Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Refine search result
3456789 251 - 300 of 17990
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 251.
    Akyurek, M L
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Wanders, A
    Department of Medical Sciences.
    Aurivillius, M
    Funa, K
    Larsson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Fellstrom, B
    Department of Medical Sciences.
    Effects of angiopeptin on transplant arteriosclerosis in the rat.1995In: Transpl Int, Vol. 2, p. 103-Article in journal (Refereed)
  • 252.
    Akyurek, ML
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Funa, K
    Wanders, A
    Larsson, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Fellstrom, BC
    Department of Medical Sciences.
    Expression of CD11b and ICAM-1 in an in vivo model of transplantarteriosclerosis.1995In: Transpl Immunol, Vol. 3, p. 107-Article in journal (Refereed)
  • 253.
    Alabas, O. A.
    et al.
    Univ Leeds, Leeds, W Yorkshire, England..
    Rutherford, M.
    Univ Leicester, Leicester, Leics, England..
    Hall, M.
    Univ Leeds, Leeds, W Yorkshire, England..
    Szummer, K.
    Karolinska Univ Hosp, Dept Med H7, Stockholm, Sweden..
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gale, C. P.
    Univ Leeds, Leeds, W Yorkshire, England..
    Jernberg, T.
    Karolinska Univ Hosp, Dept Med H7, Stockholm, Sweden..
    Lower long term relative survival and higher excess mortality in women and in elderly after acute myocardial infarction: a national cohort study using 180,368 cases from the SWEDEHEART registry2016In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 37, no Suppl. 1, p. 1385-1385Article in journal (Refereed)
  • 254.
    Alabas, Oras A.
    et al.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Bioinformat Ctr, MRC, Leeds, W Yorkshire, England..
    Gale, Chris P.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Bioinformat Ctr, MRC, Leeds, W Yorkshire, England.;York Teaching Hosp NHS Fdn Trust, Dept Cardiol, York, N Yorkshire, England..
    Hall, Marlous
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Bioinformat Ctr, MRC, Leeds, W Yorkshire, England..
    Rutherford, Mark J.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Szummer, Karolina
    Dept Med, Huddinge, Sweden..
    Lawesson, Sofia Sederholm
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Alfredsson, Joakim
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jernberg, Tomas
    Karolinska Inst, Danderyds Hosp, Dept Clin Sci, Stockholm, Sweden..
    Sex Differences in Treatments, Relative Survival, and Excess Mortality Following Acute Myocardial Infarction: National Cohort Study Using the SWEDEHEART Registry2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 12, article id e007123Article in journal (Refereed)
    Abstract [en]

    Background - This study assessed sex differences in treatments, all-cause mortality, relative survival, and excess mortality following acute myocardial infarction.

    Methods and Results - A population-based cohort of all hospitals providing acute myocardial infarction care in Sweden (SWEDEHEART [Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies]) from 2003 to 2013 was included in the analysis. Excess mortality rate ratios (EMRRs), adjusted for clinical characteristics and guideline-indicated treatments after matching by age, sex, and year to background mortality data, were estimated. Although there were no sex differences in all-cause mortality adjusted for age, year of hospitalization, and comorbidities for ST-segment-elevation myocardial infarction (STEMI) and non-STEMI at 1 year (mortality rate ratio: 1.01 [95% confidence interval (CI), 0.96-1.05] and 0.97 [95% CI, 0.95-.99], respectively) and 5 years (mortality rate ratio: 1.03 [95% CI, 0.99-1.07] and 0.97 [95% CI, 0.95-.99], respectively), excess mortality was higher among women compared with men for STEMI and non-STEMI at 1 year (EMRR: 1.89 [95% CI, 1.66-2.16] and 1.20 [95% CI, 1.16-1.24], respectively) and 5 years (EMRR: 1.60 [95% CI, 1.48-1.72] and 1.26 [95% CI, 1.21-1.32], respectively). After further adjustment for the use of guideline-indicated treatments, excess mortality among women with non-STEMI was not significant at 1 year (EMRR: 1.01 [95% CI, 0.97-1.04]) and slightly higher at 5 years (EMRR: 1.07 [95% CI, 1.02-1.12]). For STEMI, adjustment for treatments attenuated the excess mortality for women at 1 year (EMRR: 1.43 [95% CI, 1.26-1.62]) and 5 years (EMRR: 1.31 [95% CI, 1.19-1.43]).

    Conclusions - Women with acute myocardial infarction did not have statistically different all-cause mortality, but had higher excess mortality compared with men that was attenuated after adjustment for the use of guideline-indicated treatments. This suggests that improved adherence to guideline recommendations for the treatment of acute myocardial infarction may reduce premature cardiovascular death among women.

  • 255.
    Alabas, Oras A.
    et al.
    Univ Leeds, Leeds Inst Rheumat & Musculoskeletal Med, Leeds, W Yorkshire, England.
    Jernberg, Tomas
    Karolinska Inst, Danderyd Univ Hosp, Dept Clin Sci, Stockholm, Sweden.
    Pujades-Rodriguez, Mar
    Univ Leeds, Leeds Inst Hlth Sci, Leeds, W Yorkshire, England.
    Rutherford, Mark J.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England.
    West, Robert M.
    Univ Leeds, Leeds Inst Hlth Sci, Leeds, W Yorkshire, England.
    Hall, Marlous
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, Sweden.
    Timmis, Adam
    Barts Heart Ctr, Dept Cardiol, London, England.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Fox, Keith A. A.
    Univ Edinburgh, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland.
    Hemingway, Harry
    UCL, Hlth Data Res UK London, London, England;UCL, Inst Hlth Informat, London, England;UCL, Natl Inst Hlth Res, Univ Coll London Hosp, Biomed Res Ctr, London, England.
    Gale, Chris P.
    Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, Sweden;Univ Leeds, Leeds Inst Data Analyt, Leeds, W Yorkshire, England.
    Statistics on mortality following acute myocardial infarction in 842 897 Europeans2020In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 116, no 1, p. 149-157Article in journal (Refereed)
    Abstract [en]

    Aims: To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments.

    Methods and results: National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), beta-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4-8.5) vs. 6.7 (6.5-6.9)] and NSTEMI [6.8 (6.4-7.2) vs. 4.9 (4.7-5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5-3.3) vs. 2.3 (2.2-2.5)] and [21.4 (20.0-22.8) vs. 18.3 (17.6-19.0)], but was similar for STEMI [0.7 (0.4-1.0) vs. 0.9 (0.7-1.0)] and [8.4 (6.7-10.1) vs. 8.3 (7.5-9.1)].

    Conclusion: Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.

  • 256.
    Alaie, Iman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ramklint: Child and Adolescent Psychiatry.
    Philipson, Anna
    University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ssegonja, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Copeland, William E.
    Department of Psychiatry, Vermont Center for Children, Youth, and Families, University of Vermont, Burlington, USA.
    Ramklint, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ramklint: Child and Adolescent Psychiatry.
    Bohman, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ramklint: Child and Adolescent Psychiatry.
    Jonsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ramklint: Child and Adolescent Psychiatry. Karolinska Institutet Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women’s and Children’s Health, Karolinska Institutet, and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Adolescent depression and adult labor market marginalization: a longitudinal cohort study2022In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 31, no 11, p. 1799-1813Article in journal (Refereed)
    Abstract [en]

    Adolescent depression is linked to adult ill-health and functional impairment, but recent research suggests that individual/contextual factors might account for this association. This study aimed to test whether the clinical heterogeneity of adolescent depression is related to marginalization from the labor market across early to middle adulthood. Data were drawn from the Uppsala Longitudinal Adolescent Depression Study, a community-based cohort initially assessed with structured clinical interviews at age 16-17. The cohort (n = 321 depressed; n = 218 nondepressed) was followed up after 2+ decades through linkage to nationwide population-based registries. Outcomes included consecutive annual data on unemployment, work disability, social welfare recipiency, and a composite marginalization measure, spanning from age 21 to 40. Longitudinal associations were examined using logistic regression analysis in a generalized estimating equations modeling framework. Subsequent depressive episodes and educational attainment in early adulthood were explored as potential pathways. The results showed that adolescent depression was associated with adult marginalization outcomes, but the strength of association varied across depressed subgroups. Adolescents with persistent depressive disorder had higher odds of all outcomes, including the composite marginalization measure (adjusted OR = 2.0, 95% CI = 1.4-2.7, p < 0.001), and this was partially (31%) mediated by subsequent depressive episodes in early adulthood. Exploratory moderation analysis revealed that entry into tertiary education mitigated the association with later marginalization, but only for adolescents with episodic major depression. In conclusion, the risk for future labor market marginalization is elevated among depressed adolescents, particularly those presenting with persistent depressive disorder. Targeted interventions seem crucial to mitigate the long-lasting impact of early-onset depression.

    Download full text (pdf)
    fulltext
  • 257.
    Alaie, Iman
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Child and Adolescent Psychiatry. Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Stockholm, Sweden..
    Svedberg, Pia
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Stockholm, Sweden..
    Ropponen, Annina
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Stockholm, Sweden.;Finnish Inst Occupat Hlth, Helsinki, Finland..
    Narusyte, Jurgita
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Stockholm, Sweden..
    Associations of Internalizing and Externalizing Problems in Childhood and Adolescence With Adult Labor Market Marginalization2023In: JAMA Network Open, E-ISSN 2574-3805, Vol. 6, no 6, article id e2317905Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Mental health problems in early life are associated with labor market marginalization, especially in youths with persistent internalizing and externalizing problems. However, previous research has not adjusted for familial (genetic and shared environmental) factors.

    OBJECTIVE To examine associations of early-life internalizing and externalizing problems with adulthood unemployment and work disability, adjusting for familial factors.

    DESIGN, SETTING, AND PARTICIPANTS This population-based prospective cohort study included Swedish twins whowere born in 1985-1986 and surveyed at 4 consecutivewaves across childhood and adolescence until 2005. Through linkage to nationwide registries, participants were followed up from 2006 to 2018. Data analyses were conducted between September 2022 and April 2023.

    EXPOSURES Internalizing and externalizing problems, assessed with the Child Behavior Checklist. Participants were differentiated regarding duration of internalizing and externalizing problems (persistent, episodic, and noncases).

    MAIN OUTCOMES AND MEASURES Unemployment (180 days or more of being unemployed) and work disability (60 days or more of being sickness absent or disability pensioned) during follow-up. Cox proportional hazards regression models were calculated to obtain cause-specific hazard ratios (HRs) with 95% CIs in the whole cohort and exposure-discordant twin pairs.

    RESULTS Of 2845 participants, 1464 (51.5%) were female. Incident unemployment was experienced by 944 (33.2%) and incidentwork disability by 522 (18.3%) participants. Compared with noncases, persistent internalizing problemswere associated with unemployment (HR, 1.56; 95% CI, 1.27-1.92) and work disability (HR, 2.32; 95% CI, 1.80-2.99). Similarly, compared with noncases, persistent externalizing problems were associated with unemployment (HR, 1.87; 95% CI, 1.55-2.26) andwork disability (HR, 2.38; 95% CI, 1.87-3.03). Persistent cases had overall higher risks of adverse outcomes than episodic cases. After adjustment for familial factors, associations with unemployment were no longer statistically significant, whereas associations with work disability remained or were only slightly reduced.

    CONCLUSIONS AND RELEVANCE In this cohort study of young Swedish twins, familial factors explained the associations between early-life persistent internalizing and externalizing problems and unemployment; such factors were comparatively less important for the association with work disability. This suggests nonshared environmental factors may be important for the risk of future work disability among young individuals with persistent internalizing and externalizing problems.

    Download full text (pdf)
    fulltext
  • 258.
    Alaie, Iman
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Child and Adolescent Psychiatry. Karolinska Inst, Dept Clin Neurosci, Div Insurance Med, Stockholm, Sweden.;Karolinska Inst, Div Insurance Med, SE-17177 Stockholm, Sweden..
    Svedberg, Pia
    Karolinska Inst, Dept Clin Neurosci, Div Insurance Med, Stockholm, Sweden..
    Ropponen, Annina
    Karolinska Inst, Dept Clin Neurosci, Div Insurance Med, Stockholm, Sweden.;Finnish Inst Occupat Hlth, Helsinki, Finland..
    Narusyte, Jurgita
    Karolinska Inst, Dept Clin Neurosci, Div Insurance Med, Stockholm, Sweden..
    Longitudinal trajectories of sickness absence among young adults with a history of depression and anxiety symptoms in Sweden2023In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 339, p. 271-279Article in journal (Refereed)
    Abstract [en]

    Background: Depression and anxiety are associated with increased risk of sickness absence (SA), yet the developmental patterns of SA remain unclear. We aimed to identify trajectories of SA in young adults with depression and/or anxiety, accounting for sociodemographic and occupational factors.

    Methods: Longitudinal study of 1445 twin individuals with elevated depressive/anxiety symptoms in late adolescence or young adulthood (age range: 19-30), assessed in Swedish surveys completed in 2005. Through linkage to nationwide registries, individuals were prospectively followed from 2006 to 2018. The outcome included consecutive annual days of SA, which were analyzed using group-based trajectory modeling. Multinomial logistic regression estimating odds ratios (OR) with 95 % confidence intervals (CI) was used to examine associations of age, sex, and educational level with the resulting SA trajectories.

    Results: Four distinct SA trajectories were identified in the total sample: 'high-increasing' (6 %), 'low-increasing' (12 %), 'high-decreasing' (13 %), and 'low-constant' (69 %). Increasing age was associated with higher odds of belonging to the low-increasing trajectory (OR = 1.07, 95 % CI = 1.02-1.12). Women had higher odds of belonging to the low-increasing trajectory (OR = 1.67, 95 % CI = 1.10-2.53), compared with men. Higher education was associated with lower odds of belonging to high-increasing (OR = 0.34, 95 % CI = 0.22-0.54) and high-decreasing (OR = 0.59, 95 % CI = 0.43-0.81) trajectories, compared with lower education. Few differences were observed in analyses stratified by occupational sector.

    Limitations: Information on potential confounders (e.g., psychiatric comorbidity, work-environment factors) was not available.

    Conclusions: Among young adults with prior depression/anxiety, close to every fifth showed rising SA trajectories over time. This calls for targeted strategies to improve public mental health already at young ages.

    Download full text (pdf)
    fulltext
  • 259.
    Alam, Aftab
    et al.
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Singh, Tanya
    Cardiff Univ, Sch Biosci, Cardiff, Wales.;Cardiff Univ, Neurosci & Mental Hlth Innovat Inst, Cardiff, Wales..
    Kayhanian, Saeed
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England.;Univ Cambridge, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Tjerkaski, Jonathan
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Garcia, Nuria Marco
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Carpenter, Keri L. H.
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Patani, Rickie
    UCL, Inst Neurol, Queen Sq, London, England..
    Lindblad, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Acquired brain injury. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Thelin, Eric P. P.
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England.;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden..
    Syed, Yasir Ahmed
    Cardiff Univ, Sch Biosci, Cardiff, Wales.;Cardiff Univ, Neurosci & Mental Hlth Innovat Inst, Cardiff, Wales..
    Helmy, Adel
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England..
    Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia2023In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 40, no 19-20, p. 2164-2173Article in journal (Refereed)
    Abstract [en]

    The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1 & beta;, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1 & beta; (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.

  • 260.
    Al-Amin, Rasel A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Lars
    Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Center for Molecular Medicine, Department of Medicine (Solna), Science for Life Laboratory, Karolinska Institutet.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Blokzijl, Andries
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hammond, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Haybaeck, Johannes
    Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck; Diagnostic and Research Institute of Pathology, Medical University of Graz.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jenmalm Jensen, Annika
    Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Monitoring drug–target interactions through target engagement-mediated amplification on arrays and in situ2022In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, no 22, p. e129-e129Article in journal (Refereed)
    Abstract [en]

    Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug–target interactions at spatial resolution in protein arrays, cells and in tissues.

    Download full text (pdf)
    fulltext
  • 261.
    Al-Amin, Rasel A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for Life Laboratory, SciLifeLab, Science for Life Laboratory, SciLifeLab.
    Johansson, Lars
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Blokzijl, Andries
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Dept. Of Immunology, Genetics and Pathology,.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Target Engagement-Mediated Amplification for Monitoring Drug-Target Interactions in SituManuscript (preprint) (Other academic)
    Abstract [en]

    It is important to determine the localization of drugs or drug candidates at cellular and subcellular resolution in relevant clinical specimens. This is necessary to evaluate drug candidates from early stages of drug development to clinical evaluation of mutations potentially causing resistance to targeted therapy. We describe a technology where oligonucleotide-conjugated drug molecules are used to visualize and measure target engagement in situ via rolling-circle amplification (RCA) of circularized oligonucleotide probes (padlock probes). We established this target engagement-mediated amplification (TEMA) technique using kinase inhibitor precursor compounds, and we applied the assay to investigate target interactions by microscopy in pathology tissue sections and using flow cytometry for blood samples from patients, as well as in commercial arrays including almost half of all human proteins.  In the variant proxTEMAtechnique, in situ proximity ligation assays were performed by combining drug-DNA conjugates with antibody-DNA conjugates to specifically reveal drug binding to particular on- or off-targets in pathological tissues sections. In conclusion, the TEMA methods successfully visualize drug-target interaction by experimental and clinically approved kinase inhibitors in situ and with kinases among a large collection of arrayed proteins. 

  • 262.
    Alanazi, Sultan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grujic, Mirjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Sommerhoff, Christian P.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Melo, Fabio Rabelo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mast Cell β-Tryptase Is Enzymatically Stabilized by DNA2020In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, no 14, article id 5065Article in journal (Refereed)
    Abstract [en]

    Tryptase is a tetrameric serine protease located within the secretory granules of mast cells. In the secretory granules, tryptase is stored in complex with negatively charged heparin proteoglycans and it is known that heparin is essential for stabilizing the enzymatic activity of tryptase. However, recent findings suggest that enzymatically active tryptase also can be found in the nucleus of murine mast cells, but it is not known how the enzmatic activity of tryptase is maintained in the nuclear milieu. Here we hypothesized that tryptase, as well as being stabilized by heparin, can be stabilized by DNA, the rationale being that the anionic charge of DNA could potentially substitute for that of heparin to execute this function. Indeed, we showed that double-stranded DNA preserved the enzymatic activity of human β-tryptase with a similar efficiency as heparin. In contrast, single-stranded DNA did not have this capacity. We also demonstrated that DNA fragments down to 400 base pairs have tryptase-stabilizing effects equal to that of intact DNA. Further, we showed that DNA-stabilized tryptase was more efficient in degrading nuclear core histones than heparin-stabilized enzyme. Finally, we demonstrated that tryptase, similar to its nuclear localization in murine mast cells, is found within the nucleus of primary human skin mast cells. Altogether, these finding reveal a hitherto unknown mechanism for the stabilization of mast cell tryptase, and these findings can have an important impact on our understanding of how tryptase regulates nuclear events. 

    Download full text (pdf)
    Mast Cell β-Tryptase Is Enzymatically Stabilized by DNA
  • 263.
    Alarabi, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Backman, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wikstrom, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sjoberg, O
    Department of Oncology, Radiology and Clinical Immunology.
    Tufveson, G
    Department of Surgical Sciences.
    Plasmapheresis in HLA-immunosensitized patients prior to kidney transplantation1997In: J Artific Organs, Vol. 20, p. 51-Article in journal (Refereed)
  • 264.
    Alarabi, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Backman, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wikstrom, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sjoberg, O
    Department of Oncology, Radiology and Clinical Immunology.
    Tufveson, G
    Department of Surgical Sciences.
    Pretransplantation plasmapheresis in HLA-sensitized patients: five years experience.1995In: Transplant Proc, Vol. 27, p. 3448Other (Other scientific)
  • 265.
    Alarabi, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Nystrom, S-O
    Department of Surgical Sciences.
    Stahle, E
    Department of Surgical Sciences.
    Wikstrom, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Acute renal failure and outcome of continuous arteriovenous hemodialysis (CAVHD) and continuous hemofiltration (CAVH) in elderly patients following cardiovascular surgery1997In: Geriatric Nephrol Urol, Vol. 7, p. 45-Article in journal (Refereed)
  • 266.
    Alarabi, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Ronco, C
    Brendolan, A
    Raimondi, F
    Wikstrom, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Danielson, BG
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Treatment of acute renal failure in intensive care patients by continuous arteriovenous hemofiltration (CAVH): Two years' experience in two centres1995In: Upsala J Med Sci, Vol. 100, p. 143-Article in journal (Refereed)
  • 267.
    Alassaad, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Improving the Quality and Safety of Drug Use in Hospitalized Elderly: Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.

    The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.

    Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.

    The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.

    The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization. 

    List of papers
    1. Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial
    Open this publication in new window or tab >>Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial
    Show others...
    2013 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 5, p. e62401-Article in journal (Refereed) Published
    Abstract [en]

    Background: Appropriateness of prescribing can be assessed by various measures and screening instruments. The aims of this study were to investigate the effects of pharmacists' interventions on appropriateness of prescribing in elderly patients, and to explore the relationship between these results and hospital care utilization during a 12-month follow-up period. Methods: The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalization was investigated, was used. The criteria from the instruments MAI, STOPP and START were applied retrospectively to the 368 study patients (intervention group (I) n = 182, control group (C) n = 186). The assessments were done on admission and at discharge to detect differences over time and between the groups. Hospital care consumption was recorded and the association between scores for appropriateness, and hospitalization was analysed. Results: The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for I but not for C (1.42 to 0.93 vs. 1.46 to 1.66 respectively, p<0.01). The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for I but not for C (0.36 to 0.09 vs. 0.42 to 0.45 respectively, p<0.001). The summated score for MAI was reduced for I but not for C (8.5 to 5.0 and 8.7 to 10.0 respectively, p<0.001). There was a positive association between scores for MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively). No association was detected between the scores of the tools and total re-visits to hospital. Conclusion: The interventions significantly improved the appropriateness of prescribing for patients in the intervention group as evaluated by the instruments MAI, STOPP and START. High scores in MAI and STOPP were associated with a higher number of drug-related readmissions.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-203295 (URN)10.1371/journal.pone.0062401 (DOI)000319107900008 ()
    Available from: 2013-07-08 Created: 2013-07-08 Last updated: 2022-01-28Bibliographically approved
    2. The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing
    Open this publication in new window or tab >>The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing
    Show others...
    2014 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, p. e111797-Article in journal (Refereed) Published
    Abstract [en]

    Background: Clinical pharmacist interventions have been shown to have positive effect on occurrence of drug-related issues as well as on clinical outcomes. However, evidence about which patients benefiting most from the interventions is limited. We aimed to explore whether pharmacist intervention is equally effective in preventing emergency department (ED) visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing. Methods: Patient and outcome data from a randomized controlled trial exploring the clinical effects of a ward-based pharmacist intervention in patients, 80 years and older, were used. The patients were divided into subgroups according to the number of prescribed drugs (< 5 or >= 5 drugs) and the level of inappropriate prescribing [using the Screening Tool Of Older People's potentially inappropriate Prescriptions (STOPP) and the Screening Tool to Alert doctors to Right Treatment (START) with a score of >= 2 (STOPP) and >= 1 (START) as cutoff points]. The effect of the intervention on the number of times the different subgroups visited the ED was analyzed. Results: The pharmacist intervention was more effective with respect to the number of subsequent ED visits in patients taking < 5 drugs on admission than in those taking >= 5 drugs. The rate ratio (RR) for a subsequent ED visit was 0.22 [95% confidence interval (CI) 0.09-0.52] for,5 drugs and 0.70 (95% CI 0.47-1.04) for >= 5 drugs (p = 0.02 for the interaction). The effect of intervention did not differ between patients with high or low STOPP or START scores. Conclusion: In this exploratory study, the pharmacist intervention appeared to be more effective in preventing visits to the ED for patients who were taking fewer drugs before the intervention. Our analysis of STOPP and START scores indicated that the level of inappropriate prescribing on admission had no effect on the outcomes of intervention with respect to ED visits.

    Keywords
    clinical pharmacy, medication review, inappropriate prescribing, polypharmacy, geriatrics
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-234485 (URN)10.1371/journal.pone.0111797 (DOI)000345558100122 ()25364817 (PubMedID)
    Available from: 2014-10-20 Created: 2014-10-20 Last updated: 2022-01-28Bibliographically approved
    3. A tool for prediction of risk of rehospitalization and mortality in hospitalized elderly
    Open this publication in new window or tab >>A tool for prediction of risk of rehospitalization and mortality in hospitalized elderly
    Show others...
    (English)Article in journal (Refereed) Submitted
    Abstract [en]

    Importance: Older patients with multiple co-morbidities and multi-drug use are at high risk of revisits to hospital and mortality, which poses an increasing health economic burden.

    Objective: To construct and internally validate a risk score, the “80+ score”, for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person’s Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI).

    Design: Secondary use of data from a randomized controlled trial investigating effects of a comprehensive pharmacist intervention, conducted in 2005-2006.

    Setting: Two acute internal medicine wards at Uppsala University hospital.

    Participants: Data from 368 patients, 80 years and older, admitted to one of the study wards.

    Main outcomes and measures: Time to rehospitalization or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk-estimation was constructed.  The score was internally validated, and the discriminatory ability of the new score and of STOPP, START and MAI was assessed using C-statistics.

    Results: Seven variables were selected for the 80+ score. Impaired renal function, pulmonary disease (chronic obstructive pulmonary disease [COPD or asthma]), malignant disease (past or present), living in nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease was associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+ score), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI).

    Conclusion and Relevance: We developed and internally validated a score for prediction of risk of rehospitalization and mortality in hospitalized older people. The score discriminated risk considerably better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions. 

    Keywords
    Geriatrics, drugs, risk-estimation, polypharmacy, pharmacotherapy
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-234487 (URN)
    Available from: 2014-10-20 Created: 2014-10-20 Last updated: 2015-02-03Bibliographically approved
    4. Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study
    Open this publication in new window or tab >>Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study
    Show others...
    2013 (English)In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, no 1, p. 185-191Article in journal (Refereed) Published
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

    Keywords
    medication error, medication reconciliation, multi-dose dispensed medications, patient safety, prescription error, transition of care
    National Category
    Social and Clinical Pharmacy
    Research subject
    Pharmaceutical Science; Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-167137 (URN)10.1111/j.1365-2753.2011.01798.x (DOI)000314114400026 ()
    Available from: 2012-01-22 Created: 2012-01-22 Last updated: 2018-01-12
    Download full text (pdf)
    fulltext
    Download (jpg)
    presentationsbild
  • 268.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, p. e111797-Article in journal (Refereed)
    Abstract [en]

    Background: Clinical pharmacist interventions have been shown to have positive effect on occurrence of drug-related issues as well as on clinical outcomes. However, evidence about which patients benefiting most from the interventions is limited. We aimed to explore whether pharmacist intervention is equally effective in preventing emergency department (ED) visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing. Methods: Patient and outcome data from a randomized controlled trial exploring the clinical effects of a ward-based pharmacist intervention in patients, 80 years and older, were used. The patients were divided into subgroups according to the number of prescribed drugs (< 5 or >= 5 drugs) and the level of inappropriate prescribing [using the Screening Tool Of Older People's potentially inappropriate Prescriptions (STOPP) and the Screening Tool to Alert doctors to Right Treatment (START) with a score of >= 2 (STOPP) and >= 1 (START) as cutoff points]. The effect of the intervention on the number of times the different subgroups visited the ED was analyzed. Results: The pharmacist intervention was more effective with respect to the number of subsequent ED visits in patients taking < 5 drugs on admission than in those taking >= 5 drugs. The rate ratio (RR) for a subsequent ED visit was 0.22 [95% confidence interval (CI) 0.09-0.52] for,5 drugs and 0.70 (95% CI 0.47-1.04) for >= 5 drugs (p = 0.02 for the interaction). The effect of intervention did not differ between patients with high or low STOPP or START scores. Conclusion: In this exploratory study, the pharmacist intervention appeared to be more effective in preventing visits to the ED for patients who were taking fewer drugs before the intervention. Our analysis of STOPP and START scores indicated that the level of inappropriate prescribing on admission had no effect on the outcomes of intervention with respect to ED visits.

    Download full text (pdf)
    fulltext
  • 269.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study2013In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, no 1, p. 185-191Article in journal (Refereed)
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

  • 270.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gillespie, Ulrika
    Uppsala University Hospital, Uppsala, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    A tool for prediction of risk of rehospitalisation and mortality in the hospitalised elderly: secondary analysis of clinical trial data2015In: BMJ Open, E-ISSN 2044-6055, Vol. 5, no 2, article id e007259Article in journal (Refereed)
    Abstract [en]

    Objectives: To construct and internally validate a risk score, the '80+ score', for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI). Setting: Two acute internal medicine wards at Uppsala University hospital. Patient data were used from a randomised controlled trial investigating the effects of a comprehensive clinical pharmacist intervention. Participants: Data from 368 patients, aged 80 years and older, admitted to one of the study wards. Primary outcome measure: Time to rehospitalisation or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk estimation was constructed. The 80+ score was internally validated, and the discriminatory ability of the score and of STOPP, START and MAI was assessed using C-statistics. Results: Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI). Conclusions: We developed and internally validated a score for prediction of risk of rehospitalisation and mortality in hospitalised older people. The score discriminated risk better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions.

    Download full text (pdf)
    fulltext
  • 271.
    Alassaad, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    A tool for prediction of risk of rehospitalization and mortality in hospitalized elderlyArticle in journal (Refereed)
    Abstract [en]

    Importance: Older patients with multiple co-morbidities and multi-drug use are at high risk of revisits to hospital and mortality, which poses an increasing health economic burden.

    Objective: To construct and internally validate a risk score, the “80+ score”, for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person’s Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI).

    Design: Secondary use of data from a randomized controlled trial investigating effects of a comprehensive pharmacist intervention, conducted in 2005-2006.

    Setting: Two acute internal medicine wards at Uppsala University hospital.

    Participants: Data from 368 patients, 80 years and older, admitted to one of the study wards.

    Main outcomes and measures: Time to rehospitalization or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk-estimation was constructed.  The score was internally validated, and the discriminatory ability of the new score and of STOPP, START and MAI was assessed using C-statistics.

    Results: Seven variables were selected for the 80+ score. Impaired renal function, pulmonary disease (chronic obstructive pulmonary disease [COPD or asthma]), malignant disease (past or present), living in nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease was associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+ score), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI).

    Conclusion and Relevance: We developed and internally validated a score for prediction of risk of rehospitalization and mortality in hospitalized older people. The score discriminated risk considerably better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions. 

  • 272.
    Alavian-Ghavanini, Ali
    et al.
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Lin, Ping-I
    Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rimfors, Sabina Risen
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Tang, Mandy
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lindh, Christian
    Lund Univ, Div Occupat & Environm Med, S-22185 Lund, Sweden.
    Bornehag, Carl-Gustaf
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA;Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Rueegg, Joelle
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 11315Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, Iow APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and Iow APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.

    Download full text (pdf)
    fulltext
  • 273.
    Albinsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ Hosp, Lab Clin Microbiol, Uppsala, Sweden..
    Hoffman, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kolstad, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergström, Tomas
    Univ Gothenburg, Inst Biomed, Dept Infect Dis, Gothenburg, Sweden..
    Bogdanovic, Gordana
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Heydecke, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg.
    Hägg, Mirja
    Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Kjerstadius, Torbjörn
    Cent Hosp Karlstad, Lab Med, Clin Microbiol, Karlstad, Sweden..
    Lindroth, Ylva
    Lund Univ, Dept Lab Med, Skane Lab Med, Med Microbiol, Lund, Sweden..
    Petersson, Annika
    Växjö Cent Hosp, Dept Clin Chem & Transfus Med, Växjö, Sweden..
    Stenberg, Marie
    Visby Hosp, Lab Med Ctr Gotland, Visby, Sweden..
    Vene, Sirkka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala Univ Hosp, Lab Clin Microbiol, Uppsala, Sweden..
    Rönnberg, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital, Uppsala, Sweden.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Seroprevalence of tick-borne encephalitis virus and vaccination coverage of tick-borne encephalitis, Sweden, 2018 to 20192024In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 29, no 2, article id 2300221Article in journal (Refereed)
    Abstract [en]

    Background: In Sweden, information on seroprevalence of tick -borne encephalitis virus (TBEV) in the population, including vaccination coverage and infection, is scattered. This is largely due to the absence of a national tick -borne encephalitis (TBE) vaccination registry, scarcity of previous serological studies and use of serological methods not distinguishing between antibodies induced by vaccination and infection. Furthermore, the number of notified TBE cases in Sweden has continued to increase in recent years despite increased vaccination.

    Aim: The aim was to estimate the TBEV seroprevalence in Sweden.

    Methods: In 2018 and 2019, 2,700 serum samples from blood donors in nine Swedish regions were analysed using a serological method that can distinguish antibodies induced by vaccination from antibodies elicited by infection. The regions were chosen to reflect differences in notified TBE incidence.

    Results: The overall seroprevalence varied from 9.7% (95% confidence interval (CI): 6.6-13.6%) to 64.0% (95% CI: 58.3- 69.4%) between regions. The proportion of vaccinated individuals ranged from 8.7% (95% CI: 5.8-12.6) to 57.0% (95% CI: 51.2-62.6) and of infected from 1.0% (95% CI: 0.2-3.0) to 7.0% (95% CI: 4.5-10.7). Thus, more than 160,000 and 1,600,000 individuals could have been infected by TBEV and vaccinated against TBE, respectively. The mean manifestation index was 3.1%.

    Conclusion: A difference was observed between low- and high -incidence TBE regions, on the overall TBEV seroprevalence and when separated into vaccinated and infected individuals. The estimated incidence and manifestation index argue that a large proportion of TBEV infections are not diagnosed.

    Download full text (pdf)
    FULLTEXT01
  • 274.
    Albinsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Lab Clin Microbiol, Uppsala, Sweden..
    Jääskeläine, Anu E.
    Univ Helsinki, Dept Virol, Helsinki, Finland.;Helsinki Univ Hosp Lab Serv HUSLAB, Dept Virol & Immunol, Helsinki, Finland..
    Värv, Kairi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Inst Hlth Dev, Dept Virol & Immunol, Tallinn, Estonia..
    Jelovse, Mateja
    Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia..
    GeurtsvanKessel, Corine
    Erasmus MC, WHO Collaborating Ctr Arbovirus & Viral Haemorrha, Dept Virol, Rotterdam, Netherlands..
    Ven, Sirkka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Reuske, Chantal
    Erasmus MC, WHO Collaborating Ctr Arbovirus & Viral Haemorrha, Dept Virol, Rotterdam, Netherlands.;Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, Bilthoven, Netherlands..
    Golovljova, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Inst Hlth Dev, Dept Virol & Immunol, Tallinn, Estonia..
    Avsic-Zupan, Tatjana
    Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia..
    Vapalaht, Olli
    Univ Helsinki, Dept Virol, Helsinki, Finland.;Helsinki Univ Hosp Lab Serv HUSLAB, Dept Virol & Immunol, Helsinki, Finland.;Univ Helsinki, Dept Vet Biosci, Helsinki, Finland..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Multi laboratory evaluation of ReaScan TBE IgM rapid test, 2016 to 20172020In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 25, no 12, p. 27-36, article id 1900427Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis (TBE) is a potentially severe neurological disease caused by TBE virus (TBEV). In Europe and Asia, TBEV infection has become a growing public health concern and requires fast and specific detection. Aim: In this observational study, we evaluated a rapid TBE IgM test, ReaScan TBE, for usage in a clinical laboratory setting. Methods: Patient sera found negative or positive for TBEV by serological and/or molecular methods in diagnostic laboratories of five European countries endemic for TBEV (Estonia, Finland, Slovenia, the Netherlands and Sweden) were used to assess the sensitivity and specificity of the test. The patients' diagnoses were based on other commercial or quality assured in-house assays, i.e. each laboratory's conventional routine methods. For specificity analysis, serum samples from patients with infections known to cause problems in serology were employed. These samples tested positive for e.g. Epstein-Barr virus, cytomegalovirus and Anaplasma phagocytophilum, or for flaviviruses other than TBEV, i.e. dengue, Japanese encephalitis, West Nile and Zika viruses. Samples from individuals vaccinated against flaviviruses other than TBEV were also included. Altogether, 172 serum samples from patients with acute TBE and 306 TBE IgM negative samples were analysed. Results: Compared with each laboratory's conventional methods, the tested assay had similar sensitivity and specificity (99.4% and 97.7%, respectively). Samples containing potentially interfering antibodies did not cause specificity problems. Conclusion: Regarding diagnosis of acute TBEV infections, ReaScan TBE offers rapid and convenient complementary IgM detection. If used as a stand-alone, it can provide preliminary results in a laboratory or point of care setting.

    Download full text (pdf)
    FULLTEXT01
  • 275.
    Albinsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital, Uppsala.
    Vene, Sirkka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. The Public Health Agency of Sweden, Solna.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Department of Infectious diseases, Eskilstuna.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rönnberg, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital .
    Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 20172018In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 23, no 3, p. 2-7, article id 17-00838Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is an important European vaccine-preventable pathogen. Discrimination of vaccine-induced antibodies from those elicited by infection is important. We studied anti-TBEV IgM/IgG responses, including avidity and neutralisation, by multiplex serology in 50 TBEV patients and 50 TBEV vaccinees. Infection induced antibodies reactive to both whole virus (WV) and non-structural protein 1 (NS1) in 48 clinical cases, whereas 47 TBEV vaccinees had WV, but not NS1 antibodies, enabling efficient discrimination of infection/vaccination.

    Download full text (pdf)
    fulltext
  • 276. Albrecht, Eva
    et al.
    Sillanpaa, Elina
    Karrasch, Stefan
    Alves, Alexessander Couto
    Codd, Veryan
    Hovatta, Iiris
    Buxton, Jessica L.
    Nelson, Christopher P.
    Broer, Linda
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mangino, Massimo
    Willemsen, Gonneke
    Surakka, Ida
    Ferreira, Manuel A. R.
    Amin, Najaf
    Oostra, Ben A.
    Backmand, Hell M.
    Peltonen, Markku
    Sarna, Seppo
    Rantanen, Taina
    Sipila, Sarianna
    Korhonen, Tellervo
    Madden, Pamela A. F.
    Gieger, Christian
    Jorres, Rudolf A.
    Heinrich, Joachim
    Behr, Juergen
    Huber, Rudolf M.
    Peters, Annette
    Strauch, Konstantin
    Wichmann, H. Erich
    Waldenberger, Melanie
    Blakemore, Alexandra I. F.
    de Geus, Eco J. C.
    Nyholt, Dale R.
    Henders, Anjali K.
    Piirila, Paeivi L.
    Rissanen, Aila
    Magnusson, Patrik K. E.
    Vinuela, Ana
    Pietilainen, Kirsi H.
    Martin, Nicholas G.
    Pedersen, Nancy L.
    Boomsma, Dorret I.
    Spector, Tim D.
    van Duijn, Cornelia M.
    Kaprio, Jaakko
    Samani, Nilesh J.
    Jarvelin, Marjo-Riitta
    Schulz, Holger
    Telomere length in circulating leukocytes is associated with lung function and disease2014In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 43, no 4, p. 983-992Article in journal (Refereed)
    Abstract [en]

    Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

  • 277.
    Albrecht, Inka
    et al.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wick, Cecilia
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Tjarnlund, Anna
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Nagaraju, Kanneboyina
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Andrade, Felipe
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA..
    Thompson, Kathryn
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Coley, William
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Phadke, Aditi
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Diaz-Gallo, Lina-Marcela
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Bottai, Matteo
    Karolinska Inst, Inst Environm Med, Unit Biostat, SE-17176 Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Inst, Dept Lab Med, SE-17176 Stockholm, Sweden..
    Chemin, Karine
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Herrath, Jessica
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Johansson, Karin
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wikberg, Anders
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Ytterberg, A. Jimmy
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Danielsson, Olof
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Neurol, Linkoping, Sweden..
    Krystufkova, Olga
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Vencovsky, Jiri
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Wahren-Herlenius, Marie
    Karolinska Inst, Dept Med Solna, Expt Rheumatol Unit, SE-17176 Stockholm, Sweden..
    Padyukov, Leonid
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Lundberg, Ingrid E.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 12, p. 4612-4624Article in journal (Refereed)
    Abstract [en]

    Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.

  • 278.
    Aldenbratt, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lindberg, Christopher
    Johannesson, Elias
    Hammarsten, Ola
    Svensson, Maria K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Estimation of kidney function in patients with primary neuromuscular diseases: is serum cystatin C a better marker of kidney function than creatinine?2022In: JN. Journal of Nephrology, ISSN 1121-8428, E-ISSN 1724-6059, Vol. 35, no 2, p. 493-503Article in journal (Refereed)
    Abstract [en]

    Background: Using serum creatinine leads to an overestimation of kidney function in patients with primary neuromuscular disorders, and reduced kidney function may remain undetected. Cystatin C (CysC) could provide a better estimation.

    Aim: To evaluate the precision, accuracy, and bias of two creatinine-, one cystatin C-based and one combined equation to estimate glomerular filtration rate (eGFR) in patients with primary neuromuscular disease.

    Patients and methods: Of the 418 patients initially identified at the out-patient clinic, data on kidney function was obtained for 145 adult patients (age 46 ± 14 years, BMI 26 ± 6 kg/m2) with primary neuromuscular disease. Kidney function was measured by iohexol clearance, and blood samples for serum creatinine and CysC were drawn simultaneously. Bias was defined as the mean difference between eGFR and measured iohexol clearance, and accuracy as the proportion of eGFRs within ± 10% (P10) of measured clearance.

    Results: Kidney function (iohexol clearance) was 81 ± 19 (38–134) ml/min/1.73m2. All equations overestimated kidney function by 22–60 ml/min/1.73m2. eGFR CysC had the lowest bias overall 22 (95% CI 20–26) ml/min/1.73m2 also at all levels of kidney function we evaluated (at 30–59 ml/min/1.73m2 bias was 27 (95% CI 21–35), at 60–89 it was 25 (95% CI 20–28) and at ≥ 90 it was 12 (95% CI 7–22)). eGFR CysC also had the best accuracy in patients with reduced kidney function (P10 was 5.9% at 30–59 ml/min/1.73m2).

    Conclusions: Cystatin C-based estimations of kidney function performed better than creatinine-based ones in patients with primary neuromuscular disease, but most importantly, all evaluated equations overestimated kidney function, especially in patients with reduced kidney function. Therefore, kidney function should be measured by gold-standard methods when precision and accuracy are needed.

    Download full text (pdf)
    fulltext
  • 279.
    Aldenbratt, Annika
    et al.
    Sahlgrens Univ Hosp, Dept Nephrol, Gothenburg, Sweden.
    Lindberg, Christopher
    Sahlgrens Univ Hosp, Dept Neurol, Neuromuscular Ctr, Gothenburg, Sweden.
    Svensson, Maria K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Reduced renal function in patients with Myotonic Dystrophy type 1 and the association to CTG expansion and other potential risk factors for chronic kidney disease2017In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 27, no 11, p. 1038-1042Article in journal (Refereed)
    Abstract [en]

    Myotonic dystrophy type 1 (DM1) affects several organs. Disease severity and age at onset are correlated to the CTG repeat expansion. The aim of this study was to assess renal function and the association to numbers of CTG repeat expansion in patients with DM1. Ninety-eight patients with DM1 were included. Glomerular filtration rate (measured GFR) was measured using iohexol clearance. Data on CTG repeats were available in 83/98 (85%) patients. The overall mGFR was 74 (16) ml/min/1.73 m(2) (range 38-134). Sixty-four patients (69%) had a mild and sixteen patients (17%) a moderate decrease in renal function (mGFR 60-89 and 30-59 ml/min/1.73 m(2), respectively). No correlations were found between CTG repeats and mGFR (r = 0.10, p = 0.4) or between CTG repeats and serum cystatin C (r = 0.12, p = 0.29). CTG repeats was positively correlated to creatinine-based estimates of GFR (eGFR) (modified diet in renal disease r = 0.49, p < 0.001, CKD-EPI creatinine equation; r = 0.50, p < 0.001), but analyses using Structural Equation Modeling showed no correlation. The correlation was explained by an indirect effect via serum creatinine and skeletal muscle mass index. In conclusion, patients with DM1 seem to have a slight decrease in renal function but there is no association between renal function and the number of CTG repeats, a marker of disease severity.

  • 280.
    Alderborn, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Siegbahn, A
    Faculty of Medicine, Department of Medical Sciences.
    Wadelius, C
    Department of Genetics and Pathology.
    Venous thrombosis: factor V G1691A genotyping related to APC resistance as measured by 2 methods1997In: Eur J Haematol, Vol. 58, p. 229-Article in journal (Refereed)
  • 281.
    Alderborn, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundström, Jens
    Soeria-Atmadja, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandberg, Martin
    Andersson, H. Christer
    Hammerling, Ulf
    Genetically modified plants for non-food or non-feed purposes: straightforward screening for their appearance in food and feed2010In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 48, no 2, p. 453-464Article in journal (Refereed)
    Abstract [en]

    Genetically modified (GM) plants aimed at producing food/feed are part of regular agriculture in many areas of the World. Commodity plants have also found application as bioreactors, designated non-food/non-feed GM (NFGM) plants, thereby making raw material for further refinement to industrial, diagnostic or pharmaceutical preparations. Many among them may pose health challenge to consumers or livestock animals, if occurring in food/feed. NFGM plants are typically released into the environment, but are grown under special oversight and any among several containment practices, none of which provide full protection against accidental dispersal. Adventitious admixture with food or feed can occur either through distributional mismanagement or as a consequence of gene flow to plant relatives. To facilitate NFGM surveillance we propose a new mandatory tagging of essentially all such plants, prior to cultivation or marketing in the European Union. The suggested tag--Plant-Made Industrial or Pharmaceutical Products Tag (PMIP-T)--is envisaged to occur as a transgenic silent DNA identifier in host plants and designed to enable technically simple identification and characterisation of any NFGM. Implementation of PMIP-T would permit inexpensive, reliable and high-throughput screening for NFGM specifically. The paper outlines key NFGM prospects and challenges as well as the PMIP-T concept.

  • 282. Alderling, Magnus
    et al.
    de la Torre, Bartolomé
    Forsell, Yvonne
    Lundberg, Ingvar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Arbets- och miljömedicin.
    Sondergaard, Hans Peter
    Theorell, Tores
    Psychiatric diagnoses and circadian saliva cortisol variations in a Swedish population-based sample (the PART study).2008In: Psychother Psychosom, ISSN 1423-0348, Vol. 77, no 2, p. 129-31Article in journal (Refereed)
  • 283. Alderman, J. McKee
    et al.
    Flurkey, Kevin
    Brooks, Natasha L.
    Naik, Sneha B.
    Gutierrez, Jonathan M.
    Srinivas, Urmila
    Ziara, Kristen B.
    Jing, Linhong
    Boysen, Gunnar
    Bronson, Rod
    Klebanov, Simon
    Chen, Xian
    Swenberg, James A.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Parker, Carol E.
    Harrison, David E.
    Combs, Terry P.
    Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice2009In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 44, no 1-2, p. 26-33Article in journal (Refereed)
    Abstract [en]

    Pit1 null (Snell dwarf) and Proph1 null (Ames dwarf) mutant mice lack GH, PRL and TSH. Snell and Ames dwarf mice also exhibit reduced IGF-I, resistance to cancer and a longer lifespan than control mice. Endogenous glucose production during fasting is reduced in Snell dwarf mice compared to fasting control mice. In view of cancer cell dependence on glucose for energy, low endogenous glucose production may provide Snell dwarf mice with resistance to cancer. We investigated whether endogenous glucose production is lower in Snell dwarf mice during feeding. Inhibition of endogenous glucose production by glucose injection was enhanced in 12 to 14 month-old female Snell dwarf mice. Thus, we hypothesize that lower endogenous glucose production during feeding and fasting reduces cancer cell glucose utilization providing Snell dwarf mice with resistance to cancer. The elevation of circulating adiponectin, a hormone produced by adipose tissue, may contribute to the suppression of endogenous glucose production in 12 to 14 month-old Snell dwarf mice. We compared the incidence of cancer at time of death between old Snell dwarf and control mice. Only 18% of old Snell dwarf mice had malignant lesions at the time of death compared to 82% of control mice. The median ages at death for old Snell dwarf and control mice were 33 and 26 months, respectively. By contrast, previous studies showed a high incidence of cancer in old Ames dwarf mice at the time of death. Hence, resistance to cancer in old Snell dwarf mice may be mediated by neuroendocrine factors that reduce glucose utilization besides elevated adiponectin, reduced IGF-I and a lack of GH, PRL and TSH, seen in both Snell and Ames dwarf mice. Proteomics analysis of pituitary secretions from Snell dwarf mice confirmed the absence of GH and PRL, the secretion of ACTH and elevated secretion of Chromogranin B and Secretogranin II. Radioimmune assays confirmed that circulating Chromogranin B and Secretogranin II were elevated in 12 to 14 month-old Snell dwarf mice. In summary, our results in Snell dwarf mice suggest that the pituitary gland and adipose tissue are part of a neuroendocrine loop that lowers the risk of cancer during aging by reducing the availability of glucose.

  • 284.
    Alderson, Helen V
    et al.
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK.
    Chinnadurai, Rajkumar
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK..
    Ibrahim, Sara T
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK..
    Asar, Ozgur
    Department of Biostatistics and Medical Informatics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey..
    Ritchie, James P
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK..
    Middleton, Rachel
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Diggle, Peter J
    CHICAS, Lancaster Medical School, Lancaster University, Lancaster, UK..
    Larsson, Tobias E
    Department of Clinical Science, Intervention and Technology, Renal Unit, Karolinska Institute, Stockholm, Sweden..
    Kalra, Philip A
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK..
    Longitudinal change in c-terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease2021In: BMC Nephrology, ISSN 1471-2369, E-ISSN 1471-2369, Vol. 22, no 1, article id 329Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes.

    METHODS: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis.

    RESULTS: Across our population, median baseline eGFR was 32.3mls/min/1.73m2, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events.

    CONCLUSION: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.

    Download full text (pdf)
    fulltext
  • 285.
    Alderson, Helen V.
    et al.
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK;Salford Royal NHS Foundation Trust, Salford, UK..
    Ritchie, James P
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK;Salford Royal NHS Foundation Trust, Salford, UK..
    Middleton, Rachel
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK;Salford Royal NHS Foundation Trust, Salford, UK..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Tobias E
    Department of Clinical Science, Intervention and Technology, Renal Unit, Karolinska Institute, Stockholm, Sweden..
    Kalra, Philip A
    Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK;Salford Royal NHS Foundation Trust, Salford, UK..
    FGF-23 and Osteoprotegerin but not Fetuin-A are associated with death and enhance risk prediction in non-dialysis chronic kidney disease stages 3-52016In: Nephrology (Carlton. Print), ISSN 1320-5358, E-ISSN 1440-1797, Vol. 21, no 7, p. 566-573Article in journal (Refereed)
    Abstract [en]

    AIM: Numerous biomarkers have been shown to associate with clinical endpoints in chronic kidney disease (CKD). There is limited evidence whether biomarkers improve risk prediction in relation to clinical outcomes. Our study investigates whether a small suite of key chronic kidney disease-mineral and bone disorder biomarkers could be used to enhance risk assessment in CKD.

    METHODS: Fetuin-A, fibroblast growth factor-23 and osteoprotegerin were measured on baseline plasma samples from 463 patients recruited to the Chronic Renal Insufficiency Standards Implementation Study. The biomarkers were analysed in relation to progression to end stage kidney disease, death and major cardiovascular events.

    RESULTS: Over a median follow up of 46 months (interquartile range 21-69), fibroblast growth factor-23 was associated with risk for renal replacement therapy (hazard ratio (HR) 1.35, P = 0.05, 95% confidence interval (CI) 1.001-1.820), cardiovascular events (HR 1.74 P < 0.001, 95% CI 1.303-1.305) and death (HR 1.4 P = 0.005, 95% CI 1.109-1.767). Osteoprotegerin was associated with risk for death (HR 1.06, P = 0.03, 95% CI 1.006-1.117). There was no clear association between Fetuin-A and any of the clinical endpoints. The addition of biomarkers to risk models led to marginal improvement in model discrimination and reclassification.

    CONCLUSION: Biomarkers are often associated with clinical endpoints, and we observed such associations in our study of patients with advanced CKD. However, the markers analysed in our study were of limited benefit in improving the prediction of these outcomes. Any extra information biomarkers may provide to improve risk prediction in clinical practice needs to be carefully balanced against the potential cost of these tools.

  • 286. Aldridge, Ruth E.
    et al.
    Chan, Tim
    van Dalen, Christine J.
    Senthilmohan, Revathy
    Winn, Marti
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Town, G. Ian
    Kettle, Anthony J.
    Eosinophil peroxidase produces hypobromous acid in the airways of stable asthmatics2002In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 33, no 6, p. 847-856Article in journal (Refereed)
    Abstract [en]

    Eosinophil peroxidase and myeloperoxidase use hydrogen peroxide to produce hypobromous acid and hypochlorous acid. These powerful oxidants may damage the lungs if they are produced as part of the inflammatory response in asthma. The aim of this study was to determine if peroxidases generate hypohalous acids in the airways of individuals with stable asthma, and if they affect lung function. Sputum was induced from patients with mild to moderate asthma and from healthy controls. Eosinophil peroxidase, myeloperoxidase, chlorinated and brominated tyrosyl residues, and protein carbonyls were measured in sputum supernatants. Eosinophil peroxidase protein was significantly elevated in asthmatic subjects whereas myeloperoxidase protein was not. There was significantly more 3-bromotyrosine (Br-Tyr) in proteins from the sputum of asthmatics compared to controls (0.79 vs. 0.23 mmol Br-Tyr/mol Tyr; medians p < .0001). Levels of 3-chlorotyrosine (0.23 vs. 0.14 mmol Cl-Tyr/mol Tyr; medians p = .11) and protein carbonyls (0.347 vs. 0.339 nmol/mg protein; medians p = .56) were not significantly increased in asthmatics. Levels of 3-bromotyrosine were strongly correlated with eosinophil peroxidase protein (r = 0.79, p < .0001). There were no significant correlations between the markers of oxidative stress and lung function. We conclude that eosinophil peroxidase produces substantial amounts of hypobromous acid in the airways of stable asthmatics. Although this highly reactive oxidant is a strong candidate for exacerbating inflammatory tissue damage in the lung, its role in asthma remains uncertain.

  • 287.
    Aldrimer, Mattias
    et al.
    Department of Clinical Chemistry, County Hospital of Falun.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rodoo, Peo
    Department of Pediatrics, County Hospital of Falun.
    Niklasson, Frank
    Department of Clinical Chemistry, County Hospital of Falun.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hellberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Population-based pediatric reference intervals for hematology, iron and transferrin2013In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 73, no 3, p. 253-261Article in journal (Refereed)
    Abstract [en]

    Reference intervals are crucial decision-making tools aiding clinicians in differentiating between healthy and diseased populations. However, for children such values often are lacking or incomplete. Blood samples were obtained from 689 healthy children, aged 6 months to 18 years, recruited in day care centers and schools. Hematology and anemia analytes were measured on the Siemens Advia 2120 and Abbott Architect ci8200 platforms (hemoglobin, erythrocyte volume fraction [EVF], erythrocytes, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], reticulocytes, leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, platelets, iron, transferrin, transferrin saturation). Age-and gender-specific pediatric reference intervals were defined by calculating 2.5th and 97.5th percentiles. The data generated is primarily applicable to a Caucasian population, but could be used by any laboratory if verified for the local patient population.

  • 288. Aldrimer, Mattias
    et al.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rodoo, Peo
    Niklasson, Frank
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hellberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Reference intervals on the Abbot Architect for serum thyroid hormones, lipids and prolactin in healthy children in a population-based study2012In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 72, no 4, p. 326-332Article in journal (Refereed)
    Abstract [en]

    Pediatric reference intervals for thyroid hormones, prolactin and lipids are of high clinical importance as deviations might indicate diseases with serious consequences. In general, previous reference intervals are hampered by the inclusion of only hospital-based populations of children and adolescents. The study included 694 children, evenly distributed from 6 months to 18 years of age. They were recruited as volunteers at child care units and schools. All subjects were apparently healthy and a questionnaire on diseases and medications was filled out by parents and by the older children. TSH, free T4, free T3, total cholesterol, LDL, HDL, triglycerides and prolactin were analyzed on Abbott Architect ci8200. Age- and gender-related 2.5 and 97.5 percentiles were estimated. The thyroid hormone levels were similar to previous data for the Abbott Architect platform, but exhibited differences from studies performed with other methods. Prolactin displayed wide reference ranges, but relatively small age-related changes, and a marginal difference between sexes during adolescence. Reference intervals for lipids in the different age groups are known to vary geographically. Levels of LDL and total cholesterol were higher than those reported for children in Canada, but lower than those reported for children in China. The study gives age-and gender-specific pediatric reference intervals, measured with modern methods for a number of important analytes. The results presented here differ from previously recommended reference intervals. In many earlier studies, retrospective hospital-based reference intervals, which may include various sub-groups have been presented. By non-hospital studies it is possible to avoid some of these biases.

  • 289.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, SE-581 85 Linköping, Sweden.
    Aaseth, Jan
    Research Department, Innlandet Hospital Trust, N-2381 Brumunddal, Norway.
    Alexander, Jan
    Norwegian Institute of Public Health, N-0403 Oslo, Norway.
    Brismar, Kerstin
    Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Selenium and Coenzyme Q10 Supplementation Improves Renal Function in Elderly Deficient in Selenium: Observational Results and Results from a Subgroup Analysis of a Prospective Randomised Double-Blind Placebo-Controlled Trial2020In: Nutrients, E-ISSN 2072-6643, Vol. 12, no 12, article id 3780Article in journal (Refereed)
    Abstract [en]

    A low selenium intake is found in European countries, and is associated with increased cardiovascular mortality. There is an association between selenium level and the severity of kidney disease. An association between inflammation and selenium intake is also reported. The coenzyme Q10 level is decreased in kidney disease. The aim of this study was to examine a possible association between selenium and renal function in an elderly population low in selenium and coenzyme Q10, and the impact of intervention with selenium and coenzyme Q10 on the renal function. The association between selenium status and creatinine was studied in 589 elderly persons. In 215 of these (mean age 71 years) a randomised double-blind placebo-controlled prospective trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 117) or placebo (n = 98) was conducted. Renal function was determined using measures of glomerular function at the start and after 48 months. The follow-up time was 5.1 years. All individuals were low on selenium (mean 67 μg/L (SD 16.8)). The changes in renal function were evaluated by measurement of creatinine, cystatin-C, and the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm, and by the use of T-tests, repeated measures of variance and ANCOVA analyses. An association between low selenium status and impaired renal function was observed. Intervention causes a significantly lower serum creatinine, and cystatin-C concentration in the active treatment group compared with those on placebo (p = 0.0002 and p = 0.001 resp.). The evaluation with CKD-EPI based on both creatinine and cystatin-C showed a corresponding significant difference (p < 0.0001). All validations showed corresponding significant differences. In individuals with a deficiency of selenium and coenzyme Q10, low selenium status is related to impaired renal function, and thus supplementation with selenium and coenzyme Q10 results in significantly improved renal function as seen from creatinine and cystatin-C and through the CKD-EPI algorithm. The explanation could be related to positive effects on inflammation and oxidative stress as a result of the supplementation.

    Download full text (pdf)
    fulltext
  • 290.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
    Aaseth, Jan
    Research Department, Innlandet Hospital Trust, N-2381 Brumunddal, Norway.
    Alexander, Jan
    Norwegian Institute of Public Health, P.O. Box 222 Skøyen, N-0213 Oslo, Norway.
    Johansson, Peter
    Department of Social and Welfare studies & Department of Medical and Health Sciences, Linköping University, SE-601 74 Norrköping, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Supplemental selenium and coenzyme Q10 reduce glycation along with cardiovascular mortality in an elderly population with low selenium status: A four-year, prospective, randomised, double-blind placebo-controlled trial2020In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 61, article id 126541Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A low intake of selenium has been shown to increase the risk of cardiovascular mortality, and supplementation of selenium and coenzyme Q10 influences this. The mechanism behind is unclear although effects on inflammation, oxidative stress and microRNA expression have been reported. Fructosamine, a marker of long-term glycaemic control, is also a marker of increased risk of heart disease and death, even in non-diabetics.

    OBJECTIVE: To analyse the impact of selenium and coenzyme Q10 supplementation on the concentration of fructosamine. Also, the relation between pre-intervention serum selenium concentration and the effect on fructosamine of the intervention was studied.

    METHODS: Fructosamine plasma concentration was determined in 219 participants after six and 42 months of intervention with selenium yeast (200 μg/day) and coenzyme Q10 (200 mg/ day) (n = 118 of which 20 had diabetes at inclusion), or placebo (n = 101 of which 18 had diabetes at inclusion). Pre-intervention, the serum selenium levels were 67 μg/L (active treatment group: 66.6 μg/L; placebo group: 67.4 μg/L), corresponding to an estimated intake of 35 μg/day. Changes in concentrations of fructosamine following intervention were assessed by the use of T-tests, repeated measures of variance, and ANCOVA analyses.

    RESULTS: Post-intervention selenium concentrations were 210 μg/L in the active group and 72 μg/L in the placebo group. A lower concentration of fructosamine could be seen as a result of the intervention in the total population (P = 0.001) in both the males (P = 0.04) and in the females (P = 0.01) in the non-diabetic population (P = 0.002), and in both the younger (<76 years) (P = 0.01) and the older (≥76 years) participants (P = 0.03). No difference could be demonstrated in fructosamine concentration in the diabetic patients, but the total sample was small (n = 38). In subjects with a low pre-intervention level of serum selenium the intervention gave a more pronounced decrease in fructosamine compared with those with a higher baseline selenium level.

    CONCLUSION: A significantly lower concentration of fructosamine was observed in the elderly community-living participants supplemented with selenium and coenzyme Q10 for 42 months compared to those on the placebo. As oxidative mechanisms are involved in the glycation of proteins, less glycoxidation could be a result of the supplementation of selenium and coenzyme Q10, which could have contributed to lower cardiac mortality and less inflammation, as has earlier been reported.

    Download full text (pdf)
    fulltext
  • 291. Alehagen, Urban
    et al.
    Aaseth, Jan
    Alexander, Jan
    Svensson, Erland
    Johansson, Peter
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality?2018In: Biofactors, ISSN 0951-6433, E-ISSN 1872-8081, Vol. 44, no 2, p. 137-147Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In an intervention study where 221 healthy elderly persons received selenium and coenzyme Q10 as a dietary supplement, and 222 received placebo for 4 years we observed improved cardiac function and reduced cardiovascular mortality. As fibrosis is central in the aging process, we investigated the effect of the intervention on biomarkers of fibrogenic activity in a subanalysis of this intervention study.

    MATERIAL AND METHODS: In the present subanalysis 122 actively treated individuals and 101 controls, the effect of the treatment on eight biomarkers of fibrogenic activity were assessed. These biomarkers were: Cathepsin S, Endostatin, Galectin 3, Growth Differentiation Factor-15 (GDF-15), Matrix Metalloproteinases 1 and 9, Tissue Inhibitor of Metalloproteinases 1 (TIMP 1) and Suppression of Tumorigenicity 2 (ST-2). Blood concentrations of these biomarkers after 6 and 42 months were analyzed by the use of T-tests, repeated measures of variance, and factor analyses.

    RESULTS: Compared with placebo, in those receiving supplementation with selenium and coenzyme Q10, all biomarkers except ST2 showed significant decreased concentrations in blood. The changes in concentrations, that is, effects sizes as given by partial eta2 caused by the intervention were considered small to medium.

    CONCLUSION: The significantly decreased biomarker concentrations in those on active treatment with selenium and coenzyme Q10 compared with those on placebo after 36 months of intervention presumably reflect less fibrogenic activity as a result of the intervention. These observations might indicate that reduced fibrosis precedes the reported improvement in cardiac function, thereby explaining some of the positive clinical effects caused by the intervention. © 2017 BioFactors, 2017.

  • 292.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, 81 85 Linköping, Sweden..
    Aaseth, Jan
    Research Department, Innlandet Hospital Trust, 2381 Brumunddal, Norway..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Alexander, Jan
    Norwegian Institute of Public Health, 0403 Oslo, Norway..
    Decreased Concentration of Fibroblast Growth Factor 23 (FGF-23) as a Result of Supplementation with Selenium and Coenzyme Q10 in an Elderly Swedish Population: A Sub-Analysis.2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 3, article id 509Article in journal (Refereed)
    Abstract [en]

    There is a reduced intake of selenium in many countries due to low levels of selenium in the soil. This results in an increased cardiovascular risk. Fibroblast growth factor 23 (FGF-23) is active mainly in the metabolism of vitamin D and phosphorus. However, there are indications that FGF-23 may also provide information both on cardiovascular function and prognosis. The aim of the study was to evaluate the effect of supplementation with selenium and coenzyme Q10 on the FGF-23 concentration in an elderly population with low concentrations of both selenium and coenzyme Q10 and in which the supplementation improved cardiac function and mortality. In a randomised double-blind placebo-controlled trial, FGF-23 was measured in 219 individuals at the start and after 48 months. Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 118) or placebo (n = 101) were given as a dietary supplement. The intervention time was 48 months. t-Tests, repeated measures of variance, and ANCOVA analyses were used to evaluate the differences in FGF-23 concentration. Following supplementation with selenium and coenzyme Q10, a significantly lower level of FGF-23 could be seen (p = 0.01). Applying 10 years of follow-up, those who later died a cardiovascular death had a significantly higher FGF-23 concentration after 48 months compared with those who survived (p = 0.036), and a significantly lower FGF-23 concentration could be seen in those with a normal renal function compared to those with an impaired renal function (p = 0.027). Supplementation with selenium and coenzyme Q10 to an elderly community-living population low in both substances prevented an increase of FGF-23 and also provided a reduced cardiovascular risk.

    Download full text (pdf)
    fulltext
  • 293.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, SE-581 85 Linköping, Sweden..
    Aaseth, Jan
    Research Department, Innlandet Hospital Trust, N-2381 Brumunddal, Norway..
    Lindahl, Tomas L
    Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Alexander, Jan
    Norwegian Institute of Public Health, N-0403 Oslo, Norway..
    Dietary supplementation with selenium and coenzyme Q10 prevents increase in plasma D-dimer while lowering cardiovascular mortality in an elderly Swedish population.2022In: Nutrition, Exercise, and End-of-LifeDiscussion in the Cardiovascular Field / [ed] Fukumoto Y, Basel: MDPI, 2022, p. 43-56Chapter in book (Refereed)
    Abstract [en]

    A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q10. D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q10 on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 106) or placebo (n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly lower D-dimer concentration was observed in the active treatment group in comparison with those on placebo (p = 0.006). Although D-dimer values at baseline were weakly associated with high-sensitive CRP, while being more strongly associated with soluble tumour necrosis factor receptor 1 and sP-selectin, controlling for these in the analysis there was an independent effect on D-dimer. In participants with a D-dimer level above median at baseline, the supplementation resulted in significantly lower cardiovascular mortality compared to those on placebo (p = 0.014). All results were validated with a persisting significant difference between the two groups. Therefore, supplementation with selenium and coenzyme Q10 in a group of elderly low in selenium and coenzyme Q10 prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group. The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk.

  • 294.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, SE-581 85 Linköping, Sweden..
    Aaseth, Jan
    Research Department, Innlandet Hospital Trust, N-2381 Brumunddal, Norway..
    Lindahl, Tomas L
    Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85 Linköping, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Alexander, Jan
    Norwegian Institute of Public Health, N-0403 Oslo, Norway..
    Dietary Supplementation with Selenium and Coenzyme Q10 Prevents Increase in Plasma D-Dimer While Lowering Cardiovascular Mortality in an Elderly Swedish Population.2021In: Nutrients, E-ISSN 2072-6643, Vol. 13, no 4, article id 1344Article in journal (Refereed)
    Abstract [en]

    A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q10. D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q10 on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 106) or placebo (n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly lower D-dimer concentration was observed in the active treatment group in comparison with those on placebo (p = 0.006). Although D-dimer values at baseline were weakly associated with high-sensitive CRP, while being more strongly associated with soluble tumour necrosis factor receptor 1 and sP-selectin, controlling for these in the analysis there was an independent effect on D-dimer. In participants with a D-dimer level above median at baseline, the supplementation resulted in significantly lower cardiovascular mortality compared to those on placebo (p = 0.014). All results were validated with a persisting significant difference between the two groups. Therefore, supplementation with selenium and coenzyme Q10 in a group of elderly low in selenium and coenzyme Q10 prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group. The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk.

    Download full text (pdf)
    fulltext
  • 295.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, 581 85, Linköping, Sweden.
    Alexander, J.
    Norwegian Institute of Public Health, 0403, Oslo, Norway.
    Aaseth, J.
    Research Department, Innlandet Hospital Trust, 2381, Brumunddal, Norway.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lindahl, T. L.
    Division of Clinical Chemistry, Department of Experimental and Clinical Medicine, Linköping University, 581 85, Linköping, Sweden.
    Significant decrease of von Willebrand factor and plasminogen activator inhibitor-1 by providing supplementation with selenium and coenzyme Q10 to an elderly population with a low selenium status2020In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 59, no 8, p. 3581-3590Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Endothelial dysfunction and inflammation are conditions which fuel atherosclerosis and ischaemic heart disease. We have previously reported reduced cardiovascular (CV) mortality following supplementation with selenium and coenzyme Q10 to 443 elderly individuals with low selenium status (mean 67 μg/L) for 4 years. Here, we wanted to evaluate a possible association between the supplementation and the plasma concentrations of the von Willebrand factor (vWf), and the plasminogen activator inhibitor-1 (PAI-1), as they, besides other functions, are also strongly associated with endothelial function.

    METHODS: In this sub-study, 308 individuals (active substance: 157, placebo: 151) were included. Blood samples were drawn after 6 and 36 months and vWf and PAI-1 were determined in plasma by ELISA. Changes in concentrations of the biomarkers were evaluated by the use of T tests, repeated measures of variance, and ANCOVA analyses.

    RESULTS: The active treatment group presented a lower level of vWf after 36 months compared with the placebo group (1.08 U/mL vs. 5.10 U/mL; p = 0.0007). The results were validated through the repeated measures of variance evaluation. The PAI-1 levels showed an equally significant decrease in the active group (26.2 ng/mL vs. 49.2 ng/mL; p = 0.0002) and were also validated through repeated measures of variance evaluation.

    CONCLUSION: In this sub-study on elderly receiving selenium and coenzyme Q10, or placebo we found significantly lower levels of vWf and PAI-1 in the active treatment group as compared to the placebo group. We interpret this as a better endothelial function because of the intervention, which accords with a previous finding of reduced CV mortality.

    Download full text (pdf)
    fulltext
  • 296.
    Alehagen, Urban
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Div Cardiovasc Med, SE-58185 Linkoping, Sweden.
    Alexander, Jan
    Norwegian Inst Publ Hlth, N-0403 Oslo, Norway.
    Aaseth, Jan
    Innlandet Hosp Trust, Res Dept, Brumunddal, Norway;Inland Norway Univ Appl Sci, N-2411 Elverum, Norway.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK2019In: Journal of Inflammation, E-ISSN 1476-9255, Vol. 16, article id 5Article in journal (Refereed)
    Abstract [en]

    Background:

    Inflammation is central to the pathogenesis of many diseases. Supplementation with selenium and coenzyme Q10 has been shown to reduce cardiovascular mortality, and increase cardiac function in elderly persons with a low intake of selenium. There are indications that one of the mechanisms of this positive effect is a decrease in inflammation.

    Methods:

    Osteopontin, osteoprotegerin, sTNF receptor 1, sTNF receptor 2 and the tumor necrosis factor-like weak inducer of apoptosis called TWEAK, were determined in plasma after 6 months and 42months in 219 community-living elderly persons, of whom 119 received supplements of selenium (200g/day) and coenzyme Q10 (200mg/day), and 101 received a placebo. Repeated measures of variance were used to evaluate the levels, and the results were validated through ANCOVA analyses with adjustments for important covariates.

    Results:

    Significantly lower concentrations of four of the five biomarkers for inflammation were observed as a result of the intervention with the supplements. Only TWEAK did not show significant differences.

    Conclusion:

    In this sub-analysis of the intervention with selenium and coenzyme Q10 or placebo in an elderly community-living population, biomarkers for inflammation were evaluated. A significantly lower concentration in four of the five biomarkers tested could be demonstrated as a result of the supplementation, indicating a robust effect on the inflammatory system. The decrease in inflammation could be one of the mechanisms behind the positive clinical results on reduced cardiovascular morbidity and mortality reported earlier as a result of the intervention. The study is small and should be regarded as hypothesis-generating, but nonetheless adds important data about mechanisms presently known to increase the risk of clinical effects such as reduced cardiovascular mortality, increased cardiac function and better health-related quality of life scoring, as previously demonstrated in the active treatment group.

    Download full text (pdf)
    FULLTEXT01
  • 297.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, 581 85, Linköping, Sweden..
    Alexander, Jan
    Norwegian Institute of Public Health, Oslo, Norway..
    Aaseth, Jan O
    Department of Research, Innlandet Hospital Trust, Brumunddal, Norway..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Opstad, Trine B
    Center for Clinical Heart Research - Laboratory, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway..
    Supplementation with selenium and coenzyme Q10 in an elderly Swedish population low in selenium - positive effects on thyroid hormones, cardiovascular mortality, and quality of life2024In: BMC Medicine, E-ISSN 1741-7015, Vol. 22, no 1, article id 191Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q10 on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL).

    METHODS: Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses.

    RESULTS: In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q10 for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group.

    CONCLUSIONS: Supplementation with selenium and coenzyme Q10 had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency.

    TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

    Download full text (pdf)
    fulltext
  • 298.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, 581 85 Linköping, Sweden.
    Alexander, Jan
    Norwegian Institute of Public Health, 0213 Oslo, Norway.
    Aaseth, Jan O.
    Department of Research, Innlandet Hospital Trust, 2382 Brumunddal, Norway;Faculty of Health and Social Sciences, Inland Norway University of Applied Sciences, 2624 Lillehammer, Norway.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Svensson, Erland
    Swedish Defence Research Agency, 164 40 Stockholm, Sweden (Ret.).
    Opstad, Trine B.
    Centre for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, 0450 Oslo, Norway;Faculty of Medicine, University of Oslo, 0313 Oslo, Norway.
    Effects of an Intervention with Selenium and Coenzyme Q10 on Five Selected Age-Related Biomarkers in Elderly Swedes Low in Selenium: Results That Point to an Anti-Ageing Effect—A Sub-Analysis of a Previous Prospective Double-Blind Placebo-Controlled Randomised Clinical Trial2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 13, article id 1773Article in journal (Refereed)
    Abstract [en]

    Background: Ageing is associated with cardiovascular disease (CVD). As no single biomarker reflects the full ageing process, we aimed to investigate five CVD- and age-related markers and the effects of selenium and coenzyme Q10 intervention to elucidate the mechanisms that may influence the course of ageing. Methods: This is a sub-study of a previous prospective double-blind placebo-controlled randomized clinical trial that included 441 subjects low in selenium (mean age 77, 49% women). The active treatment group (n = 220) received 200 µg/day of selenium and 200 mg/day of coenzyme Q10, combined. Blood samples were collected at inclusion and after 48 months for measurements of the intercellular adhesion molecule (ICAM-1), adiponectin, leptin, stem cell factor (SCF) and osteoprotegerin (OPG), using ELISAs. Repeated measures of variance and ANCOVA evaluations were used to compare the two groups. In order to better understand and reduce the complexity of the relationship between the biomarkers and age, factor analyses and structural equation modelling (SEM) were performed, and a structural model is presented. Results: Correlation analyses of biomarker values at inclusion in relation to age, and relevant markers related to inflammation, endothelial dysfunction and fibrosis, demonstrated the biomarkers’ association with these pathological processes; however, only ICAM1 and adiponectin were directly correlated with age. SEM analyses showed, however, that the biomarkers ICAM-1, adiponectin, SCF and OPG, but not leptin, all had significant associations with age and formed two independent structural factors, both significantly related to age. While no difference was observed at inclusion, the biomarkers were differently changed in the active treatment and placebo groups (decreasing and increasing levels, respectively) at 48 months (p ≤ 0.02 in all, adjusted), and in the SEM model, they showed an anti-ageing impact. Conclusions: Supplementation with selenium/Q10 influenced the analysed biomarkers in ways indicating an anti-ageing effect, and by applying SEM methodology, the interrelationships between two independent structural factors and age were validated.

    Download full text (pdf)
    fulltext
  • 299.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden..
    Opstad, Trine B
    Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, P.O. Box 4950 Nydalen, N-0424 Oslo, Norway..
    Alexander, Jan
    Norwegian Institute of Public Health, P.O. Box 222 Skøyen, N-0213 Oslo, Norway..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Aaseth, Jan
    Department of Research, Innlandet Hospital Trust, P.O. Box 104, N-2381 Brumunddal, Norway..
    Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing: A Review2021In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 10, article id 1478Article in journal (Refereed)
    Abstract [en]

    Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.a., the enzymes thioredoxin reductases (TXNRD1-3), glutathione peroxidases (GPX1-4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.a., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1-4 and TXNRD1-3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.

    Download full text (pdf)
    fulltext
  • 300.
    Alemany, Montserrat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Stenborg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Terent, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sonninen, Pirkko
    Röntgenavdelningen, Åbo universitetssjukhus, Åbo, Finland.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Coexistence of microhemorrhages and acute spontaneous brain hemorrhage: correlation with signs of microangiopathy and clinical data2006In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 238, no 1, p. 240-7Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To evaluate prospectively with magnetic resonance (MR) imaging the coexistence of microhemorrhages (MHs) in white patients with acute spontaneous intraparenchymal hemorrhage (IPH) and acute ischemic stroke and to study the association with imaging findings of microangiopathy and various clinical data. MATERIALS AND METHODS: Before examinations, informed consents were signed by either the patient or a relative. The study was carried out with the approval of the local ethics committee. MR imaging was performed in 90 patients with acute stroke: 45 with acute spontaneous IPHs (24 men and 21 women; median age, 65 and 68 years, respectively) and 45 age-matched control subjects without intracranial hemorrhages (26 men and 19 women; median age for both, 67 years), as determined at computed tomography. MR imaging included transverse T1- and T2-weighted spin-echo, transverse fluid-attenuated inversion recovery, transverse and coronal T2*-weighted gradient-echo, and, in 50 patients, diffusion-weighted sequences. Presence of MHs and signs of microangiopathy, such as T2 hyperintensities or lacunae, were recorded in the white and deep gray matter. The relationships between MH and IPH and between MH and T2 hyperintensities were analyzed by means of regression analysis. Different clinical features, such as arterial hypertension or diabetes, were registered and correlated with the image findings by means of regression analysis. RESULTS: MHs were found in 64% of patients with IPH (29 of 45) and 18% of control subjects (eight of 45). A statistically significant relationship between MH and IPH was determined (P < .001). Among the 29 patients with IPH and MH, 24 (83%) had T2 hyperintensities and 13 (45%) had lacunae; among the 16 patients without MH, seven (44%) had T2 hyperintensities and three (19%) had lacunae. A relationship between MH and occurrence and extent of T2 hyperintensities was also identified (P < .001). There was no clear relationship with the clinical data studied. CONCLUSION: The results support a correlation between the presence of imaging signs of cerebral microangiopathy, clinically silent MHs, and acute IPHs. RSNA, 2006.

3456789 251 - 300 of 17990
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf