis on up to five occasions during Days 1-28 after hospital admission. We found the reproducibility of the qRT-PCR method to be high by demonstrating low threshold variations (<0.11 standard deviation (SD)) of the qRT-PCR system, low intra-assay variation of Ct-values within triplicates (≤0.15 SD) and low inter-assay variations (12%) of the calculated target gene ratios. Our results also revealed dynamic HLA-DRA expression patterns during the course of sepsis that reflected those of mHLA-DR measured by FCM. Furthermore, HLA-DRA and mHLA-DR recovery slopes in patients with non-severe sepsis differed from those in patients with severe sepsis, shown by mixed model for repeated measurements (p<0.05). However, during the first seven days of sepsis, PCR-measurements showed a higher magnitude of difference between the two sepsis groups. Mean differences (95% CI) between severe sepsis (n = 20) and non-severe sepsis (n = 40) were; on day 1-2, HLA-DRA 0.40 (0.28-0.59) p<0.001, CIITA 0.48 (0.32-0.72) p = 0.005, mHLA-DR 0.63 (0.45-1.00) p = 0.04, day 7 HLA-DRA 0.59 (0.46-0.77) p<0.001, CIITA 0.56 (0.41-0.76) p<0.001, mHLA-DR 0.81 (0.66-1.00) p = 0.28.

    Conclusion: We conclude that qRT-PCR measurement of HLA-DRA expression is robust, and that this method appears to be preferable to FCM in identifying patients with severe sepsis that may benefit from immunostimulation.

  • 27.
    Cheng, Helen
    et al.
    Department of Psychology, University College London, London, United Kingdom; ESRC Centre for Learning and Life Chances in Knowledge Economies and Societies, Institute of Education, University of London, London, United Kingdom .
    Treglown, Luke
    Department of Psychology, University College London, London, United Kingdom; Department of Psychology, University of Bath, United Kingdom .
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Research Department of Epidemiology and Public Health, UCL, London, United Kingdom .
    Furnham, Adrian
    Department of Psychology, University College London, London, United Kingdom; Norwegian Business School, Oslo, Norway .
    Associations between familial factor, trait conscientiousness, gender and the occurrence of type 2 diabetes in adulthood: evidence from a British cohort2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, e0122701Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate social, familial, and psychological factors in influencing the occurrence of type 2 diabetes in adulthood.

    Method: Some 17,415 babies born in Great Britain in 1958 and followed up at 7, 11, 33, and 50 years of age. The prevalence of type 2 diabetes at age 50 years was the outcome measure.

    Results: Some 5,032 participants with data on parental social class, childhood cognitive ability tests scores at age 11 years, educational qualifications at age 33 years, personality traits, occupational levels, and type 2 diabetes (all measured at age 50 years) were included in the study. Available information also included whether cohort members' parents or siblings had diabetes. Using logistic regression analyses, results showed that sex (OR= 0.63: 0.42-0.92, p<. 05), family history (OR= 3.40: 1.76-6.55, p<. 01), and trait conscientiousness (OR= 0.76: 0.64-0.90, p<. 001) were all significantly and independently associated with the occurrence of type 2 diabetes in adulthood. It appears that the occurrence of type 2 diabetes is greater among men than women (4.3% vs 2.5%).

    Conclusion: Familial (genetic and non-genetic) and psychological factors are significantly associated with the prevalence of type 2 diabetes in adulthood.

  • 28.
    Choi, Hyunok
    et al.
    Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States.
    Schmidbauer, Norbert
    Norwegian Institute for Air Research, Kjeller, Norway.
    Sundell, Jan
    Department of Building Science, School of Architecture, Tsinghua University, Beijing, China.
    Hasselgren, Mikael
    Primary Care Research Unit, County Council of Värmland, Karlstad, Sweden.
    Spengler, John
    Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States.
    Bornehag, Carl-Gustaf
    Public Health Sciences, Karlstad University, Karlstad, Sweden; SP Technical Research Institute of Sweden, Borås, Sweden.
    Common household chemicals and the allergy risks in pre-school age children2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 10, e13423Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The risk of indoor exposure to volatile organic compounds (VOCs) on allergic airway diseases in children remains unknown.

    OBJECTIVE: We examined the residential concentrations of VOCs, emitted from building materials, paints, furniture, and other lifestyle practices and the risks of multiple allergic diseases as well as the IgE-sensitization in pre-school age children in Sweden.

    METHODS: In a case-control investigation (198 case children with asthma and allergy and 202 healthy controls), air samples were collected in the room where the child slept. The air samples were analyzed for the levels of eight classes of VOCs.

    RESULTS: A natural-log unit of summed propylene glycol and glycol ethers (PGEs) in bedroom air (equal to interquartile range, or 3.43 - 15.65 µg/m(3)) was associated with 1.5-fold greater likelihood of being a case (95% CI, 1.1 - 2.1), 1.5-fold greater likelihood of asthma (95% CI, 1.0 - 2.3), 2.8-fold greater likelihood of rhinitis (95% CI, 1.6 - 4.7), and 1.6-fold greater likelihood of eczema (95% CI, 1.1 - 2.3), accounting for gender, secondhand smoke, allergies in both parents, wet cleaning with chemical agents, construction period of the building, limonene, cat and dog allergens, butyl benzyl phthalate (BBzP), and di(2-ethylhexyl)phthalate (DEHP). When the analysis was restricted to the cases, the same unit concentration was associated with 1.8-fold greater likelihood of IgE-sensitization (95% CI, 1.1 - 2.8) compared to the non-IgE sensitized cases. No similar associations were found for the other classes of VOCs.

    CONCLUSION: We propose a novel hypothesis that PGEs in indoor air exacerbate and/or induce the multiple allergic symptoms, asthma, rhinitis and eczema, as well as IgE sensitization respectively.

  • 29.
    Crommert, Martin Eriksson
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. The Swedish School of Sport and Health Sciences (GIH), Stockholm, Sweden.
    Halvorsen, K.
    School of Technology and Health, KTH Royal Institute of Technology, Stockholm, Sweden; Department of Information Technology, Uppsala University, Uppsala, Sweden.
    Ekblom, M. M.
    The Swedish School of Sport and Health Sciences (GIH), Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Trunk Muscle Activation at the Initiation and Braking of Bilateral Shoulder Flexion Movements of Different Amplitudes2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, e0141777Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate if trunk muscle activation patterns during rapid bilateral shoulder flexions are affected by movement amplitude. Eleven healthy males performed shoulder flexion movements starting from a position with arms along sides (0 degrees) to either 45 degrees, 90 degrees or 180 degrees. EMG was measured bilaterally from transversus abdominis (TrA), obliquus internus (OI) with intra-muscular electrodes, and from rectus abdominis (RA), erector spinae (ES) and deltoideus with surface electrodes. 3D kinematics was recorded and inverse dynamics was used to calculate the reactive linear forces and torque about the shoulders and the linear and angular impulses. The sequencing of trunk muscle onsets at the initiation of arm movements was the same across movement amplitudes with ES as the first muscle activated, followed by TrA, RA and OI. All arm movements induced a flexion angular impulse about the shoulders during acceleration that was reversed during deceleration. Increased movement amplitude led to shortened onset latencies of the abdominal muscles and increased level of activation in TrA and ES. The activation magnitude of TrA was similar in acceleration and deceleration where the other muscles were specific to acceleration or deceleration. The findings show that arm movements need to be standardized when used as a method to evaluate trunk muscle activation patterns and that inclusion of the deceleration of the arms in the analysis allow the study of the relationship between trunk muscle activation and direction of perturbing torque during one and the same arm movement.

  • 30.
    Daskalopoulou, Marina
    et al.
    Department of Infection & Population Health, University College London, London, United Kingdom.
    George, Julie
    Farr Institute of Health Informatics Research, University College London, London, United Kingdom.
    Walters, Kate
    Department of Primary Care & Population Health, University College London, London, United Kingdom.
    Osborn, David P.
    Division of Psychiatry, University College London, London, United Kingdom.
    Batty, G. David
    Department of Epidemiology & Public Health, University College London, London, United Kingdom.
    Stogiannis, Dimitris
    Farr Institute of Health Informatics Research, University College London, London, United Kingdom.
    Rapsomaniki, Eleni
    Farr Institute of Health Informatics Research, University College London, London, United Kingdom.
    Pujades-Rodriguez, Mar
    Farr Institute of Health Informatics Research, University College London, London, United Kingdom.
    Denaxas, Spiros
    Farr Institute of Health Informatics Research, University College London, London, United Kingdom.
    Udumyan, Ruzan
    Örebro University, School of Health Sciences. Clinical Epidemiology and Biostatistics.
    Kivimaki, Mika
    Department of Epidemiology & Public Health, University College London, London, United Kingdom.
    Hemingway, Harry
    Farr Institute of Health Informatics Research, University College London, London, United Kingdom.
    Depression as a Risk Factor for the Initial Presentation of Twelve Cardiac, Cerebrovascular, and Peripheral Arterial Diseases: Data Linkage Study of 1.9 Million Women and Men2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, e0153838Article in journal (Refereed)
    Abstract [en]

    Background: Depression is associated with coronary heart disease and stroke, but associations with a range of pathologically diverse cardiovascular diseases are not well understood. We examine the risk of 12 cardiovascular diseases according to depression status (history or new onset).

    Methods: Cohort study of 1,937,360 adult men and women, free from cardiovascular disease at baseline, using linked UK electronic health records between 1997 and 2010. The exposures were new-onset depression (a new GP diagnosis of depression and/or prescription for antidepressants during a one-year baseline), and history of GP-diagnosed depression before baseline. The primary endpoint was initial presentation of 12 cardiovascular diseases after baseline. We used disease-specific Cox proportional hazards models with multiple imputation adjusting for cardiovascular risk factors (age, sex, socioeconomic status, smoking, blood pressure, diabetes, cholesterol).

    Results: Over a median [IQR] 6.9 [2.1-10.5] years of follow-up, 18.9% had a history of depression and 94,432 incident cardiovascular events occurred. After adjustment for cardiovascular risk factors, history of depression was associated with: stable angina (Hazard Ratio = 1.38, 95%CI 1.32-1.45), unstable angina (1.70, 1.60-1.82), myocardial infarction (1.21, 1.16-1.27), unheralded coronary death (1.23, 1.14-1.32), heart failure (1.18, 1.13-1.24), cardiac arrest (1.14, 1.03-1.26), transient ischemic attack (1.31, 1.25-1.38), ischemic stroke (1.26, 1.18-1.34), subarachnoid haemorrhage (1.17, 1.01-1.35), intracerebral haemorrhage (1.30, 1.17-1.45), peripheral arterial disease (1.24, 1.18-1.30), and abdominal aortic aneurysm (1.12,1.01-1.24). New onset depression developed in 2.9% of people, among whom 63,761 cardiovascular events occurred. New onset depression was similarly associated with each of the 12 diseases, with no evidence of stronger associations compared to history of depression. The strength of association between depression and these cardiovascular diseases did not differ between women and men.

    Conclusions: Depression was prospectively associated with cardiac, cerebrovascular, and peripheral diseases, with no evidence of disease specificity. Further research is needed in understanding the specific pathophysiology of heart and vascular disease triggered by depression in healthy populations.

  • 31.
    De Craemer, Marieke
    et al.
    Ghent University, Ghent, Belgium.
    Lateva, Mina
    Medical University Varna, Varna, Bulgaria.
    Iotova, Violeta
    Medical University Varna, Varna, Bulgaria.
    De Decker, Ellen
    Ghent University, Ghent, Belgium.
    Verloigne, Maite
    Ghent University, Ghent, Belgium; Research Foundation Flanders, Brussels, Belgium.
    De Bourdeaudhuij, Ilse
    Ghent University, Ghent, Belgium.
    Androutsos, Odysseas
    Harokopio University, Athens, Greece.
    Socha, Piotr
    Children’s Memorial Health Institute, Warsaw, Poland.
    Kulaga, Zbigniew
    Children’s Memorial Health Institute, Warsaw, Poland.
    Moreno, Luis
    University of Zaragoza, Zaragoza, Spain.
    Koletzko, Berthold
    University of Munich Medical Centre, Munich, Germany.
    Manios, Yannis
    Harokopio University, Athens, Greece.
    Cardon, Greet
    Ghent University, Ghent, Belgium.
    Differences in Energy Balance-Related Behaviours in European Preschool Children: The ToyBox-Study2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, e0118303Article in journal (Refereed)
    Abstract [en]

    Background: The aim of the current study was to compare levels of energy balance-related behaviours (physical activity, sedentary behaviour, and dietary behaviours (more specifically water consumption, sugar-sweetened beverage consumption and unhealthy snacking)) in four-to six-year-old preschoolers from six European countries (Belgium, Bulgaria, Germany, Greece, Poland, and Spain) within the ToyBox cross-sectional study.

    Methods: A sample of 4,045 preschoolers (4.77 +/- 0.43 years; 52.2% boys) had valid physical activity data (steps per day), parents of 8,117 preschoolers (4.78 +/- 0.46 years; 53.0% boys) completed a parental questionnaire with questions on sedentary behaviours (television viewing, computer use, and quiet play), and parents of 7,244 preschoolers (4.77 +/- 0.44 years; 52.0% boys) completed a food frequency questionnaire with questions on water consumption, sugar-sweetened beverage consumption and unhealthy snacking.

    Results: The highest levels of physical activity were found in Spain (12,669 steps/day on weekdays), while the lowest levels were found in Bulgaria and Greece (9,777 and 9,656 steps/day on weekdays, respectively). German preschoolers spent the least amount of time in television viewing (43.3 min/day on weekdays), while Greek preschoolers spent the most time in television viewing (88.5 min/day on weekdays). A considerable amount of time was spent in quiet play in all countries, with the highest levels in Poland (104.9 min/day on weekdays), and the lowest levels in Spain (60.4 min/day on weekdays). Belgian, German, and Polish preschoolers had the lowest intakes of water and the highest intakes of sugar-sweetened beverages. The intake of snacks was the highest in Belgian preschoolers (73.1 g/day) and the lowest in Greek preschoolers (53.3 g/day).

    Conclusions: Across six European countries, differences in preschoolers' energy balance-related behaviours were found. Future interventions should target European preschoolers' energy balance-related behaviours simultaneously, but should apply country-specific adaptations.

  • 32.
    Ekici, Halime
    et al.
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden,.
    Amogne, Wondwossen
    Department of Medicine, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Aderaye, Getachew
    Department of Medicine, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Lindquist, Lars
    Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Sonnerborg, Anders
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Abdurahman, Samir
    Örebro University, School of Science and Technology. Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
    Minority drug-resistant HIV-1 variants in treatment Naive East-African and Caucasian patients detected by allele-specific real-time PCR2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, e111042- p.Article in journal (Refereed)
    Abstract [en]

    Objective: To assess the presence of two major non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance mutations (DRMs), Y181C and K103N, in minor viral quasispecies of treatment naive HIV-1 infected East-African and Swedish patients by allele-specific polymerase chain reaction (AS-PCR).

    Methods: Treatment naive adults (n = 191) with three epidemiological backgrounds were included: 92 Ethiopians living in Ethiopia; 55 East-Africans who had migrated to Sweden; and 44 Caucasians living in Sweden. The pol gene was analysed by standard population sequencing and by AS-PCR for the detection of Y181C and K103N.

    Results: The Y181C was detected in the minority quasispecies of six Ethiopians (6.5%), in two Caucasians (4.5%), and in one East-African (1.8%). The K103N was detected in one East-African (1.8%), by both methods. The proportion of mutants ranged from 0.25% to 17.5%. Additional DRMs were found in all three treatment naive patient groups by population sequencing.

    Conclusions: Major NNRTI mutations can be found by AS-PCR in minor quasispecies of treatment naive HIV-1 infected Ethiopians living in Ethiopia, in East-African and Caucasian patients living in Sweden in whom population sequencing reveal wild-type virus only. Surveys with standard sequencing are likely to underestimate transmitted drug resistance and the presence of resistant minor quasispecies in treatment naive patients should be topic for future large scale studies.

  • 33.
    Elgbratt, Kristina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jansson, Andreas
    Systems Biology Research Centre, University of Skövde, Skövde, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    A quantitative study of the mechanisms behind thymic atrophy in G alpha i2-deficient mice during colitis development2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, e36726Article in journal (Refereed)
    Abstract [en]

    Mice deficient for the G protein subunit G alpha i2 spontaneously develop colitis, a chronic inflammatory disease associated with dysregulated T cell responses. We and others have previously demonstrated a thymic involution in these mice and an aberrant thymocyte dynamics. The G alpha i2(-/-) mice have a dramatically reduced fraction of double positive thymocytes and an increased fraction of single positive (SP) thymocytes. In this study, we quantify a number of critical parameters in order to narrow down the underlying mechanisms that cause the dynamical changes of the thymocyte development in the G alpha i2(-/-) mice. Our data suggest that the increased fraction of SP thymocytes results only from a decreased number of DP thymocytes, since the number of SP thymocytes in the Gai2(-/-) mice is comparable to the control littermates. By measuring the frequency of T cell receptor excision circles (TRECs) in the thymocytes, we demonstrate that the number of cell divisions the G alpha i2(-/-) SP thymocytes undergo is comparable to SP thymocytes from control littermates. In addition, our data show that the mature SP CD4(+) and CD8(+) thymocytes divide to the same extent before they egress from the thymus. By estimating the number of peripheral TREC+ T lymphocytes and their death rate, we could calculate the daily egression of thymocytes. G alpha i2(-/-) mice with no/mild and moderate colitis were found to have a slower export rate in comparison to the control littermates. The quantitative measurements in this study suggest a number of dynamical changes in the thymocyte development during the progression of colitis.

  • 34.
    Elmabsout, Ali Ateia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kumawat, Ashok K.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Saenz-Méndez, Patricia
    Computational Chemistry and Biology Group, Facultad de Química, UdelaR, Montevideo, Uruguay.
    Krivospitskaya, Olesya
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sävenstrand, Helena
    Örebro University, School of Science and Technology.
    Olofsson, Peder S.
    Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden; Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.
    Eriksson, Leif A.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Valen, Guro
    Department of Physiology, Institute of Basic Medical Science and Center for Heart Failure Research, University of Oslo, Oslo, Norway.
    Törmä, Hans
    Department of Medical Sciences, Dermatology and Venereology, Uppsala University, Uppsala, Sweden.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Cloning and functional studies of a splice variant of CYP26B1 expressed in vascular cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, e36839Article in journal (Refereed)
    Abstract [en]

    Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene.

    Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells.

    Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the fulllength enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

  • 35. Erickson, Alison R
    et al.
    Cantarel, Brandi L
    Lamendella, Regina
    Darzi, Youssef
    Mongodin, Emmanuel F
    Pan, Chongle
    Shah, Manesh
    Halfvarson, Jonas
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Internal Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Internal Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Henrissat, Bernard
    Raes, Jeroen
    Verberkmoes, Nathan C
    Fraser, Claire M
    Hettich, Robert L
    Jansson, Janet K
    Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, e49138Article in journal (Refereed)
    Abstract [en]

    Crohn's disease (CD) is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD) or colon (CCD). Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers.

  • 36.
    Evans, Alina L.
    et al.
    Department of Forestry and Wildlife Management, Hedmark University College, Campus Evenstad, Elverum, Norway; Section of Arctic Veterinary Medicine, Norwegian School of Veterinary Science, Tromsø, Norway.
    Sahlén, Veronica
    Department of Ecology and Natural Resource Management, Norwegian University of Life Sciences, Ås, Norway.
    Stoen, Ole-Gunnar
    Department of Ecology and Natural Resource Management, Norwegian University of Life Sciences, Ås, Norway; Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Fahlman, Åsa
    Section of Anesthesiology, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden; Department of Veterinary Clinical and Diagnostic Sciences, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
    Brunberg, Sven
    Department of Ecology and Natural Resource Management, Norwegian University of Life Sciences, Ås, Norway.
    Madslien, Knut
    Section for Wildlife Health, National Veterinary Institute, Oslo, Norway.
    Fröbert, Ole
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Cardiology.
    Swenson, Jon E.
    Department of Ecology and Natural Resource Management, Norwegian University of Life Sciences, Ås, Norway; Norwegian Institute for Nature Research, Trondheim, Norway.
    Arnemo, Jon M.
    Department of Forestry and Wildlife Management, Hedmark University College, Campus Evenstad, Elverum, Norway; Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Capture, Anesthesia, and Disturbance of Free-Ranging Brown Bears (Ursus arctos) during Hibernation2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, e40520Article in journal (Refereed)
    Abstract [en]

    We conducted thirteen immobilizations of previously collared hibernating two-to four-year-old brown bears (Ursus arctos) weighing 21-66 kg in central Sweden in winter 2010 and 2011 for comparative physiology research. Here we report, for the first time, an effective protocol for the capture and anesthesia of free-ranging brown bears during hibernation and an assessment of the disturbance the captures caused. Bears were darted in anthill, soil, or uprooted tree dens on eleven occasions, but two bears in rock dens fled and were darted outside the den. We used medetomidine at 0.02-0.06 mg/kg and zolazepam-tiletamine at 0.9-2.8 mg/kg for anesthesia. In addition, ketamine at 1.5 mg/kg was hand-injected intramuscularly in four bears and in six it was included in the dart at 1.1-3.0 mg/kg. Once anesthetized, bears were removed from the dens. In nine bears, arterial blood samples were analyzed immediately with a portable blood gas analyzer. We corrected hypoxemia in seven bears (PaO2 57-74 mmHg) with supplemental oxygen. We placed the bears back into the dens and antagonized the effect of medetomidine with atipamezole. Capturing bears in the den significantly increased the risk of den abandonment. One of twelve collared bears that were captured remained at the original den until spring, and eleven, left their dens (mean +/- standard deviation) 3.2 +/- 3.6 (range 0.5-10.5) days after capture. They used 1.9 +/- 0.9 intermediate resting sites, during 6.2 +/- 7.8 days before entering a new permanent den. The eleven new permanent dens were located 730 +/- 589 m from the original dens. We documented that it was feasible and safe to capture hibernating brown bears, although they behaved differently than black bears. When doing so, researchers should use 25% of the doses used for helicopter darting during the active period and should consider increased energetic costs associated with den abandonment.

  • 37.
    Fang, Fang
    et al.
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Kasperzyk, Julie L.
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Shui, Irene
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Hendrickson, Whitney
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Hollis, Bruce W.
    Department of Pediatrics, Medical University of South Carolina, USA.
    Fall, Katja
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Clinical Epidemiology and Biostatistics Unit, Örebro University Hospital, Örebro.
    Ma, Jing
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Gaziano, J. Michael
    Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital, Boston, USA; Massachusetts Veteran's Epidemiology, Research and Information Center, Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Boston, USA.
    Stampfer, Meir J.
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Nutrition, Harvard School of Public Health, Boston, USA.
    Mucci, Lorelei A.
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Giovannucci, Edward
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Nutrition, Harvard School of Public Health, Boston, USA.
    Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, e18625Article in journal (Refereed)
    Abstract [en]

    Background: Laboratory evidence suggests that vitamin D might influence prostate cancer prognosis.

    Methodology/principal findings: We examined the associations between prediagnostic plasma levels of 25(OH)vitamin D [25(OH)D] and 1,25(OH)(2) vitamin D [1,25(OH)(2)D] and mortality among 1822 participants of the Health Professionals Follow-up Study and Physicians' Health Study who were diagnosed with prostate cancer. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total mortality (n = 595) and lethal prostate cancer (death from prostate cancer or development of bone metastases; n = 202). In models adjusted for age at diagnosis, BMI, physical activity, and smoking, we observed a HR of 1.22 (95% CI: 0.97, 1.54) for total mortality, comparing men in the lowest to the highest quartile of 25(OH)D. There was no association between 1,25(OH)(2)D and total mortality. Men with the lowest 25(OH)D quartile were more likely to die of their cancer (HR: 1.59; 95% CI: 1.06, 2.39) compared to those in the highest quartile (P(trend) = 0.006). This association was largely explained by the association between low 25(OH)D levels and advanced cancer stage and higher Gleason score, suggesting that these variables may mediate the influence of 25(OH)D on prognosis. The association also tended to be stronger among patients with samples collected within five years of cancer diagnosis. 1,25(OH)(2)D levels were not associated with lethal prostate cancer.

    Conclusions/significance: Although potential bias of less advanced disease due to more screening activity among men with high 25(OH)D levels cannot be ruled out, higher prediagnostic plasma 25(OH)D might be associated with improved prostate cancer prognosis.

  • 38.
    Fang, Xin
    et al.
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Fang, Bo
    Division of Vital Statistics, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China; Department of Environmental Health, School of Public Health, Fudan University, Shanghai, China.
    Wang, Chunfang
    Division of Vital Statistics, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
    Xia, Tian
    Institute of Health Information, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
    Bottai, Matteo
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Fang, Fang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Cao, Yang
    Örebro University, School of Medical Sciences. Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Relationship between fine particulate matter, weather condition and daily non-accidental mortality in Shanghai, China: A Bayesian approach2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, e0187933Article in journal (Refereed)
    Abstract [en]

    There are concerns that the reported association of ambient fine particulate matter (PM2.5) with mortality might be a mixture of PM2.5 and weather conditions. We evaluated the effects of extreme weather conditions and weather types on mortality as well as their interactions with PM2.5 concentrations in a time series study. Daily non-accidental deaths, individual demographic information, daily average PM2.5 concentrations and meteorological data between 2012 and 2014 were obtained from Shanghai, China. Days with extreme weather conditions were identified. Six synoptic weather types (SWTs) were generated. The generalized additive model was set up to link the mortality with PM2.5 and weather conditions. Parameter estimation was based on Bayesian methods using both the Jeffreys' prior and an informative normal prior in a sensitivity analysis. We estimate the percent increase in non-accidental mortality per 10 mu g/m(3) increase in PM2.5 concentration and constructed corresponding 95% credible interval (CrI). In total, 336,379 non-accidental deaths occurred during the study period. Average daily deaths were 307. The results indicated that per 10 mu g/m(3) increase in daily average PM2.5 concentration alone corresponded to 0.26-0.35% increase in daily non-accidental mortality in Shanghai. Statistically significant positive associations between PM2.5 and mortality were found for favorable SWTs when considering the interaction between PM2.5 and SWTs. The greatest effect was found in hot dry SWT (percent increase = 1.28, 95% CrI: 0.72, 1.83), followed by warm humid SWT (percent increase = 0.64, 95% CrI: 0.15, 1.13). The effect of PM2.5 on non-accidental mortality differed under specific extreme weather conditions and SWTs. Environmental policies and actions should take into account the interrelationship between the two hazardous exposures.

  • 39.
    Fazel, Seena
    et al.
    Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Wolf, Achim
    Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Fimińska, Zuzanna
    Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mortality, Rehospitalisation and Violent Crime in Forensic Psychiatric Patients Discharged from Hospital: Rates and Risk Factors2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, e0155906Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine rates and risk factors for adverse outcomes in patients discharged from forensic psychiatric services.

    Method: We conducted a historical cohort study of all 6,520 psychiatric patients discharged from forensic psychiatric hospitals between 1973 and 2009 in Sweden. We calculated hazard ratios for mortality, rehospitalisation, and violent crime using Cox regression to investigate the effect of different psychiatric diagnoses and two comorbidities (personality or substance use disorder) on outcomes.

    Results: Over mean follow-up of 15.6 years, 30% of patients died (n = 1,949) after discharge with an average age at death of 52 years. Over two-thirds were rehospitalised (n = 4,472, 69%), and 40% violently offended after discharge (n = 2,613) with a mean time to violent crime of 4.2 years. The association between psychiatric diagnosis and outcome varied-substance use disorder as a primary diagnosis was associated with highest risk of mortality and rehospitalisation, and personality disorder was linked with the highest risk of violent offending. Furthermore comorbid substance use disorder typically increased risk of adverse outcomes.

    Conclusion: Violent offending, premature mortality and rehospitalisation are prevalent in patients discharged from forensic psychiatric hospitals. Individualised treatment plans for such patients should take into account primary and comorbid psychiatric diagnoses.

  • 40. Fortugno, Federico
    et al.
    Katsakou, Christina
    Bremner, Stephen
    Kiejna, Andrzej
    Kjellin, Lars
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nawka, Petr
    Raboch, Jiri
    Kallert, Thomas
    Priebe, Stefan
    Symptoms associated with victimization in patients with schizophrenia and related disorders2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, e58142- p.Article in journal (Refereed)
    Abstract [en]

    Background: Patients with psychoses have an increased risk of becoming victims of violence. Previous studies have suggested that higher symptom levels are associated with a raised risk of becoming a victim of physical violence. There has been, however, no evidence on the type of symptoms that are linked with an increased risk of recent victimization.

    Methods: Data was taken from two studies on involuntarily admitted patients, one national study in England and an international one in six other European countries. In the week following admission, trained interviewers asked patients whether they had been victims of physical violence in the year prior to admission, and assessed symptoms on the Brief Psychiatric Rating Scale (BPRS). Only patients with a diagnosis of schizophrenia or related disorders (ICD-10 F20-29) were included in the analysis which was conducted separately for the two samples. Symptom levels assessed on the BPRS subscales were tested as predictors of victimization. Univariable and multivariable logistic regression models were fitted to estimate adjusted odds ratios.

    Results: Data from 383 patients in the English sample and 543 patients in the European sample was analysed. Rates of victimization were 37.8% and 28.0% respectively. In multivariable models, the BPRS manic subscale was significantly associated with victimization in both samples.

    Conclusions: Higher levels of manic symptoms indicate a raised risk of being a victim of violence in involuntary patients with schizophrenia and related disorders. This might be explained by higher activity levels, impaired judgement or poorer self-control in patients with manic symptoms. Such symptoms should be specifically considered in risk assessments.

  • 41.
    Fransén, Karin
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Franzén, Petra
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnuson, Anders
    Örebro University Hospital, Örebro, Sweden.
    Elmabsout, Ali
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Nyhlin, Nils
    Örebro University Hospital.
    Wickbom, Anna
    Örebro University Hospital, Örebro, Sweden.
    Curman, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Törkvist, Leif
    Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, Mauro
    Karolinska University Hospital, Stockholm, Sweden.
    Bohr, Johan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Tysk, Curt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Sirsjö, Allan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's disease2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, e72739- p.Article in journal (Refereed)
    Abstract [en]

    Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.

  • 42.
    Fröbert, Ole
    et al.
    Örebro University Hospital. Dept Cardiol.
    Sarno, Giovanna
    Uppsala Univ, Inst Med Sci, Uppsala, Sweden..
    James, Stefan K.
    Uppsala Univ, Inst Med Sci, Uppsala, Sweden..
    Saleh, Nawsad
    Karolinska Hosp, Dept Cardiol, S-10401 Stockholm, Sweden..
    Lagerqvist, Bo
    Uppsala Univ, Inst Med Sci, Uppsala, Sweden..
    Effect of Stent Inflation Pressure and Post-Dilatation on the Outcome of Coronary Artery Intervention. A Report of More than 90 000 Stent Implantations2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, e56348Article in journal (Refereed)
    Abstract [en]

    Background: Percutaneous coronary intervention (PCI) stent inflation pressure correlates to angiographic lumen improvement and stent expansion but the relation to outcome is not clarified. Using comprehensive registry data our aim was to evaluate how stent inflation pressure influences restenosis, stent thrombosis and death following PCI. Methods: We evaluated all consecutive coronary stent implantations in Sweden during 46 months from 2008 using data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). We used logistic regression and Cox proportional hazard modeling to estimate risk of outcomes with different balloon pressures. Results: In total, 93 697 stents were eligible for analysis and divided into five different pressure interval groups: <= 15 atm, 16-17 atm, 18-19 atm, 20-21 atm and >= 22 atm. The risks of stent thrombosis and restenosis were significantly higher in the <= 15 atm, 18-19 atm and >= 22 atm groups (but not in the 16-17 atm group) compared to the 20-21 atm group. There were no differences in mortality. Post-dilatation was associated with a higher restenosis risk ratio (RR) of 1.22 (95% confidence interval (CI) 1.14-1.32, P < 0.001) but stent thrombosis did not differ statistically between procedures with or without post-dilatation. The risk of death was lower following post-dilatation (RR 0.81 (CI 0.71-0.93) P = 0.003) and the difference compared to no post-dilatation was seen immediately after PCI. Conclusion: Our retrospective study of stent inflation pressure identified a possible biological pattern-the risks of stent thrombosis and of restenosis appeared to be higher with low and very high pressures. Post-dilatation might increase restenosis risk.

  • 43. Gotlind, Yu-Yuan C.
    et al.
    Raghavan, Sukanya
    Bland, Paul W.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences.
    CD4(+)FoxP3(+) Regulatory T Cells from G alpha i2(-/-) Mice Are Functionally Active In Vitro, but Do Not Prevent Colitis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, e25073- p.Article in journal (Refereed)
    Abstract [en]

    Background: Mice deficient in the inhibitory G protein subunit G alpha i2 spontaneously develop a T helper 1 dominated colitis. We examined whether a defect in CD4(+) FoxP3(+) regulatory T cells (Treg) underpins the pathogenesis of colitis in the G alpha i2(-/-) (G alpha i2-deficient) colitis model. Methodology/Principal Findings: Using flow cytometry, we found that thymus and colonic lamina propria, but not spleen and mesenteric lymph nodes, of colitic G alpha i2(-/-) mice contained increased frequencies of Treg, whereas FoxP3 expression intensity was similar in G alpha i2(-/-) compared to G alpha i2(-/-) or G alpha i2(+/+) wild type (WT) mice. The frequency of CD4(+)FoxP3(+) T cells expressing CD103 was significantly increased in G alpha i2(-/-) compared to WT mice. Treg in colons from WT mice clustered in the T cell areas of colonic lymphoid patches (CLP), with relatively few Treg in the lamina propria, as demonstrated by immunohistochemistry. In G alpha i2(-/-) mice, CLP were not observed but lamina propria Treg were increased in number and frequency within the CD4(+) infiltrate, compared to WT mice. Using an in vitro co-culture system and flow cytometric analysis of cell division we could demonstrate that the in vitro suppressive function of WT and G alpha i2(-/-) CD4(+)FoxP3(+) regulatory T cells (WT-Treg and KO-Treg) was indistinguishable, but that T effector cells (CD4(+)25(-) T cells) from G alpha i2(-/-) mice were less readily suppressed than WT effectors (WT-Teff) by Treg from either source. However, neither WT nor G alpha i2(-/-) Treg was able to suppress colitis induced by adoptive transfer of G alpha i2(-/-) effector T cells (KO-Teff) to RAG2(-/-) recipients. The enhanced inflammatory activity of G alpha i2(-/-) effectors was accompanied by increased expression of an effector/memory T cell phenotype and increased cytokine secretion, especially IL-4, IL-6 and IFN-gamma. Conclusions: There is an increased frequency of G alpha i2(-/-) Treg in the colon, and they demonstrate no endogenous functional defect. However, G alpha i2(-/-) T effector cells are dramatically less susceptible to suppression in vitro, and in vivo, despite increased effective numbers of Treg, they cannot prevent disease.

  • 44.
    Graunke, Katharina L
    et al.
    Ethology Unit, Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany; Faculty of Agricultural and Environmental Sciences (AUF), PHENOMICS office, University of Rostock, Rostock, Germany.
    Nürnberg, Gerd
    Institute of Genetics and Biometry, Bioinformatics and Biomathematics Unit, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Repsilber, Dirk
    Institute of Genetics and Biometry, Bioinformatics and Biomathematics Unit, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Puppe, Birger
    Ethology Unit, Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany; Faculty of Agricultural and Environmental Sciences (AUF), Behavioural Sciences, University of Rostock, Rostock, Germany.
    Langbein, Jan
    Ethology Unit, Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
    Describing temperament in an ungulate: a multidimensional approach2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, e74579Article in journal (Refereed)
    Abstract [en]

    Studies on animal temperament have often described temperament using a one-dimensional scale, whereas theoretical framework has recently suggested two or more dimensions using terms like "valence" or "arousal" to describe these dimensions. Yet, the valence or assessment of a situation is highly individual. The aim of this study was to provide support for the multidimensional framework with experimental data originating from an economically important species (Bos taurus). We tested 361 calves at 90 days post natum (dpn) in a novel-object test. Using a principal component analysis (PCA), we condensed numerous behaviours into fewer variables to describe temperament and correlated these variables with simultaneously measured heart rate variability (HRV) data. The PCA resulted in two behavioural dimensions (principal components, PC): novel-object-related (PC 1) and exploration-activity-related (PC 2). These PCs explained 58% of the variability in our data. The animals were distributed evenly within the two behavioural dimensions independent of their sex. Calves with different scores in these PCs differed significantly in HRV, and thus in the autonomous nervous system's activity. Based on these combined behavioural and physiological data we described four distinct temperament types resulting from two behavioural dimensions: "neophobic/fearful--alert", "interested--stressed", "subdued/uninterested--calm", and "neoophilic/outgoing--alert". Additionally, 38 calves were tested at 90 and 197 dpn. Using the same PCA-model, they correlated significantly in PC 1 and tended to correlate in PC 2 between the two test ages. Of these calves, 42% expressed a similar behaviour pattern in both dimensions and 47% in one. No differences in temperament scores were found between sexes or breeds. In conclusion, we described distinct temperament types in calves based on behavioural and physiological measures emphasising the benefits of a multidimensional approach.

  • 45.
    Grönberg, Malin
    et al.
    Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden .
    Ahlin, Cecilia
    Örebro University Hospital. Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden .
    Naeser, Ylva
    Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden.
    Janson, Eva Tiensuu
    Department of Medical Sciences, Section of Endocrine Oncology, Uppsala University, Uppsala, Sweden.
    Holmberg, Lars
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom .
    Fjällskog, Marie-Louise
    Ghrelin is a prognostic marker and a potential therapeutic target in breast cancer2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, e0176059Article in journal (Refereed)
    Abstract [en]

    Ghrelin and obestatin are gastrointestinal peptides, encoded by the same preproghrelin gene. Both are expressed in breast cancer tissue and ghrelin has been implicated in breast cancer tumorigenesis. Despite recent advances in breast cancer management the need for new prognostic markers and potential therapeutic targets in breast cancer remains high. We studied the prognostic impact of ghrelin and obestatin in women with node negative breast cancer. Within a cohort of women with breast cancer with tumor size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy, 190 women were identified who died from breast cancer and randomly selected 190 women alive at the corresponding time as controls. Tumor tissues were immunostained with antibodies versus the peptides. Ghrelin expression was associated with better breast cancer specific survival in univariate analyses (OR 0.55, 95% CI 0.36-0.84) and in multivariate models, adjusted for endocrine treatment and age (OR 0.57, 95% CI 0.36-0.89). Obestatin expression was non-informative (OR 1.2, 95% CI 0.60-2.46). Ghrelin expression is independent prognostic factor for breast cancer death in node negative patients-halving the risk for dying of breast cancer. Our data implies that ghrelin could be a potential therapeutic target in breast cancer treatment.

  • 46.
    Hagemann, Urs B.
    et al.
    Affitech Research AS, Oslo, Norway; Algeta/Bayer AS, Oslo, Norway.
    Gunnarsson, Lavinia
    Örebro University, School of Science and Technology. Affitech Research AS, Oslo, Norway.
    Geraudie, Solene
    Affitech Research AS, Oslo, Norway; Radiumhospitalet, Oslo, Norway.
    Scheffler, Ulrike
    Affitech Research AS, Oslo, Norway; ProBioGen AG, Berlin, Germany.
    Griep, Remko A.
    Affitech Research AS, Oslo, Norway; AbCheck, Plzen, Czech Republic.
    Reiersen, Herald
    Affitech Research AS, Oslo, Norway; Jiffy International AS, Aas, Norway .
    Duncan, Alexander R.
    Affitech Research AS, Oslo, Norway; Actigen Ltd, Cambridge, United Kingdom.
    Kiprijanov, Sergej M.
    Affitech Research AS, Oslo, Norway; BerGenBio AS, Bergen, Norway.
    Fully Human Antagonistic Antibodies against CCR4 Potently Inhibit Cell Signaling and Chemotaxis2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, e103776Article in journal (Refereed)
    Abstract [en]

    Background: CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis.

    Methodology: Using phage display, human antibody library, affinity maturation and a cell-based antibody selection strategy, the antibody variants against human CCR4 were generated. These antibodies effectively competed with ligand binding, were able to block ligand-induced signaling and cell migration, and demonstrated efficient killing of CCR4-positive tumor cells via ADCC and phagocytosis. In a mouse model of human T-cell lymphoma, significant survival benefit was demonstrated for animals treated with the newly selected anti-CCR4 antibodies.

    Significance: For the first time, successful generation of anti-G-protein coupled chemokine receptor (GPCR) antibodies using human non-immune library and phage display on GPCR-expressing cells was demonstrated. The generated anti-CCR4 antibodies possess a dual mode of action (inhibition of ligand-induced signaling and antibody-directed tumor cell killing). The data demonstrate that the anti-tumor activity in vivo is mediated, at least in part, through Fc-receptor dependent effector mechanisms, such as ADCC and phagocytosis. Anti-CC chemokine receptor 4 antibodies inhibiting receptor signaling have potential as immunomodulatory antibodies for cancer.

  • 47.
    Hajiebrahimi, Mohammadhossein
    et al.
    Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Public Health, Health Faculty, Golestan University of Medical Sciences, Gorgan, Iran .
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Clinical Epidemiology and Biostatistics; Department of Epidemiology and Public Health, University College London, London, United Kingdom .
    Burkill, Sarah
    Center for Pharmacoepidemiology & Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, Shahram
    Center for Pharmacoepidemiology & Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Public Health, Health Faculty, Golestan University of Medical Sciences, Gorgan, Iran .
    Risk of Premenopausal and Postmenopausal Breast Cancer among Multiple Sclerosis Patients2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, e0165027Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate risk of premenopausal and postmenopausal breast cancer among Multiple Sclerosis (MS) patients, considering tumor stage.

    Methods: The Swedish Patient Register identified 19,330 women with MS between 1968 and 2012, matched individually with a cohort of 193,458 without MS. Matching variables were year of birth, sex, region of residence and vital status at the time of diagnosis. The cancer register identified 471 and 5,753 breast cancer cases among the MS and non-MS cohorts, respectively. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal and postmenopausal breast cancer.

    Results: Overall risk of postmenopausal breast cancer was 13% higher among MS patients compared with women without MS (HR = 1.13, 95% CI 1.02-1.26). Stratified analyses showed that the risk was statistically significantly increased in women diagnosed between 1968 and 1980 and those who were diagnosed at age 65 or older age. We observed a non-statistically significant risk only for stage 0-1 postmenopausal breast cancer (HR = 1.17, 95% CI 0.93-1.48). MS was not associated with premenopausal breast cancer.

    Conclusion: The modest increased risk of postmenopausal breast cancer in women with MS may be due to surveillance bias, where contact with health services for one disease increases the risk of a second diagnosis being recorded.

  • 48.
    Halim, Abdul
    et al.
    Centre for Injury Prevention and Research Bangladesh (CIPRB), Dhaka, Bangladesh.
    Dewez, Juan Emmanuel
    Centre for Maternal and Newborn Health, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
    Biswas, Animesh
    Örebro University, School of Health Sciences. Centre for Injury Prevention and Research Bangladesh (CIPRB), Dhaka, Bangladesh.
    Rahman, Fazlur
    Centre for Injury Prevention and Research Bangladesh (CIPRB), Dhaka, Bangladesh.
    White, Sarah
    Centre for Maternal and Newborn Health, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
    van den Broek, Nynke
    Centre for Maternal and Newborn Health, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
    When, Where, and Why Are Babies Dying?: Neonatal Death Surveillance and Review in Bangladesh2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, e0159388Article in journal (Refereed)
    Abstract [en]

    Background: Better data on cause of, and factors contributing to, neonatal deaths are needed to improve interventions aimed at reducing neonatal mortality in low-and middle-income countries.

    Methods: Community surveillance to identify all neonatal deaths across four districts in Bangladesh. Verbal autopsy for every fifth case and InterVA-4 used to assign likely cause of death.

    Findings: 6748 neonatal deaths identified, giving a neonatal mortality rate of 24.4 per 1000 live births. Of these, 51.3% occurred in the community and 48.7% at or on the way to a health facility. Almost half (46.1%) occurred within 24 hours of birth with 83.6% of all deaths occurring in the first seven days of life. Birth asphyxia was the leading cause of death (43%), followed by infections (29.3%), and prematurity (22.2%). In 68.3% of cases, care had been provided at a health facility before death occurred. Care-seeking was significantly higher among mothers who were educated (RR 1.18, 95% CI: 1.04-1.35) or who delivered at a health facility (RR 1.48, 95% CI 1.37-1.60) and lower among mothers who had 2-4 previous births (RR 0.89, 95% CI 0.82-0.96), for baby girls (RR 0.87, 95% CI 0.80-0.93), and for low birth weight babies (RR 0.89, 95% CI 0.82-0.96).

    Interpretation: Most parents of neonates who died had accessed and received care from a qualified health-care provider. To further reduce neonatal mortality, it is important that the quality of care provided, particularly skilled birth attendance, emergency obstetric care, and neonatal care during the first month of life is improved, such that it is timely, safe, and effective.

  • 49.
    Hiesmayr, Michael
    et al.
    Med Univ Vienna, Dept Anaesthesiol Gen Intens Care & Pain Control, Div Cardiac Thorac Vasc Anaesthesia & Intens Care, Vienna, Austria..
    Frantal, Sophie
    Ctr Med Stat Informat & Intelligent Syst, Sect Med Stat, Vienna, Austria..
    Schindler, Karin
    Med Univ Vienna, Med Clin 3, Div Endocrinol, Vienna, Austria..
    Themessl-Huber, Michael
    Ctr Med Stat Informat & Intelligent Syst, Sect Med Stat, Vienna, Austria..
    Mouhieddine, Mohamed
    Med Univ Vienna, Dept Anaesthesiol Gen Intens Care & Pain Control, Div Cardiac Thorac Vasc Anaesthesia & Intens Care, Vienna, Austria..
    Schuh, Christian
    Ctr Med Stat Informat & Intelligent Syst, Sect Med Stat, Vienna, Austria..
    Pernicka, Elisabeth
    Ctr Med Stat Informat & Intelligent Syst, Sect Med Stat, Vienna, Austria..
    Schneider, Stephane
    Hop Archet, Pole Digestif, Nutr Support Unit, Nice, France..
    Singer, Pierre
    Univ Hosp, Rabin Med Ctr, Gen Intens Care Dept, Petah Tiqwa, Israel..
    Ljunqvist, Olle
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Pichard, Claude
    Univ Hosp Geneva, Clin Nutr, Geneva, Switzerland..
    Laviano, Alessandro
    Univ Roma La Sapienza, Dept Clin Med, I-00185 Rome, Italy..
    Kosak, Sigrid
    Med Univ Vienna, Dept Anaesthesiol Gen Intens Care & Pain Control, Div Cardiac Thorac Vasc Anaesthesia & Intens Care, Vienna, Austria..
    Bauer, Peter
    Ctr Med Stat Informat & Intelligent Syst, Sect Med Stat, Vienna, Austria..
    The Patient- And Nutrition-Derived Outcome Risk Assessment Score (PANDORA): Development of a Simple Predictive Risk Score for 30-Day In-Hospital Mortality Based on Demographics, Clinical Observation, and Nutrition2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, e0127316Article in journal (Refereed)
    Abstract [en]

    Objective To develop a simple scoring system to predict 30 day in-hospital mortality of in-patients excluding those from intensive care units based on easily obtainable demographic, disease and nutrition related patient data. Methods Score development with general estimation equation methodology and model selection by P-value thresholding based on a cross-sectional sample of 52 risk indicators with 123 item classes collected with questionnaires and stored in an multilingual online database. Setting Worldwide prospective cross-sectional cohort with 30 day in-hospital mortality from the nutritionDay 2006-2009 and an external validation sample from 2012. Results We included 43894 patients from 2480 units in 32 countries. 1631(3.72%) patients died within 30 days in hospital. The Patient-And Nutrition-Derived Outcome Risk Assessment (PANDORA) score predicts 30-day hospital mortality based on 7 indicators with 31 item classes on a scale from 0 to 75 points. The indicators are age (0 to 17 points), nutrient intake on nutritionDay (0 to 12 points), mobility (0 to 11 points), fluid status (0 to 10 points), BMI (0 to 9 points), cancer (9 points) and main patient group (0 to 7 points). An appropriate model fit has been achieved. The area under the receiver operating characteristic curve for mortality prediction was 0.82 in the development sample and 0.79 in the external validation sample. Conclusions The PANDORA score is a simple, robust scoring system for a general population of hospitalised patients to be used for risk stratification and benchmarking.

  • 50.
    Howard, Bethany J.
    et al.
    Baker IDI Heart and Diabetes Institute, Melbourne, Australia; School of Public Health & Preventive Medicine, Monash University, Melbourne, Australia.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health Sciences.
    Olsson, Lovisa A.
    Department of Laboratory Medicine Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Nilsson, Torbjörn K.
    Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
    Dunstan, David W.
    Baker IDI Heart and Diabetes Institute, Melbourne, Australia; School of Public Health & Preventive Medicine, Monash University, Melbourne, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Australia; School of Sports Science, Exercise and Health, The University of Western Australia, Perth, Australia; School of Population Health, The University of Queensland, Brisbane, Australia .
    Wennberg, Patrik
    Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden .
    Self-Reported Sitting Time, Physical Activity and Fibrinolytic and Other Novel Cardio-Metabolic Biomarkers in Active Swedish Seniors2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, e0163409Article in journal (Refereed)
    Abstract [en]

    Background: Too much sitting is linked with an increased risk of cardiovascular disease and mortality. The mediating mechanisms for these associations are largely unknown, however dysregulated fibrinolysis have emerged as a possible contributor.

    Objective: We examined the associations of self-reported overall sitting time and physical activity with fibrinolytic and other novel cardio-metabolic biomarkers in older adults.

    Materials and Methods: Data was analysed for 364 participants (74±7 yrs) of the Active Seniors group (retired, living independently in their own homes). Linear regression analyses examined associations of categories of categories of sitting time (≤3, 3-6, >6 hrs/day) and overall physical activity (Low, Moderate and High) with biomarkers in serum or plasma, adjusting for age, gender and smoking (with further adjustment for either overall physical activity or sitting time and BMI in secondary analyses).

    Results: Compared to sitting ≤ 3 hrs/day, sitting >6 hrs/day was associated with higher tissue plasminogen activator (tPA) and tissue plasminogen activator/plasminogen activator inhibitor-1 complex (tPA-PAI-1 complex). These associations were not independent of overall physical activity or BMI. Compared to those in the high physical activity, low physical activity was associated with a higher BMI, high-sensitivity C-reactive protein (hs-CRP) and tPA-PAI-1 complex levels. Only the associations of BMI and hs-CRP were independent of sitting time.

    Conclusions: These findings provide preliminary cross-sectional evidence for the relationships of sitting time with fibrinolytic markers in older adults. They also reinforce the importance of regular physical activity for cardio-metabolic health.

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