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  • 1.
    Alvehus, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blomquist, Caroline
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Larsson, Christel
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sandberg, Susanne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ingegerd, Söderström
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Decreased TLR4 and Increased MIF Adipose Gene Expression Following Long-Term Diet InterventionManuscript (preprint) (Other academic)
  • 2.
    Alvehus, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Simonyte, Kotryna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Andersson, Therése
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rask, Eva
    Örebro Univ Hosp, Dept Med, Örebro, Sweden.
    Mattsson, Cecilia
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Adipose tissue IL-8 is increased in normal weight women after menopause and reduced after gastric bypass surgery in obese women2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 5, p. 684-690Article in journal (Refereed)
    Abstract [en]

    Objective:  The menopausal transition is characterized by increased body fat accumulation, including redistribution from peripheral to central fat depots. This distribution is associated with an increased risk of type 2 diabetes and cardiovascular disease which are linked to low-grade inflammation. We determined whether postmenopausal women have higher levels of inflammatory markers, compared to premenopausal women. We also wanted to determine if these markers are reduced by stable weight loss in obese women. Design and methods:  Anthropometric data, blood samples, and subcutaneous adipose tissue biopsies were collected from normal weight premenopausal and postmenopausal women and obese women before and 2 years after gastric bypass surgery. Serum protein levels and adipose tissue gene expression of inflammatory markers were investigated. Results:  IL-8 expression in adipose tissue and circulating levels were higher in postmenopausal versus premenopausal women. IL-8 expression was associated with waist circumference, independent of menopausal status. IL-6 expression and serum levels of monocyte chemoattractant protein (MCP)-1 were higher in postmenopausal versus premenopausal women. Two years after gastric bypass surgery, adipose expression of IL-8, tumor necrosis factor-α, and MCP-1 decreased significantly. Serum insulin levels were associated with inflammation-related gene expression before gastric bypass surgery, but these associations disappeared after surgery. Conclusion:  Postmenopausal women have an increased inflammatory response in the subcutaneous fat and circulation. Inflammatory markers in adipose tissue decreased significantly after surgery-induced weight loss. This effect may be beneficial for metabolic control and reduced cardiovascular risk after weight loss. © 2011 Blackwell Publishing Ltd.

  • 3.
    Andersson, Therese
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    McInnes, Kerry
    Endocrine Unit, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
    Simonyte, Kotryna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rask, Eva
    Institutionen för medicin, Örebro universitetssjukhus, Örebro, Sverige.
    Mattsson, Cecilia
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Seckl, Jonathan R
    Endocrinology Unit, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Estrogen upregulates 11β-hydroxysteroid dehydrogenase type 1 in adipose tissues via estrogen receptor βManuscript (preprint) (Other academic)
  • 4.
    Andersson, Therése
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Simonyté, Kotryna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Estrogen reduces 11beta-hydroxysteroid dehydrogenase type 1 in liver and visceral, but not subcutaneous, adipose tissue in rats2010In: Obesity (Silver Spring, Md.), ISSN 1930-7381, Vol. 18, no 3, p. 470-475Article in journal (Refereed)
    Abstract [en]

    Following menopause, body fat is redistributed from peripheral to central depots. This may be linked to the age related decrease in estrogen levels. We hypothesized that estrogen supplementation could counteract this fat redistribution through tissue-specific modulation of glucocorticoid exposure. We measured fat depot masses and the expression and activity of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in fat and liver of ovariectomized female rats treated with or without 17beta-estradiol. 11betaHSD1 converts inert cortisone, or 11-dehydrocorticosterone in rats into active cortisol and corticosterone. Estradiol-treated rats gained less weight and had significantly lower visceral adipose tissue weight than nontreated rats (P < 0.01); subcutaneous adipose weight was unaltered. In addition, 11betaHSD1 activity/expression was downregulated in liver and visceral, but not subcutaneous, fat of estradiol-treated rats (P < 0.001 for both). This downregulation altered the balance of 11betaHSD1 expression and activity between adipose tissue depots, with higher levels in subcutaneous than visceral adipose tissue of estradiol-treated animals (P < 0.05 for both), opposite the pattern in ovariectomized rats not treated with estradiol (P < 0.001 for mRNA expression). Thus, estrogen modulates fat distribution, at least in part, through effects on tissue-specific glucocorticoid metabolism, suggesting that estrogen replacement therapy could influence obesity related morbidity in postmenopausal women.

  • 5.
    Blomquist, Caroline
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alvehus, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Larsson, Christel
    Department of Food and Nutrition and Sport Science, University of Gothenburg, Gothenburg, Sweden..
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Mellberg, Caroline
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Chorell, Elin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Attenuated Low-Grade Inflammation Following Long-Term Dietary Intervention in Postmenopausal Women with Obesity2017In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 25, no 5, p. 892-900Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Abdominal fat accumulation after menopause is associated with low-grade inflammation and increased risk of metabolic disorders. Effective long-term lifestyle treatment is therefore needed.

    METHODS: Seventy healthy postmenopausal women (age 60 ± 5.6 years) with BMI 32.5 ± 5.5 were randomized to a Paleolithic-type diet (PD) or a prudent control diet (CD) for 24 months. Blood samples and fat biopsies were collected at baseline, 6 months, and 24 months to analyze inflammation-related parameters.

    RESULTS: Android fat decreased significantly more in the PD group (P = 0.009) during the first 6 months with weight maintenance at 24 months in both groups. Long-term significant effects (P < 0.001) on adipose gene expression were found for toll-like receptor 4 (decreased at 24 months) and macrophage migration inhibitory factor (increased at 24 months) in both groups. Serum interleukin 6 (IL-6) and tumor necrosis factor α levels were decreased at 24 months in both groups (P < 0.001) with a significant diet-by-time interaction for serum IL-6 (P = 0.022). High-sensitivity C-reactive protein was decreased in the PD group at 24 months (P = 0.001).

    CONCLUSIONS: A reduction of abdominal obesity in postmenopausal women is linked to specific changes in inflammation-related adipose gene expression.

  • 6.
    Buren, Jonas
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Bergström, Sven-Anders
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Loh, Edmund
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Mattsson, Cecilia
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Hippocampal 11beta-hydroxysteroid dehydrogenase type 1 messenger ribonucleic acid expression has a diurnal variability that is lost in the obese Zucker rat.2007In: Endocrinology, ISSN 0013-7227, Vol. 148, no 6, p. 2716-22Article in journal (Refereed)
  • 7.
    Dahlqvist, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rönnbäck, Annica
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bergström, Sven-Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats2004In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 19, no 8, p. 2288-2298Article in journal (Refereed)
    Abstract [en]

    Cognitive impairment is common after ischemic stroke. In rodent stroke models using occlusion of the middle cerebral artery (MCA) this is reflected by impaired spatial memory associated with the size of the ischemic lesion. Housing in an enriched environment enhances brain plasticity and improves recovery of sensorimotor functions after experimental stroke in rats. In this study we report that postischemic housing in an enriched environment also attenuates the long-term spatial memory impairment after MCA occlusion and extinguishes the association between spatial memory and infarct volume. An enriched environment did not significantly alter the expression of selected neuronal plasticity-associated genes 1 month after MCA occlusion, indicating that most of the adaptive changes induced by an enriched environment have already occurred at this time point. We conclude that the attenuated memory impairment induced by environmental enrichment after MCA occlusion provides a useful model for further studies on the neurobiological mechanisms of recovery of cognitive functions after ischemic stroke.

  • 8.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 1, p. 81-84Article in journal (Refereed)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 9.
    Evans, Juliet
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Collins, Malcolm
    Jennings, Courtney
    van der Merwe, Lize
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Levitt, Naomi S
    Lambert, Estelle V
    Goedecke, Julia H
    The association of interleukin-18 genotype and serum levels with metabolic risk factors for cardiovascular disease.2007In: Eur J Endocrinol, ISSN 1479-683X, Vol. 157, no 5, p. 633-40Article in journal (Refereed)
  • 10. Evans, Juliet
    et al.
    Goedecke, Julia H
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alvehus, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Blomquist, Caroline
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jonsson, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hayes, Philip M
    Adams, Kevin
    Dave, Joel A
    Levitt, Naomi S
    Lambert, Estelle V
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Depot- and ethnic-specific differences in the relationship between adipose tissue inflammation and insulin sensitivity2011In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 74, no 1, p. 51-59Article in journal (Refereed)
    Abstract [en]

    Objective  It is unclear whether there are differences in inflammatory gene expression between abdominal and gluteal subcutaneous adipose tissue (SAT), and between black and white women. We therefore tested the hypotheses that SAT inflammatory gene expression is greater in the abdominal compared to the gluteal depot, and SAT inflammatory gene expression is associated with differential insulin sensitivity (S(I) ) in black and white women.

    Design and methods  S(I) (frequently sampled intravenous glucose tolerance test) and abdominal SAT and gluteal SAT gene expression levels of 13 inflammatory genes were measured in normal-weight (BMI 18-25 kg/m(2) ) and obese (BMI >30 kg/m(2) ) black (n = 30) and white (n = 26) South African women.

    Results  Black women had higher abdominal and gluteal SAT expression of CCL2, CD68, TNF-α and CSF-1 compared to white women (P < 0·01). Multivariate analysis showed that inflammatory gene expression in the white women explained 56·8% of the variance in S(I) (P < 0·005), compared to 20·9% in black women (P = 0·30). Gluteal SAT had lower expression of adiponectin, but higher expression of inflammatory cytokines, macrophage markers and leptin than abdominal SAT depots (P < 0·05).

    Conclusions  Black South African women had higher inflammatory gene expression levels than white women; however, the relationship between AT inflammation and S(I) was stronger in white compared to black women. Further research is required to explore other factors affecting S(I) in black populations. Contrary to our original hypothesis, gluteal SAT had a greater inflammatory gene expression profile than abdominal SAT depots. The protective nature of gluteo-femoral fat therefore requires further investigation.

  • 11.
    Hillörn, Valter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Feld, Sari
    Cilio, Corrado
    Forsgren, Stina
    Hägg, Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundkvist, inger
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Aberrant VHGene Utilization in Patients with Established Insulin-Dependent Diabetes Mellitus1997In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 10, no 2, p. 157-163Article in journal (Refereed)
    Abstract [en]

    We have compared the B-lymphocyte repertoire in seven IDDM patients with 12 healthy controls by examining the variable heavy (VH) gene expression. The VHgene representation in the pool of pokeweed mitogen (PWM) stimulated, immunocompetent B cells and in the pool of naturally activated plasma cells (actual repertoire) was analysed by RNA-RNA in situ hybridization. Differences between IDDM patients and normal controls in the relative expression of several VHgene families were observed. In IDDM patients, the VH3 was significantly underrepresented in the PWM stimulated repertoire. In the actual B cell repertoire the VH5 clones were underrepresented among diabetic patients. Moreover, the altered distribution of VHgene usage between the PWM stimulated repertoire and the actual repertoire observed in normal controls was found to be less pronounced in the IDDM patients. This observation suggests a defect in the V-gene directed cellular selection occurring between resting, immunocompetent B cells and naturally activated plasma cells. The possible implication of the observed aberrations in the B cell selection process for the pathogenesis of autoimmunity is discussed.

  • 12.
    Karling, Pontus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Danielsson, Åke
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikgren, Mikael
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Del-Favero, Jurgen
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    The relationship between the val158met catechol-o-methyltransferase (COMT) polymorphism and irritable bowel syndrome.2011In: PloS one, ISSN 1932-6203, Vol. 6, no 3, p. e18035-Article in journal (Refereed)
    Abstract [en]

    Background

    The catechol-O-methyltransferase (COMT) enzyme has a key function in the degradation of catecholamines and a functional polymorphism is val158met. The val/val genotype results in a three to fourfold higher enzymatic activity compared with the met/met genotype, with the val/met genotype exhibiting intermediate activity. Since pain syndromes as well as anxiety and depression are associated to low and high COMT activity respectively and these conditions are all associated with irritable bowel syndrome (IBS) we wanted for the first time to explore the relationship between the polymorphism and IBS.

    Methodology/Principal Findings

    867 subjects (445 women) representative of the general population and 70 consecutively sampled patients with IBS (61 women) were genotyped for the val158met polymorphism and the IBS patients filled out the Hospital-Anxiety-and-Depression-Scale (HADS) questionnaire, and an IBS symptom diary.

    Results

    There was a significantly higher occurrence of the val/val genotype in patients compared with controls (30% vs 20%; Chi2 (1) 3.98; p = 0.046) and a trend toward a lower occurrence of the val/met genotype in IBS patients compared with controls (39% vs 49%; Chi2 (1) 2.89; p = 0.089). Within the IBS patients the val/val carriers exhibited significantly increased bowel frequency (2.6 vs 1.8 stools per day; Chi2 (1) 5.3; p = 0.03) and a smaller proportion of stools with incomplete defecation (41% vs 68%; Chi2 (1) 4.3; p = 0.04) compared with the rest (val/met+met/met carriers). The val/val carriers also showed a trend for a smaller proportion of hard stools (0% vs 15%; Chi2 (1) 3.2; p = 0.08) and a higher frequency of postprandial defecation (26% vs 21%; Chi2 (1) 3.0; p = 0.08).

    Conclusions/Significance

    In this study we found an association between the val/val genotype of the val158met COMT gene and IBS as well as to specific IBS related bowel pattern in IBS patients.

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  • 13.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 2, p. 383-391Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).

    METHODS: A nested case-control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system.

    RESULTS: The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1beta [IL-1beta], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-gamma, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow-derived factors (IL-7, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1alpha). The levels were particularly increased in anti-cyclic citrullinated peptide antibody- and rheumatoid factor-positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell-related cytokines, while chemokines, stromal cell-derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA.

    CONCLUSION: Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell-related factors); after disease onset, the involvement and activation of the immune system was more general and widespread.

  • 14.
    Ljung, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Bergholm, Robert
    Brink, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karp, Kjell
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Leirisalo-Repo, Marjatta
    Yki-Järvinen, Hannele
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Inflammatory markers in serum and adipose tissue in relation to markers of sub-clinical atherosclerosis in rheumatoid arthritis patientsManuscript (preprint) (Other academic)
  • 15. Macleod, Malcolm R
    et al.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lai, Maggie
    Gidö, Gunilla
    Wieloch, Tadeusz
    Seckl, Jonathan R
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mineralocorticoid receptor expression and increased survival following neuronal injury2003In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 17, no 8, p. 1549-1555Article in journal (Refereed)
    Abstract [en]

    Glucocorticoids, acting via the mineralocorticoid receptor, are required for granule neuronal survival in the rat dentate gyrus. Whether this mineralocorticoid receptor-mediated neuroprotective effect has more general applicability is unknown. Here we report increased mineralocorticoid receptor expression in rat hippocampal and cortical neurons exposed in vitro to low levels of staurosporine and in rat hippocampal pyramidal neurons exposed in vivo to hypothermic transient global ischaemia. In both the cell culture system and the in vivo system increased mineralocorticoid receptor expression is associated with increased neuronal survival, and this increase is reversed by mineralocorticoid receptor antagonism. Modulation of mineralocorticoid receptor gene expression may therefore be an important target for reduction of brain injury in conditions caused by cerebral ischaemia including brain damage following cardiac arrest and stroke.

  • 16. McInnes, Kerry J.
    et al.
    Andersson, Therese C.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Simonyte, Kotryna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mattsson, Cecilia
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Seckl, Jonathan R.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Association of 11 beta-hydroxysteroid dehydrogenase type I expression and activity with estrogen receptor beta in adipose tissue from postmenopausal women2012In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 19, no 12, p. 1347-1352Article in journal (Refereed)
    Abstract [en]

    Objective: 11 beta-Hydroxysteroid dehydrogenase type I (11 beta HSD1) regenerates active cortisol from inert cortisone in adipose tissue. Elevated adipose tissue 11 beta HSD1 activity is observed in obese humans and rodents, where it is linked to obesity and its metabolic consequences. Menopause is also associated with increased abdominal fat accumulation, suggesting that estrogen is also important in adipose tissue metabolism. The purpose of this current study was to establish whether estrogen signaling through estrogen receptor alpha (ER-alpha) and estrogen receptor beta (ER-beta) could influence 11 beta HSD1 in premenopausal and postmenopausal adipose tissues. Methods: Nineteen premenopausal (aged 26 +/- 5 y; body mass index, 23.6 +/- 1.6 kg/m(2)) and 23 postmenopausal (aged 63 +/- 4 y; body mass index, 23.4 +/- 1.9 kg/m(2)) healthy women were studied. Subcutaneous adipose tissue biopsies and fasting venous blood samples were taken. Body composition was measured by bioelectrical impedance analysis. Human Simpson-Golabi-Behmel syndrome adipocyte cells were treated with ER-alpha- and ER-beta-specific agonists for 24 hours. Basic anthropometric data, serum 17 beta-estradiol and progesterone concentrations, ER-alpha and ER-beta messenger RNA (mRNA) levels, and 11 beta HSD1 mRNA, protein, and activity levels were assessed. Results: ER-beta and 11 beta HSD1, but not ER-alpha, mRNAs were significantly increased in adipose tissue from postmenopausal women compared with premenopausal women. ER-beta had a significant positive correlation with the mRNA level of 11 beta HSD1 in adipose tissue from premenopausal and postmenopausal women. This association between ER-beta and 11 beta HSD1 was greatest in adipose tissue from postmenopausal women. In human Simpson-Golabi-Behmel syndrome adipocytes, diarylpropiolnitrile, a selective ER-beta agonist, increased 11 beta HSD1 mRNA, protein, and activity levels. Conclusions: We conclude that, in adipose tissue, ER-beta-mediated estrogen signaling can up-regulate 11 beta HSD1 and that this may be of particular importance in postmenopausal women.

  • 17.
    Otten, Julia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stomby, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waling, Maria
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Isaksson, Andreas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Svensson, Michael
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Hauksson, Jón
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A heterogeneous response of liver and skeletal muscle fat to the combination of a Paleolithic diet and exercise in obese individuals with type 2 diabetes: a randomised controlled trial2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 7, p. 1548-1559Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The aim of the study was to investigate ectopic fat deposition and insulin sensitivity, in a parallel single-blinded randomised controlled trial, comparing Paleolithic diet alone with the combination of Paleolithic diet and exercise in individuals with type 2 diabetes. Methods: Thirty-two individuals with type 2 diabetes with BMI 25-40 kg/m(2) and 30-70 years of age followed a Paleolithic diet ad libitum for 12 weeks. In addition, study participants were randomised by computer program to either supervised combined exercise training (PD-EX group) or standard care exercise recommendations (PD group). Staff performing examinations and assessing outcomes were blinded to group assignment. Thirteen participants were analysed in each group: hepatic and peripheral insulin sensitivity were measured using the hyperinsulinaemic-euglycaemic clamp technique combined with [6,6-H-2(2)]glucose infusion, and liver fat was assessed by proton magnetic resonance spectroscopy; both analyses were secondary endpoints. Intramyocellular lipid (IMCL) content was measured by magnetic resonance spectroscopy as a secondary analysis. All examinations were performed at Umca University Hospital, Umca, Sweden. Results: Both study groups showed a median body weight loss of 7 kg. Fat mass decreased by 5.7 kg in the PD group and by 6.5 kg in the PD-EX group. Maximum oxygen uptake increased in the PD-EX group only. Liver fat showed a consistent reduction (74% decrease) in the PD group, while the response in the PD-EX group was heterogeneous (p < 0.05 for the difference between groups). IMCL content of the soleus muscle decreased by 40% in the PD group and by 22% in the PD-EX group (p < 0.05 for the difference between groups). Both groups improved their peripheral and adipose tissue insulin sensitivity, but not their hepatic insulin sensitivity. Plasma fetuin-A decreased by 11% in the PD group (p < 0.05) and remained unchanged in the PD-EX group. Liver fat changes during the intervention were correlated with changes in fetuin-A (r(S) = 0.63, p < 0.01). Participants did not report any important adverse events caused by the intervention. Conclusions/interpretation: A Paleolithic diet reduced liver fat and IMCL content, while there was a tissue-specific heterogeneous response to added exercise training.

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  • 18.
    Otten, Julia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stomby, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waling, Maria
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Isaksson, Andreas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Svensson, Michael
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Hauksson, Jón
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Exercise training reverses the effect of a Paleolithic diet on liver fat and intramyocellular lipid content in patients with type 2 diabetes2017Conference paper (Refereed)
  • 19.
    Otten, Julia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stomby, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waling, Maria
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Isaksson, Andreas
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Svensson, Michael
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Hauksson, Jón
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Exercise training reverses the effect of a Paleolithic diet on liver fat and intramyocellular lipid content in patients with type 2 diabetes2017Conference paper (Refereed)
  • 20.
    Rojo, Maria Luisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Söderstrom, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Simonyte, Kotryna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effects of dietary glucose and fructose upon cannabinoid CB1 receptor functionality in the rat brain: a pilot study2014In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 108, no 2, p. 116-121Article in journal (Refereed)
    Abstract [en]

    Aims: A high consumption of fructose leads not only to peripheral changes in insulin sensitivity and vascular function, but also to central changes in several brain regions. Given the role of the endogenous cannabinoid system in the control of energy intake, we undertook a pilot study to determine whether a high fructose diet produced changes in brain CB1 receptor functionality. Main methods: Male rats given access ad libitum to normal chow were given either water, glucose or fructose solutions to drink. CBI receptor functionality was measured autoradiographically as the increase in [35SJGTP)/S binding produced by the agonist CP55,940. Key findings: Seven regions were investigated: the prefrontal cortex, caudate-putamen, hippocampal CAI-CA3, dentate gyrus, amygdala, and dorsomedial and ventromedial hypothalami. Two-way robust Wilcoxon analyses for each brain region indicated that the dietary treatment did not produce significant main effects upon agonist-stimulated [35S]GThyS binding in any of the regions, in contrast to a significant main effect upon both leptin and adiponectin levels in the blood. However, a MANCOVA of the data controlling for leptin and adiponectin as co-variables identified a significant effect of glucose and fructose treatment for five weeks upon the [35S]GTPI/S response in the ventromedial hypothalamus, a region of importance for regulation of appetite. Significance: It is concluded from this pilot study that palatable solutions do not produce overt changes in brain CBI receptor functionality, although subtle changes in discrete brain regions may occur.

  • 21.
    Rojo, Maria Luisa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Residual effects of focal brain ischaemia upon cannabinoid CB(1) receptor density and functionality in female rats2011In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1373, p. 195-201Article in journal (Refereed)
    Abstract [en]

    Ischaemic insult results in short-term changes in cannabinoid-1 (CB(1)) receptor expression in the brain, but it is not known whether long-term changes occur, which could potentially mean a change in the intrinsic ability of the brain to withstand new ischaemic episodes. In this study, we have investigated the expression and functionality of CB(1) receptors in coronal brain slices obtained from ovariectomised female rats 46days after middle cerebral artery occlusion (MCAO). The animals were treated with either 17ß-oestradiol or placebo pellets 6h after MCAO and thereafter housed either in isolated or enriched environments. [(3)H]CP55,940 autoradiography indicated no significant effect of 17ß-oestradiol treatment or housing environment upon CB(1) receptor densities. There was, however, a modest but significant decrease in the CB(1) receptor density on the ipsilateral side relative to the contralateral side in the frontal cortex, parietal cortex, CA1-CA3 regions of the hippocampus, thalamus and hypothalamus. CB(1) receptor functionality was assessed by measurement of basal and CP55,940-stimulated [(35)S]GTPγS autoradiography. In the frontal cortex, parietal cortex, CA1-CA3 regions of the hippocampus and dentate gyrus, a robust stimulation, blocked by the CB(1) receptor inverse agonist AM251, was seen. There were no significant changes in the response to CP55,940 with respect either to the 17ß-oestradiol treatment, housing environment or MCAO. Our results reveal that although there are modest long-term decreases in ipsilateral CB(1) receptor densities following MCAO in female rats, these decreases do not result in a functional CB(1) receptor deficit.

  • 22.
    Rojo, Maria Luisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fower, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Changes in cannabinoid CB(1) receptor functionality in the female rat prefrontal cortex following a high fat diet.2013In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 92, no 13, p. 757-762Article in journal (Refereed)
    Abstract [en]

    Aims: A high fat diet (HFD) has been found to affect neurotransmission in the prefrontal cortex, but the effects of this dietary regime upon the endocannabinoid system has not been studied in this brain region. In consequence, in the present study, we have investigated the effect of HFD for up to 20 weeks upon the endocannabinoid system in the prefrontal cortex of female rats.

    Main methods: CB1 receptor functionality was measured using CP55,940-stimulated [S-35] GTP gamma S autoradiography. Fatty acid amide hydrolase and monoacylglycerol lipase activities were analysed in brain regions by assessing rates of [H-3] anandamide and JZL184-sensitive [H-3]2-oleoylglycerol hydrolysis, respectively.

    Key findings: In the prefrontal cortex, a significantly greater stimulation of [S-35] GTP gamma S binding by CP55,940 was seen following 4-12, but not 16-20 weeks of HFD. No significant changes were seen for the caudate-putamen, CA1-CA3 region of the hippocampus or the dentate gyrus. The increased response for the 12 week animals was not accompanied by a significant change in the receptor density, measured with [H-3]CP55,940 autoradiography. No significant changes in the activity of the endocannabinoid hydrolytic enzymes fatty acid amide or monoacylglycerol lipase were seen in the prefrontal cortex, hippocampus, amygdala or hypothalamus following either 12 or 20 weeks of HFD.

    Significance: It is concluded that HFD produces an increased CB1 receptor functionality in the prefrontal cortex of female rats. Given that the endocannabinoid system regulates neurotransmission in the prefrontal cortex, the present data would implicate this system in the disturbed prefrontal cortical activity in this region following a high fat diet.

  • 23.
    Simonyté, Kotryna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sjödin, Andreas
    Division of CBRN Security and Defense, FOI-Swedish Defense Research Agency, Umeå, Sweden .
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Short- and long-term effects of high-fat diet on 11ßHSD1 expression in subcutaneous adipose tissue and liver of female Sprague-Dawley ratsManuscript (preprint) (Other academic)
  • 24.
    Steneberg, Pär
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sykaras, Alexandros G.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Backlund, Fredrik
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Straseviciene, Jurate
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 31, p. 19034-19043Article in journal (Refereed)
    Abstract [en]

    Hepatosteatosis is associated with the development of both hepatic insulin resistance and Type 2 diabetes. Hepatic expression of Cd36, a fatty acid transporter, is enhanced in obese and diabetic murine models and human nonalcoholic fatty liver disease, and thus it correlates with hyperinsulinemia, steatosis, and insulin resistance. Here, we have explored the effect of hyperinsulinemia on hepatic Cd36 expression, development of hepatosteatosis, insulin resistance, and dysglycemia. A 3-week sucrose-enriched diet was sufficient to provoke hyperinsulinemia, hepatosteatosis, hepatic insulin resistance, and dysglycemia in CBA/J mice. The development of hepatic steatosis and insulin resistance in CBA/J mice on a sucrose-enriched diet was paralleled by increased hepatic expression of the transcription factor Ppar gamma and its target gene Cd36 whereas that of genes implicated in lipogenesis, fatty acid oxidation, and VLDL secretion was unaltered. Additionally, we demonstrate that insulin, in a Ppar gamma-dependent manner, is sufficient to directly increase Cd36 expression in perfused livers and isolated hepatocytes. Mouse strains that display low insulin levels, i.e. C57BL6/J, and/or lack hepatic Ppar gamma, i.e. C3H/HeN, do not develop hepatic steatosis, insulin resistance, or dysglycemia on a sucrose-enriched diet, suggesting that elevated insulin levels, via enhanced CD36 expression, provoke fatty liver development that in turn leads to hepatic insulin resistance and dysglycemia. Thus, our data provide evidence for a direct role for hyperinsulinemia in stimulating hepatic Cd36 expression and thus the development of hepatosteatosis, hepatic insulin resistance, and dysglycemia.

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  • 25.
    Strand, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Estrogen Receptor Alpha Gene Polymorphisms and First-Ever Intracerebral Hemorrhage.2007In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 24, no 6, p. 500-508Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Signaling through estrogen receptor alpha (ER alpha) regulates vasodilatation and atherogenesis. Since hypertension and atherosclerosis are major mechanisms in stroke development, we hypothesized that genetic variants of the ER alpha gene (ESR1) are determinants of future ischemic stroke or intracerebral hemorrhage (ICH). METHODS: In a population-based prospective nested case-control study, the relationships between ESR1 polymorphisms (c.454-397T>C and c.454-351A>G) and ischemic stroke and ICH were examined in univariate and multivariate models using conditional logistic regression, which included established risk factors.Definitive first-ever stroke events (n = 388), including ischemic stroke (n = 320), ICH (n = 61), and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex, and geographical region were included. RESULTS: Carriers of the c.454-397T/T genotype had a significantly (p = 0.017) increased risk of ICH (OR 2.31, 95% CI 1.16-4.60) in a univariate analysis. This association persisted (OR 3.94, 95% CI 1.54-10.03), after adjustment for stroke risk determinants. Carriers of c.454-397T/T or c.454-397T/C genotypes had significantly (p = 0.002 and p = 0.004, respectively) higher mean systolic blood pressure (SBP), than carriers of c.454-397C/C, and a similar relationship was observed for diastolic blood pressure (DBP). The combinations of c.454-397T/T genotype and hypertension (OR 21.46, 95% CI 5.20-88.51), or high SBP (OR 18.17, 95% CI 4.91-67.31) or DBP (OR 11.94, 95% CI 3.75-38.03), were strongly associated with increased risk of ICH. CONCLUSIONS: In this population,the c.454-397T/T genotype associates with first-ever ICH, particularly in combination with hypertension. This implies that alterations in ER alpha-mediated signaling may be involved in the pathophysiology of this disease, with a putative impact on primary prevention.

  • 26.
    Strand, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Polymorphisms at the osteoprotegerin and interleukin-6 genes in relation to first-ever stroke.2007In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 24, no 5, p. 418-425Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Arterial calcification and osteoporosis often coexist, especially in postmenopausal women. Osteoporosis associates with a substantially increased risk of stroke in elderly women, suggesting that impaired estrogen signaling may link stroke and osteoporosis. Osteoprotegerin (OPG, TNFRSF11B) and interleukin-6 (IL-6, IL6) are putative target genes for estrogen signaling and have been implicated in both cardiovascular diseases and osteoporosis. We hypothesized that specific polymorphisms in these genes may be associated with increased risk of ischemic stroke or intracerebral hemorrhage (ICH). METHODS: We performed a population-based prospective nested case-control study, in which the relationships between polymorphisms (OPG-1181G/C, OPG-950T/C and IL6-174G/C) and ischemic stroke and ICH were examined. Definitive first-ever stroke events (n = 388), i.e. ischemic stroke (n = 320), ICH (n = 61) and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex and geographical region were studied. Univariate and multivariate models using conditional logistic regression, which included traditional risk factors, were used to test for association. RESULTS: Carriers of the OPG-1181C/C genotype had a significantly (p = 0.018) increased risk of ICH (OR, 2.69; 95% CI, 1.19-6.12) in the univariate analysis. After adjustments (hypertension, diabetes, BMI and triglycerides), this genotype remained significantly (p = 0.005) associated with ICH (OR, 6.04; 95% CI, 1.71-21.29). By contrast, no correlations were found between this genotype and ischemic stroke, nor between the OPG-950T/C or IL6-174G/C polymorphisms and stroke subtypes. CONCLUSIONS: In this population, the OPG-1181C/C genotype associates with first-ever ICH, implying that alterations in OPG-mediated signaling in the vasculature may be involved in the pathophysiology of this disease.

  • 27.
    Svenson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grönlund, Elisabeth
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sitaram, Raviprakash T
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length in relation to immunological parameters in patients with renal cell carcinoma2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 2, article id e55543Article in journal (Refereed)
    Abstract [en]

    Over the last decade, telomere length (TL) has gained attention as a potential biomarker in cancer disease. We previously reported that long blood TL was associated with a poorer outcome in patients with breast cancer and renal cell carcinoma. Based on these findings, we hypothesized that certain immunological components may have an impact on TL dynamics in cancer patients. One aim of the present study was to investigate a possible association between serum cytokines and TL of peripheral blood cells, tumors and corresponding kidney cortex, in patients with clear cell renal cell carcinoma. For this purpose, a multiplex cytokine assay was used. Correlation analysis revealed significant positive correlations between tumor TL and peripheral levels of three cytokines (IL-7, IL-8 and IL-10). In a parallel patient group with various kidney tumors, TL was investigated in whole blood and in immune cell subsets in relation to peripheral levels of regulatory T cells (Tregs). A significant positive association was found between whole blood TL and Treg levels. However, the strongest correlation was found between Tregs and TL of the T lymphocyte fraction. Thus, patients with higher Treg levels displayed longer T cell telomeres, which might reflect a suppressed immune system with fewer cell divisions and hence less telomere shortening. These results are in line with our earlier observation that long blood TL is an unfavorable prognostic factor for cancer-specific survival. In summary, we here show that immunological components are associated with TL in patients with renal cell carcinoma, providing further insight into the field of telomere biology in cancer. 

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    Telomere length in relation to immunological parameters in patients with renal cell carcinoma
  • 28.
    Söderström, Ingegerd
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergman, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Colucci, F.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergqvist, Ingela
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Establishment and characterization of RAG-2 deficient non-obese diabetic mice1996In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 43, no 5, p. 525-530Article in journal (Refereed)
    Abstract [en]

    The authors have established a new immunodeficient mouse strain on the genetic background of the diabetes prone non-obese diabetic (NOD) mouse. A deletion mutant of the RAG-2 gene was back crossed 10 generations onto the NOD/Bom strain background. The homozygous NODrag-2-/- mice lack functionally mature B and T lymphocytes and do not develop insulitis or diabetes throughout life. In contrast, heterozygous NODrag-2+/- develop both insulitis and diabetes with an incidence similar to the wild type NOD mice. In transfer experiments, spleen cells from diabetic NOD donors were found to transfer disease to NODrag-2-/- recipients similar to what has been previously observed in transfer to irradiated NOD recipients or to immunodeficient NOD-scid/scid mice. While resembling the recently established NOD-scid/scid mice in many respects, the NODrag-2-/- mice represents an advantageous model for reconstitution of the pathogenesis of murine IDDM as it does not produce any endogenous, mature T or B lymphocytes.

  • 29.
    Söderström, Ingegerd
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Strand, Magnus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ingridsson, Anna-Cajsa
    Nasic, Salmir
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    17beta-estradiol and enriched environment accelerate cognitive recovery after focal brain ischemia2009In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 29, no 6, p. 1215-1224Article in journal (Refereed)
    Abstract [en]

    Cognitive impairments, including spatial memory and learning deficiencies, are common after ischemic stroke. Estrogen substitution improves cognitive functions in post-menopausal women and ovariectomized rodents, partially through induction of neuroplasticity in the hippocampal formation. Post-ischemic housing of male rats in an enriched environment (EE) improves functional outcome, without changing infarct volume. We hypothesized that 17beta-estradiol combined with an EE would accelerate cognitive recovery after focal brain ischemia in ovariectomized rats and that recovery would be related to altered expression of nerve growth factor-induced gene (NGFI)-A in the hippocampus. 17beta-estradiol or placebo pellets were implanted 6 h after transient middle cerebral artery occlusion. Two days later, rats were placed in an EE or a deprived environment (DE) for 6 weeks. At 5 weeks after middle cerebral artery occlusion, 17beta-estradiol-treated rats housed in an EE showed improvements in cognitive function (i.e. shorter latency and path in the Morris water maze task) compared with placebo-treated animals housed in an EE. Furthermore, beneficial effects on latency and path were observed when comparing EE-housed vs. DE-housed 17beta-estradiol-treated rats. When comparing 17beta-estradiol-treated EE-housed rats vs. placebo-treated DE-housed rats, pronounced effects on latency and path were observed. Infarct volumes did not differ between groups. 17beta-estradiol-treated EE-housed rats had significantly higher NGFI-A mRNA expression bilaterally in the cornu ammonis 1 region and in the ipsilateral dentate gyrus of the hippocampus, compared with placebo-treated EE-housed rats. In conclusion, 17beta-estradiol treatment combined with an EE improved recovery of cognitive function after experimental brain ischemia, putatively through the upregulation of NGFI-A in hippocampal subregions.

  • 30.
    Söderström, Ingegerd
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    van Dijk-Härd, Iris
    Division for Clinical Immunology, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden.
    Feld, Sari
    Division for Clinical Immunology, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden.
    Hillörn, Valter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundkvist, Inger
    Division for Clinical Immunology, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden.
    Altered VH6-D-JH repertoire in human insulin-dependent diabetes mellitus and autoimmune idiopathic thrombocytopenic purpura1999In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 29, no 9, p. 2853-2862Article in journal (Refereed)
    Abstract [en]

    We have characterized the peripheral B cell repertoire in T cell-mediated insulin-dependent diabetes mellitus (IDMM) and in B cell-mediated autoimmune idiopathic thrombocytopenic purpura (AITP). The VH6-containing repertoire in adult patients with IDDM or AITP and healthy control subjects was investigated by PCR amplification using VH6- and JH-specific primers. Nucleotide sequence analysis of VH6-D-JH rearrangements showed an abnormally high frequency of somatic mutations in non-functional rearrangements from diabetic (3. 58 %) as well as AITP patients (3.18 %), compared to controls (0.4 % and 1.43 %, respectively; p < 0.05). In contrast, the mutation frequency among functional rearrangements was 2.4 - 3 times lower in patients compared to controls ( p < 0.05). Detailed analysis of the VH6 genes carrying mutations showed that the underlying mechanism for this observation is probably different for the two diseases. Analysis of D- and JH gene usage revealed additional deviations from the normal pattern. Taken together, these results suggest defects in the mechanisms controlling selection of the B cell repertoire in patients with IDDM or AITP.

  • 31.
    van Dijk-Härd, Iris
    et al.
    Division for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Feld, Sari
    ivision for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundkvist, Inger
    Division for Clinical Immunology, Karolinska Institute, Huddinge Hospital, Sweden..
    Age-related impaired affinity maturation and differential D-JH gene usage in human VH6-expressing B lymphocytes from healthy individuals1997In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 27, no 6, p. 1381-1386Article in journal (Refereed)
    Abstract [en]

    To elucidate the basic molecular events underlying humoral immunity during ontogeny and senescence, we analyzed a panel of 179 polymerase chain reaction-derived VH6-D-JH rearrangements from cord blood, peripheral blood, and spleen. Nucleotide sequence analysis of the CDR3 region shows that there is a difference in D and JH gene usage in functional rearrangements between lymphocytes from peripheral blood and spleen. Analysis of the VH6 gene shows that the mutational frequencies rise from 0.81% in cord blood to 1.96% in peripheral blood lymphocytes derived from young adults, and decrease to 0.80% in samples from individuals older than 50 years. The number of rearrangements carrying mutations follows a similar pattern: 22% in cord blood, 73% in the age group 20-49 years, and 57% in the age group over 50 years. The mutational frequencies among the mutated genes are, however, similar for cord blood and young adults, 2.76% and 2.51%, respectively, and 1.3% in older adults. These data show an age-related impaired affinity maturation which might relate to the decrease in immunological responsiveness among the elderly.

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