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  • 1. Bonaïti, Bernard
    et al.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bonaïti-Pellié, Catherine
    Planté-Bordeneuve, Violaine
    TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

  • 2.
    Carlsson, Anna
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nylander, P-O
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsman-Semb, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.2002In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 59, no 11, p. 1804-1807Article in journal (Refereed)
    Abstract [en]

    Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.

  • 3.
    Do, Lan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Dahl, Christen P
    Kerje, Susanne
    Hansell, Peter
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Ulla
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    High Sensitivity Method to Estimate Distribution of Hyaluronan Molecular Sizes in Small Biological Samples Using Gas-Phase Electrophoretic Mobility Molecular Analysis.2015In: International Journal of Cell Biology, ISSN 1687-8876, E-ISSN 1687-8884, article id 938013Article in journal (Refereed)
    Abstract [en]

    Hyaluronan is a negatively charged polydisperse polysaccharide where both its size and tissue concentration play an important role in many physiological and pathological processes. The various functions of hyaluronan depend on its molecular size. Up to now, it has been difficult to study the role of hyaluronan in diseases with pathological changes in the extracellular matrix where availability is low or tissue samples are small. Difficulty to obtain large enough biopsies from human diseased tissue or tissue from animal models has also restricted the study of hyaluronan. In this paper, we demonstrate that gas-phase electrophoretic molecular mobility analyzer (GEMMA) can be used to estimate the distribution of hyaluronan molecular sizes in biological samples with a limited amount of hyaluronan. The low detection level of the GEMMA method allows for estimation of hyaluronan molecular sizes from different parts of small organs. Hence, the GEMMA method opens opportunity to attain a profile over the distribution of hyaluronan molecular sizes and estimate changes caused by disease or experimental conditions that has not been possible to obtain before.

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  • 4.
    Do, Lan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Geijer, Mats
    Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, United States; Department of Radiology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, United States; Faculty of Medicine, Lund University, Lund, Sweden.
    Baraliakos, Xenofon
    Department of Biochemistry, Ruhr-Universität Bochum, Bochum, Germany.
    Witte, Torsten
    Department of Rheumatology and Clinical Immunology, Medical University Hannover, Hannover, Germany.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Rheumatology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Anti-CD74 IgA autoantibodies in radiographic axial spondyloarthritis: a longitudinal Swedish study2021In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 60, no 9, p. 4085-4093Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Antibodies against anti-CD74 are related to axial spondyloarthritis (axSpA). The objectives were (i) to study IgA anti-CD74 in radiographic (r)-axSpA patients in the Backbone cohort and to calculate the sensitivity and specificity of anti-CD74, (ii) to study the fluctuation of IgA anti-CD74 levels in prospectively collected samples, and (iii) to explore the relation between IgA anti-CD74 and radiographic spinal changes.

    METHODS: IgA anti-CD74 was analysed by ELISA in 155 patients with r-axSpA and age- and sex-matched controls. BASDAI, ASDAS, BASFI and BASMI were assessed and spinal radiographs were scored for r-axSpA-related changes with mSASSS. Previously donated samples, before inclusion in the Backbone study, were identified in the Medical Biobank of Northern Sweden.

    RESULTS: A total of 155 patients comprising 69% men and 31% women, age [mean (s.d.)] 55.5 (11.4) years and 152 (98.1%) HLA-B27 positive, were included. The plasma level of IgA anti-CD74 was significantly higher in the patients [median (interquartile range), 12.9 (7.9-17.9) U/ml] compared with controls [10.9 (7.2-14.6) U/ml, P = 0.003]. IgA anti-CD74 was above the cut-off level of 20 U/ml in 36/155 (23.2%) patients and in 15/151 (9.9%) controls (P = 0.002). Multivariable logistic regression analyses revealed ≥1 syndesmophyte associated with IgA anti-CD74 (odds ratio 5.64; 95% CI: 1.02, 35.58; P = 0.048) adjusted for hsCRP, smoking, BMI, sex and age. No distinct pattern of IgA anti-CD74 over time was revealed.

    CONCLUSION: Plasma levels of IgA anti-CD74 were increased in r-axSpA and independently associated with radiographic spinal changes, which suggests that IgA anti-CD74 could play a role in the pathogenies of r-axSpA.

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  • 5. Forsblad-D'elia, H.
    et al.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kumar, A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    DECREASED LEVELS OF T FOLLICULAR HELPER (CD4+CXCR5+) CELLS AND CD27+CD38+ AND CD27+CD38- B CELLS IN ANKYLOSING SPONDYLITIS PATIENTS CORRELATE WITH MARKER OF INFLAMMATION2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no Suppl 1, p. 13-14, article id OP0024Article in journal (Other academic)
  • 6.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Wanzhong
    Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed)
    Abstract [en]

    The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

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  • 7.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wang, Wanzhong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    CD44 receptors and stromal CD44 ligands as prognostic markers in pancreatic ductal adenocarcinomaManuscript (preprint) (Other academic)
  • 8.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Cardiology, Heart Centre, Umeå University, Umeå, Sweden.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Institutionen för skoglig genetik och växtfysiologi, Sveriges lantbruks universitet.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rongquist, Gunnar
    Institutionen för medicinska vetenskaper, Klinisk kemi.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Cardiology, Heart Centre, Umeå University, Umeå, Sweden.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Growth factor stimulation of cardiomyocytes induces changes in the transcriptional contents of secreted exosomes2013In: Journal of Extracellular Vesicles, E-ISSN 2001-3078, article id 20167Article in journal (Refereed)
    Abstract [en]

    Exosomes are nano-sized extracellular vesicles, released from various cells, which can stimulate or repress responses in targets cells. We recently reported that cultured cardiomyocytes are able to release exosomes and that they, in turn, are involved in facilitating events in target cells by alteration of gene expression. We investigated whether external stimuli of the cardiomyocyte might influence the transcriptional content of the released exosomes.

    Exosomes were isolated from media collected from cultured cardiomyocytes (HL-1) with or without growth factor treatment (TGF-β2 and PDGF-BB), with a series of differential centrifugations, including preparative ultracentrifugation and separation with a sucrose gradient. The exosomes were characterized with dynamic light scattering (DLS), electron microscopy (EM) and Western blot and analyzed with Illumina whole genome microarray gene expression.

    The exosomes were rounded in shape and had an average size of 50–90 nm in diameter with no difference between treatment groups. Analysis of the mRNA content in repeated experiments conclusively revealed 505 transcripts in the control group, 562 in the TGF-β2-treated group and 300 in the PDGF-BB-treated group. Common transcripts (217) were found in all 3 groups.

    We show that the mode of stimulation of parental cells affects the characteristics of exosomes released. Hence, there is a difference in mRNA content between exosomes derived from cultured cardiomyocytes stimulated, or not stimulated, with growth factors. We also conclude that all exosomes contain a basic package consisting of ribosomal transcripts and mRNAs coding for proteins with functions within the energy supply system.

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  • 9.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ronquist, Gunnar
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Growth factor stimulation of cardiomyocytes induces changes in the transcriptional contents of secreted exosomes2013In: Journal of Extracellular Vesicles, E-ISSN 2001-3078, Vol. 2Article in journal (Refereed)
    Abstract [en]

    Exosomes are nano-sized extracellular vesicles, released from various cells, which can stimulate or repress responses in targets cells. We recently reported that cultured cardiomyocytes are able to release exosomes and that they, in turn, are involved in facilitating events in target cells by alteration of gene expression. We investigated whether external stimuli of the cardiomyocyte might influence the transcriptional content of the released exosomes. Exosomes were isolated from media collected from cultured cardiomyocytes (HL-1) with or without growth factor treatment (TGF-β2 and PDGF-BB), with a series of differential centrifugations, including preparative ultracentrifugation and separation with a sucrose gradient. The exosomes were characterized with dynamic light scattering (DLS), electron microscopy (EM) and Western blot and analyzed with Illumina whole genome microarray gene expression. The exosomes were rounded in shape and had an average size of 50-90 nm in diameter with no difference between treatment groups. Analysis of the mRNA content in repeated experiments conclusively revealed 505 transcripts in the control group, 562 in the TGF-β2-treated group and 300 in the PDGF-BB-treated group. Common transcripts (217) were found in all 3 groups. We show that the mode of stimulation of parental cells affects the characteristics of exosomes released. Hence, there is a difference in mRNA content between exosomes derived from cultured cardiomyocytes stimulated, or not stimulated, with growth factors. We also conclude that all exosomes contain a basic package consisting of ribosomal transcripts and mRNAs coding for proteins with functions within the energy supply system.

  • 10.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Institutionen för skoglig genetik och växtfysiologi, Sveriges lantbruks universitet.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    OPLS-DA of myocardial gene expression in the progression of cardiac hypertrophy in aorta ligated ratManuscript (preprint) (Other academic)
  • 11.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Malm, Linus
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Using OPLS-DA to find new hypotheses in vast amounts of gene expression data - Studying the progression of cardiac hypertrophy in the heart of aorta ligated rat2013In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 522, no 1, p. 27-36Article in journal (Refereed)
    Abstract [en]

    One of the great problems facing science today lies in data mining of the vast amount of data. In this study we explore a new way of using orthogonal partial least squares-discrimination analysis (OPLS-DA) to analyze multidimensional data. Myocardial tissues from aorta ligated and control rats (sacrificed at the acute, the adaptive and the stable phases of hypertrophy) were analyzed with whole genome microarray and OPLS-DA. Five functional gene transcript groups were found to show interesting clusters associated with the aorta ligated or the control animals. Clustering of "ECM and adhesion molecules" confirmed previous results found with traditional statistics. The clustering of "Fatty acid metabolism", "Glucose metabolism", "Mitochondria" and "Atherosclerosis" which are new results is hard to interpret, thereby being possible subject to new hypothesis formation. We propose that OPLS-DA is very useful in finding new results not found with traditional statistics, thereby presenting an easy way of creating new hypotheses.

  • 12.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wikström, Gerhard
    Institutionen för Medicinska Vetenskaper, Kardiologi, Uppsala univerisitet.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Samuel, Jane-Lise
    INSERM U 942, Hôpital Lariboisière, Paris, France.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellam
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Transcriptional regulation of cardiac genes balance pro and anti hypertrophic mechanisms in hypertrophic cardiomyopathy2012In: Cardiogenetics, ISSN 2035-8148, Vol. 2, no 1Article in journal (Refereed)
    Abstract [en]

    Background: Hypertrophic cardiomyopathy (HCM) is characterised by unexplained left ventricular hypertrophy. HCM is often hereditary, but the knowledge about the mechanisms leading from mutation to phenotype is incomplete. The transcriptional expression patterns in the myocardium of HCM patients may contribute to the understanding of the mechanisms that drive and stabilize the hypertrophy.

    Design and Methods: Cardiac myectomies/biopsies from 8 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 5 controls were studied with whole genome Illumina microarray gene expression (detecting 18 189 mRNA).

    Results: When comparing HOCM myocardium to controls, there was significant transcriptional down-regulation of the MYH6, EGR1, APOB and FOS genes, and significant transcriptional up-regulation of the ACE2, JAK2, NPPA (ANP), APOA1 and HDAC5genes. 

    Conclusion: The transcriptional regulation revealed both pro and anti hypertrophic mechanisms. The pro hypertrophic response was explained by the transcriptional down-regulation of MYH6, indicating that the switch to the fetal gene program is maintained, and the transcriptional up-regulation of JAK2 in JAK-STAT pathway. The anti hypertrophic response was seen as a transcriptional down-regulation of the immediate early genes (IEGs), FOS and EGR1, and a transcriptional up-regulation of ACE2 and HDAC5. This can be interpreted as a transcriptional endogenous protection system in the heart of the HOCM patients, neither growing nor suppressing the already hypertrophic myocardium.

  • 13.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bäckman, Birgitta
    Umeå University, Faculty of Medicine, Odontology, Pediatric Dentistry.
    Coates, Philip J
    Cullman, Inger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Exclusion of p63 as a candidate gene for autosomal-dominant amelogenesis imperfecta.2006In: Acta Odontologica Scandinavica, ISSN 0001-6357, E-ISSN 1502-3850, Vol. 64, no 2, p. 111-114Article in journal (Refereed)
  • 14.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hyaluronan, a beneficial glycosaminoglycan that may affect the phenotype of cardiac hypertrophy: a hypothesis2014In: International Cardiovascular Forum Journal, ISSN 2410-2636, Vol. 1, no 5, p. 226-229Article in journal (Refereed)
    Abstract [en]

    Myocardial hypertrophy contribute to ventricular diastolic dysfunction and can lead to heart failure, arrhythmia and evensudden death. It have been shown that during development of hypertrophy the concentration of the glycosaminoglycanhyaluronan increases. The increased concentration correlates to the increased gene expression of fetal and extracellularmatrix genes that is associated with cardiac remodeling.Moreover it has been shown that high molecular weight hyaluronan depolarize the membrane potential of cells.The increase of hyaluronan in cardiac hypertrophy could hypothetically affect the resting membrane potential incardiomyocytes and thus affect the conduction through the heart.Hypothesis. The role of hyaluronan as a molecule adapting the extracellular matrix when the heart is growing could potentiallydevelop to be harmful to cardiomyocyte resting membrane potential and hence contribute to the risk of arrhythmia.

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  • 15.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alarcon, Flora
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bonaiti-Pellié, Catherine
    Planté-Bordeneuve, Violaine
    Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population.2008In: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis, ISSN 1744-2818, Vol. 15, no 3, p. 181-6Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) familial amyloid polyneuropathies (FAP) are autosomal dominant devastating afflictions. They were first described in Portugal, later in Japan and Sweden and are now recognized worldwide. The TTR Val30Met mutation is the most common, and depending on the geographic origin, a wide variation in age at onset of the disease is observed. In Europe, northern Sweden is the second most prevalent area of the disease, and a late age of onset of 56 years has been reported. The present study aims to estimate the penetrance in TTR Val30Met Swedish families. Genealogical investigations, clinical data and genotyping were obtained in 77 TTR-Val30Met Swedish families. The penetrance in Val30Met carriers and variation within the endemic area, according to gender and transmitting parents were calculated by a newly developed bias-free method. The penetrance estimates were low, i.e. 1.7% and 22% at age 30 and 60 years, respectively, and far from complete (69%) by age 90 years. Differences between Piteå and Skellefteå regions were observed. Moreover, penetrance was significantly higher when the mutation was inherited from the mother than from the father. The low penetrance observed in TTR FAP kindreds and its variations is important information for the genetic counseling and treatment of Swedish FAP patients and their families.

  • 16.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Larsson, Anders
    Lindqvist, Ulla
    Hyaluronan concentration and molecular mass in psoriatic arthritis: biomarkers of disease severity, resistance to treatment, and outcome2019In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 48, no 4, p. 284-293Article in journal (Refereed)
    Abstract [en]

    Objective: Low molecular mass hyaluronan causes inflammatory processes and can act as a pro-inflammatory cytokine in skin and other sites of activity in psoriatic arthritis (PsA). This study investigated whether the molecular mass distribution of hyaluronan (HA) in skin and the quantity of circulating HA are related to the clinical inflammatory picture in PsA with active disease and to the effect of treatment with anti-tumour necrosis factor-α (anti-TNF-α) adalimumab.

    Methods: Twenty patients with TNF-α-naïve active polyarticular PsA were included in this prospective clinical trial of treatment with 40 mg s.c. adalimumab according to standard procedure. Clinical activity, patients’ assessments, and skin biopsies were captured at inclusion and at the 12 week follow-up. Ten healthy individuals were recruited for comparison of HA analyses. Histochemistry of skin inflammation, serum HA, and molecular mass of HA were determined.

    Results: Overall improvements in clinical parameters were observed. Eight of 18 patients reached minimum disease activity after 12 weeks and disease activity was significantly reduced (p < 0.0001). Patients with elevated serum HA values were significantly older, had later onset of arthritis and more deformed joints, still had swollen joints after treatment, and had more circulating inflammatory biomarkers. More severe disease pathology showed a wide spectrum of high-molecular-mass HA accompanied by low mass HA. The treatment appears partly to normalize the HA mass distribution.

    Conclusion: HA concentration and mass seem to be two possible factors in the inflammatory pathology of PsA acting as biomarkers for disease severity, resistance to treatment, and worse outcome.

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  • 17.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hellström, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Engström Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Aberg, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Oliviero, Patricia
    Samuel, Jane-Lise
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Parallel up-regulation of FGF-2 and hyaluronan during development of cardiac hypertrophy in rat2008In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 332, no 1, p. 49-56Article in journal (Refereed)
  • 18.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Karlsson, Mats G.
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Cajander, Sara
    Dorofte, Luiza
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Laurent, Claude
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Presence of hyaluronan in lung alveoli in severe Covid-19: an opening for new treatment options?2020In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 295, no 45, p. 15418-15422Article in journal (Refereed)
    Abstract [en]

    Severe corona virus disease 2019 (Covid-19) is characterized by inflammation of the lungs with increasing respiratory impairment. In fatal Covid-19, lungs at autopsy have been filled with a clear liquid jelly. However, the nature of this finding has not yet been determined.The aim of the study was to demonstrate if the lungs of fatal Covid-19 contain hyaluronan as it is associated with inflammation and acute respiratory distress syndrome (ARDS) and may have the appearance of liquid jelly.Lung tissue obtained at autopsy from three deceased Covid-19 patients was processed for hyaluronan histochemistry using a direct staining method and compared with staining in normal lung tissue.Stainings confirmed that hyaluronan is obstructing alveoli with presence in exudate and plugs, as well as in thickened perialveolar interstitium. In contrast, normal lungs only showed hyaluronan in intact alveolar walls and perivascular tissue. This is the first study to confirm prominent hyaluronan exudates in the alveolar spaces of Covid-19 lungs, supporting the notion that the macromolecule is involved in ARDS caused by SARS-CoV-2. The present finding may open up for new treatment options in severe Covid-19, aiming at reducing the presence and production of hyaluronan in the lungs.

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  • 19.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Westermark, Per
    Stafberg, Christina
    Nahi, Hareth
    Tachlinski, Sascha
    Guggi, Michael
    Flogegard, Max
    Hamid, Mehmet
    Andersson Escher, Stefan
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family2015In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 58, no 4, p. 211-215Article in journal (Refereed)
    Abstract [en]

    In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (similar to 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. In conclusion: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.

  • 20.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lång, Kenneth
    Department of Medicine, Piteå Hospital , Piteå , Sweden..
    Ihse, Elisabet
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 6, p. 372-376Article in journal (Refereed)
    Abstract [en]

    For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

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  • 21.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Growth factor PDGF-BB stimulates cultured cardiomyocytes to synthesize the extracellular matrix component hyaluronan2010In: PLOS ONE, E-ISSN 1932-6203, Vol. 5, no 12, p. e14393-Article in journal (Refereed)
    Abstract [en]

    Co-cultivation of cardiomyocytes and fibroblasts (80%/20%) increased HA concentration far more that can be explained by HA synthesis by the two cell types separately, revealing a crosstalk between cardiomyocytes and fibroblasts that induces HA synthesis. We conclude that dynamic changes of the myocardium, such as in cardiac hypertrophy, do not depend on the cardiomyocyte alone, but are achieved when both cardiomyocytes and fibroblasts are present.

  • 22.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hyaluronan is both a product and stimulator of cardiomyocytes: a study in cell cultures of cardiomyocytes and fibroblastsManuscript (preprint) (Other academic)
  • 23.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Samuel, Jane-Lise
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Temporal correlation between transcriptional changes and increased synthesis of hyaluronan in experimental cardiac hypertrophy2010In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 96, no 2, p. 73-81Article in journal (Refereed)
    Abstract [en]

    The role of hyaluronan in cardiac growth has become evident, previously shown by increased myocardial levels of hyaluronan in a rat model of cardiac hypertrophy. To further investigate the role of hyaluronan and regulation of its synthesis in cardiac hypertrophy, quantitative measurements of myocardial hyaluronan concentration was correlated to gene transcription in hypertrophic cardiac tissue. Factor analysis was used to study this correlation over time. A subset of differentially expressed genes was identified with a transcriptional regulation correlating to the increased synthesis of hyaluronan, suggesting a common regulatory pathway. Four transcription factors, Myc, Fos, Junb and Egr1, were also up-regulated. Furthermore, the Ace gene was up-regulated, representing increase of angiotensin II, an inducer of these transcription factors and fetal genes in cardiac hypertrophy. This demonstrates a coordinated synthesis of hyaluronan and pro-hypertrophic gene expression, regulated by immediate early genes, with angiotensin II as a possible mediator.

  • 24.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Molecular & Clinical Sciences Research Institute, St. George University, London; Brunel University, Middlesex, UK.
    Genetic variants in cardiac calcification in Northern Sweden2019In: Medicine, ISSN 0025-7974, E-ISSN 1536-5964, Vol. 98, no 15, article id e15065Article in journal (Refereed)
    Abstract [en]

    Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a discrepancy in the expression pattern of CCAD compared to the well-known atherosclerotic disease which raises questions about the exact pathophysiology of coronary calcification and whether there is a genetic etiology for it.

    In this pilot study we studied 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification. We studied 70 patients with calcific cardiac disease; 65 with CCAD (age 43-83 years) and 5 with calcific aortic valve disease (CAVD) (age 76-82 years).

    Five DNA variants potentially affecting protein function were found in 6 patients. One variant is a known disease-causing mutation in the ABCC6 gene. Our findings support that disturbances in the PPi and Pi metabolism might influence the development of CCAD and CAVD. However, segregation in the families must first be performed to ascertain any damaging effect of these variants we have found.

    We report 4 new genetic variants potentially related to coronary calcification, through the disturbed Pi and PPi metabolism. The search for direct causative genetic variants in coronary artery and aortic valve calcification must be broadened with other genes particularly those involved with Pi and PPi metabolism.

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  • 25.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ronquist, Gunnar
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Cardiomyocyte microvesicles convey bioinformatic messages to target cellsManuscript (preprint) (Other academic)
  • 26.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Regional differences and similarities of FAP in Sweden2012In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 19, no S1, p. 53-54Article in journal (Refereed)
    Abstract [en]

    Marked differences in phenotype in familial amyloid polyneuropathy (FAP) populations have been noted between but also within FAP populations. Initially, it was believed that patients with FAP, caused by the TTR V30M mutation, shared the same founder. However, recent studies have clearly shown that the V30M mutation in Sweden occurred spontaneously later in time than that in Portugal. The Swedish FAP-population's phenotype differs between various areas within northern Sweden. Thus the age at onset is in average 20 years earlier in Skelleftea than in Pitea areas, a distance of only 60 km. Age at onset appears also to have an impact on complications of the disease. Late-onset cases often develop a cardiomyopathy, especially male patients. Mitochondrial haplotype distribution has been noted to differ between early- and late- onset patients in the Swedish population. Mitochondrial function is one possible factor contributing to the differences seen both between and within populations.

  • 27.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Laurent, Claude
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Speech and Language Pathology and Audiology, University of Pretoria, South Africa.
    Laurell, Göran
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis2018In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 138, no 11, p. 1020-1027Article in journal (Refereed)
    Abstract [en]

    Background: Hyaluronan (HA) is a glycosaminoglycan with viscoelastic properties necessary for vocal fold (VF) vibration and voice production. Changes in HAs molecular mass, possibly related to human papilloma virus, could affect formation/persistence of recurrent respiratory papillomatosis (RRP).

    Aims/Objective: Describing mass and localization of HA and localization of HA receptor CD44 in VF and false vocal folds (FVF) in RRP.

    Materials and Methods: Biopsies from VF and FVF from 24 RRP patients. Twelve were studied with histo-/immunohistochemistry for HA and CD44 in epithelium, stroma and RRP lesions. Twelve samples were analyzed for HA molecular mass distribution with gas-phase-electrophoretic-molecular-mobility-analyzer (GEMMA).

    Results: Three of 23 stains (VF and FVF combined) showed faint HA staining in the epithelium; there was more extensive staining in the stroma. CD44 was present throughout all areas in FVF and VF, it did not concur with HA. GEMMA analysis revealed very high mass HA (vHMHA) with more varying amounts in VF.

    Conclusions/Significance: HA was mainly distributed in the stroma. CD44 not binding to HA might explain the non-inflammatory response described in RRP. Possibly crosslinked vHMHA was seen in VF and FVF, with more variable amounts in VF samples. Counteracting HA crosslinking could become a treatment option in RRP.

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  • 28.
    Holmgren, Gösta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundgren, Hans-Eric
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jonasson, Jenni
    Stafberg, Christina
    Fahoum, Saomi
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cardiomyopathy in Swedish patients with the Gly53Glu and His88Arg transthyretin variants.2005In: Amyloid, ISSN 1350-6129, Vol. 12, no 3, p. 184-8Article in journal (Refereed)
  • 29.
    Holmgren, Gösta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Jonasson, Jenni
    Lundgren, Hans-Eric
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Westermark, Per
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    A Swedish family with the rare Phe33Leu transthyretin mutation.2005In: Amyloid, ISSN 1350-6129, Vol. 12, no 3, p. 189-92Article in journal (Refereed)
  • 30.
    Holmgren, Gösta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Impact of homozygosity for an amyloidogenic transthyretin mutation on phenotype and long term outcome.2005In: Journal of Medical Genetics, ISSN 1468-6244, Vol. 42, no 12, p. 953-6Article in journal (Refereed)
  • 31. Kerje, Susanne
    et al.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kämpe, Olle
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Ulla
    Is low molecular hyaluronan an early indicator of disease in avian systemic sclerosis?2016In: Connective Tissue Research, ISSN 0300-8207, E-ISSN 1607-8438, Vol. 57, no 5, p. 337-346Article in journal (Refereed)
    Abstract [en]

    AIM OF THE STUDY: To further elucidate the pathogenesis of systemic sclerosis (SSc) an experimental avian model was used. University of California at Davies line 200-chicken (UCD-200) spontaneously develops a SSc like disease that has most features of human SSc with vascular effects, inflammation, autoimmunity and fibrosis. The first signs of disease in UCD-200 are swelling and ischemic lesions of the comb, a tissue containing high amounts of the glycosaminoglycan hyaluronan. The aim was to evaluate inflammatory and fibrotic processes of the disease with regard to the molecular weight of hyaluronan.

    MATERIAL AND METHODS: Comb biopsies from UCD-200 and healthy White Leghorn (WL) chickens as controls at different ages were studied with histochemical localization of hyaluronan, hyaluronidase 1, CD3, IgY and collagen I and III. Hyaluronan molecular weight distribution was estimated with gas phase electrophoretic analysis.

    RESULTS: At 2 days of age hyaluronan was visualized in UCD-200 at the dermal part of the comb with no simultaneous staining of Hyal-1. In adult UCD-200 the comb skin was almost totally devoid of hyaluronan compared to WL of the same age. An increase of low molecular weight (LMW) hyaluronan was detected in comb tissue from UCD-200 at 1 day, 1, 2, 4 weeks in contrast to adult animals.

    CONCLUSIONS: An early inflammatory process involving LMW hyaluronan was confirmed as a possible profibrotic process. This indicates that hyaluronan might be an important participant in early inflammatory events of SSc in UCD-200 chicken and that disappearance of hyaluronan in skin predisposes to fibrosis.

  • 32.
    Kumar, A.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    OVEREXPRESSION OF MACROPHAGE MIGRATION INHIBITORY FACTOR IN PATIENTS WITH ANKYLOSING SPONDYLITIS AND ITS RELATION TO SEX, INFLAMMATION AND TREATMENT2018In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 36, no 4, p. 716-716Article in journal (Other academic)
  • 33.
    Kumar, Anjani
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Overexpression of macrophage migration inhibitory factor in patients with ankylosing spondylitis and its relation to sex, inflammation and treatment2018In: Clinical and Experimental Rheumatology, ISSN 0392-856X, Vol. 36, no 4, p. 716-716Article in journal (Refereed)
    Abstract [en]

    Background: Macrophage migration inhibitory factor (MIF) is a multipotent cytokine involved in the regulation of immune and inflammatory responses. The present study aimed to investigate the MIF expression in patients with ankylosing spondylitis (AS) compared with controls and to examine associations between MIF and demographic and inflammation related factors in AS overall and stratified by sex.

    Methods: MIF in plasma was measured in a cohort of patients with AS from Northern Sweden (n= 155) and age- & sex-matched controls (n=151) using Human MIF Quantikine ELISA Kit (R&D). The patients were assessed with laboratory markers of inflammation, ASDAS-CRP, BASDAI, BASMI and BASFI. Comparisons were analyzed by T-test and associations by bivariate Pearson correlations.

    Results: The expression of MIF was significantly augmented in the AS patients (Mean 65.1 ng/ml±2.0 SEM) compared with the controls (Mean 42.0 ng/ml±2.1 SEM) (p<0.001), the difference was also found in sex stratified analyses. MIF had a weak negative correlation with age in AS (-0.144, p=0.07) but not in controls (-0.037, p=0.66). Stratified by sex, the inverse correlation with age was shown in the AS men only (-0.28, p=0.004). When analyzing MIF in different age-groups it was revealed that MIF was significantly higher in the men ≤50 years compared to the women with AS ≤50 years. Moreover, MIF was positively correlated with inflammation related variables; swollen joint count, ESR, hsCRP, thrombocytes and leukocytes. The expression of MIF was significantly increased in AS patients on cDMARDs with or without a biological drug, while NSAIDs, glucocorticosteriods or single therapy with a biological drug did not influence the MIF levels.

    Conclusions: Our results suggest that MIF is overexpressed in AS patients. MIF was associated with inflammation and treatment and, in addition, sex seemed to have an impact on MIF plasma levels in the AS patients. MIF might be a potential biomarker for the development of new treatment-strategies in AS.

  • 34.
    Law, Lucy
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Liv, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Geijer, Mats
    Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Radiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinic of Rheumatology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Increased carotid intima-media thickness in patients with radiographic axial spondyloarthritis compared to controls and associations with markers of inflammation2024In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: There is an increased risk for cardiovascular disease (CVD) in patients with radiographic axial spondyloarthritis (r-axSpA). In this cross-sectional study, we aimed to, overall and stratified by sex, (i) compare ultrasound derived carotid intima media thickness (cIMT), between patients and controls, and (ii) investigate associations between cIMT, clinical disease activity and inflammation-related laboratory markers in patients with r-axSpA.

    METHOD: In total, 155 patients diagnosed with r-axSpA using the modified New York criteria and 400 controls were included. Bilateral carotid ultrasound, laboratory testing, and questionaries were acquired. Disease-specific assessments were carried out for patients. Linear regression analysis was used to assess associations.

    RESULTS: Linear regression analyses showed that patients with r-axSpA had increased mean cIMT compared to controls (mean ± SD, 0.8 ± 0.1 mm vs 0.7± 0.1 mm, respectively, unstandardized β (95% CI) -0.076 (-0.10, -0.052), P < 0.001) adjusted for smoking status and age. Linear regression analyses for patients with r-axSpA showed that only males presented significant associations between cIMT and inflammation-related laboratory markers, white blood cell (WBC) count (mean ± SD, 6.8 ± 1.6 109/L) and monocytes (0.6 ± 0.2 109/L); WBC count (unstandardized β (95% CI) 0.019 (0.0065, 0.031), P = 0.003, R2 = 0.57) and monocytes (0.13 (0.0047, 0.26), P = 0.041, R2 = 0.55), adjusted for age, smoking status, body mass index, hypertension, dyslipidemia, diabetes mellitus, ASDAS-CRP, and treatment with DMARDs and glucocorticoids. No significant association was found between cIMT and clinical disease activity assessed by ASDAS-CRP.

    CONCLUSION: Patients with r-axSpA had significantly increased cIMT compared to controls. In male patients, higher WBC and monocyte count were associated with an increase in cIMT suggesting the role of inflammation in the development of atherosclerosis. 

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  • 35.
    Lejon, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kumar, Anjani
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Increased Proportion of TH17, TH22 and TC17 Cells and the Correlation to IL-22 and Clinical Parameters in Patients with Ankylosing Spondylitis from Northern Sweden2020In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 72, article id 1858Article in journal (Other academic)
    Abstract [en]

    Background/Purpose: Increased levels of TH17 and TH22 as well as TC17 and TC22 cells have previously been associated with ankylosing spondylitis (AS). The correlation between these inflammatory T cell subsets and clinically relevant parameters as well as cytokines has also been reported. However, the status of these inflammatory cells in a well characterized AS cohort from northern Sweden has not been studied. The purpose of this study was to confirm the increased presence of inflammatory T cell subsets in peripheral blood of patients with AS from northern Sweden in relation to age and sex-matched controls. In addition, associations of clinically relevant parameters with the level of the inflammatory T cell subset(s) and cytokines of interest were performed.

    Methods: Peripheral blood mononuclear cells (PBMCs) from a cohort of 50 patients with AS from Region Västerbotten (Modif NY, mean age 52±9.1 years, 33 (66 %) men, 50 (100 %) HLAB27) and 50 pair wise matched blood donor controls (mean age 54±8.8 years, 33 (66 %) men) were stained with a combination of antibodies allowing for the detection of surface expressed CD45, CD3, CD4, CD8, intracellular IL-17 and IL-22 and analyzed by flow cytometry. In addition, levels of IL-17 and IL-22 in plasma were determined by the Meso Scale Discovery platform. The patient with AS were examined with spinal x-ray for radiographic alterations assessed with mSASSS. CRP and ESR were measured and physical function and disease activity were registered with BASMI and BASFI respectively ASDAS-CRP and BASDAI.

    Results: Pair wise comparison of AS patients and controls showed a 1,5 to 2-fold increase of TH17, TH22 and TC22 cells among CD45+CD3+ lymphocytes in PBMCs of male patients (p=0,013, p=0,003 and p=0,024 respectively). Levels of IL-22 in plasma and proportion of TC17 correlated in male patients (Rs=0,499 p=0,003) and plasma levels of IL10 showed an inverse correlation in relation to TC17 in all patients (Rs=-0,276 p=0,05). In female AS patients there was a negative correlation between TC22 and CRP (Rs = -0,573, p=0,016). In addition, after splitting the group of female into pre- and postmenopausal correlation between TC17 and mSASSS (Rs = 0,845, p=0,034), TC22 and BASFI (Rs = 0,986, p=0,0003) (premenopausal) and TC22 and BASMI (Rs = 0,764, p=0,006) (postmenopausal) was observed.

    Conclusion: We confirm an increased proportion of TH17, TH22 and TC17 cells in blood in AS male patients from northern Sweden. In addition, positive correlation of the proinflammatory cytokine IL-22 and negative correlation of anti-inflammatory cytokine IL-10 in relation to TC17 corroborate the influence of these cells in the disease process. Interestingly, in female AS patients there was a correlation between clinical relevant parameters to particular inflammatory T cell subset dependent on the menopausal status, suggesting a role of female sex hormones in AS pathogenesis.

  • 36.
    Lejon, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kumar, Anjani
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Rheumatology and Inflammation Research Institute of Medicine, Sahlgrenska Academy, University of Gothenburg Gothenburg Sweden.
    Increased proportions of inflammatory T cells and their correlations with cytokines and clinical parameters in patients with ankylosing spondylitis from northern Sweden2022In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 96, no 3, article id e13190Article in journal (Refereed)
    Abstract [en]

    Ankylosing spondylitis (AS) is an autoimmune disease affecting parts of the skeletal structure in particular. Previously increased levels of the inflammatory cell types Th17, Th22, Tc17 and Tc22 cells have been shown to be associated with AS. Here, we analysed the levels of inflammatory T cell subsets, related cytokines and clinical characteristics of AS patients vs controls from northern Sweden. Peripheral blood mononuclear cells (PBMCs) obtained from 50 AS patients and 50 matched controls were short term stimulated with PMA/Ionomycin, stained and analysed by flow cytometry. Plasma levels of Interleukin (IL)-17, IL-22, IL-10 as well as clinically relevant markers were determined. Compared to male controls, male AS patients showed 1.5- to 2-fold increases of Th17 (P = .013), Th22 (P = .003) and Tc22 (P = .024) among CD45+CD3+ lymphocytes. Plasma IL-22 levels correlated with the Tc17 proportion in male patients (Rs = 0.499, P = .003) and plasma IL-10 levels were inversely correlated with Tc17 among all patients (Rs = −0.276, P = .05). Male patients with syndesmophytes showed significantly higher Th17 proportions (P = .038). In female AS patients, Tc22 was negatively correlated with C-reactive protein (high sensitivity) (hsCRP) (Rs = −0.573, P = .016). We confirmed increased proportions of inflammatory T cells and correlations with relevant cytokines from male AS patients. The correlation between Th17 and syndesmophytes supports a role of Th17 in the pathogenic process.

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  • 37.
    Lejon, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Kumar, Anjani
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Forsblad-d'Elia, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Decreased levels of T follicular helper (CD4+CXCR5+) cells and CD27+CD38+ and CD27+CD38− B cells in ankylosing spondylitis patients correlate with markers of inflammation2023In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 97, no 1, article id e13235Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to study CD4+CXCR5+ T follicular helper (TFH) cells, CD27+CD38+ plasmablasts and CD27+CD38− memory B cells, as well as disease-related factors in patients with ankylosing spondylitis (AS) from northern Sweden. Peripheral blood mononuclear cells (PBMC) from 50 patients with AS (mean age 52 ± 9 years, 66% men, 100% HLA-B27 positive) and 50 pairwise matched blood donor controls (mean age 54 ± 9 years, 66% men) were stained with antibodies for CD27, CD38, CD19, CD3, CD4 and CXCR5 markers and analysed by flow cytometry. Patients with AS were examined with spinal x-ray for radiographic alterations (mSASSS), and plasma levels of C-reactive protein, erythrocyte sedimentation rate, as well as selected proinflammatory and regulatory cytokines were determined. Physical mobility, function and disease activity were registered by BASMI, BASFI and ASDAS-CRP, BASDAI, respectively. Comparing AS patients and controls pairwise, we observed a 56% reduction of TFH cells in PBMCs from AS patients (P =.000008). Furthermore, a 20%-30% reduction in plasmablasts and B memory cells (P ≤.002 and P ≤.007, respectively) was observed. In female patients, negative correlations between ESR and TFH, plasmablasts and B memory cells were observed; Rs = −0.551, P ≤.02; Rs = −0.476, P ≤.05 and Rs = −0.522, P ≤.03, respectively. In addition, positive correlations between the regulatory cytokine IL-10 and the proportion of B cells, IL-22, and the proportion of plasmablasts as well as a negative correlation between levels of the proinflammatory cytokine IL-6 and TFH were detected. Our observations indicate a role of an aberrant humoral immune response related to inflammation in AS.

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  • 38.
    Lorén, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Dahl, Christen P.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Almaas, Vibeke M.
    Geiran, Odd R.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy2019In: Cells, E-ISSN 2073-4409, Vol. 8, no 2, article id 97Article in journal (Refereed)
    Abstract [en]

    During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.

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  • 39.
    MacLeod, Rebecca
    et al.
    Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, 10010, NY, United States.
    Chan, Fok Vun
    Echelon Biosciences Inc., 675 Arapeen Drive, Suite 302, Salt Lake City, 84108, UT, United States.
    Yuan, Han
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    Ye, Xin
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    Sin, Yun Jin Ashley
    Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, 10010, NY, United States.
    Vitelli, Teraesa M.
    Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, 10010, NY, United States.
    Cucu, Tudor
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    Leung, Annie
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    Baljak, Irene
    Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, 10010, NY, United States.
    Osinski, Samantha
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    Fu, Yuhong
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    Jung, Gyu Ik Daniel
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    Amar, Anant
    Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States.
    DeAngelis, Paul L.
    Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Oklahoma, 73104, OK, United States.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Cowman, Mary K.
    Department of Biomedical Engineering, Tandon School of Engineering, New York University, 433 First Avenue, 9thfloor, New York, 10010, NY, United States; Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, 6 Metrotech Center, Brooklyn, 11201, NY, United States .
    Selective isolation of hyaluronan by solid phase adsorption to silica2022In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 652, article id 114769Article in journal (Refereed)
    Abstract [en]

    A solid phase adsorption method for selective isolation of hyaluronan (HA) from biological samples is presented. Following enzymatic degradation of protein, HA can be separated from sulfated glycosaminoglycans, other unsulfated glycosaminoglycans, nucleic acids, and proteolytic fragments by adsorption to amorphous silica at specific salt concentrations. The adsorbed HA can be released from silica using neutral and basic aqueous solutions. HA ranging in size from ∼9 kDa to MDa polymers has been purified by this method from human serum and conditioned medium of cultured cells.

  • 40.
    Malm, Linus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Size determination of hyaluronan using a gas-phase electrophoretic mobility molecular analysis2012In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 22, no 1, p. 7-11Article in journal (Refereed)
    Abstract [en]

    Hyaluronan (HA) is a linear non-sulfated polysaccharide mainly found in the extracellular matrix. The size of HA can vary from a fewq saccharides up to at least 25,000 units, reaching molecular weights of 10x103 kDa. HA has mainly biological functions, and both its size and tissue concentration play an important role in many physiological and phatological processes. It is relatively easy ti determine the HA concentration using enzyme-linked binding protein assays, but the molecular weight of HA has so far been shown to be a more challenging task to measure. Here, we present a method for size determination of HA using gas-phase electrophoretic mobility molecular analysis (GEMMA), which utilizes the electrophoretic mobility of molecules in air to estimate the molecular weight of the analyte. We show that this method gives reliable molecular weight estimations of HA in the range 30-2400 kDa, which covers almost its whole biological range. The average measuring time for one GEMMA spectrum is between 5 and 10 min using only 6 pg of HA. In addition the peak area in a GEMMA spectrum can be used to estimate the HA concentration in the sample. The high sensitivity and small sample volumes make GEMMA an excellent tool for both size determination and estimation of concentration of samples with low HA concentration, as is the case for HA extracted from small tissue samples.

  • 41.
    Mörner, Stellan
    et al.
    Centrum för kardiovaskulär genetik, Hjärtcentrum, Norrlands universitetssjukhus, Umeå, Sverige.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Rydberg, Annika
    Centrum för kardiovaskulär genetik, Barn- och ungdomscentrum, Norrlands universitetssjukhus, Umeå, Sverige.
    Jensen, Steen M.
    Centrum för kardiovaskulär genetik, Hjärtcentrum, Norrlands universitetssjukhus, Umeå, Sverige.
    Lundström, Anna
    Centrum för kardiovaskulär genetik, Klinisk genetik, Laboratoriemedicin, Norrlands universitetssjukhus, Umeå, Sverige.
    Nyberg, Peter
    Centrum för kardiovaskulär genetik, Klinisk genetik, Laboratoriemedicin, Norrlands universitetssjukhus, Umeå.
    Diamant, Ulla-Britt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johnson, Owe
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ärftliga hjärt–kärlsjukdomar – ett multidisciplinärt arbetssätt krävs: [Experiences from a multidisciplinary cardiogenetic clinic]2021In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 118, no 40, article id 21083Article in journal (Refereed)
    Abstract [sv]

    Comprehensive genetic and clinical care of families with monogenic cardiovascular diseases requires competences from different medical specialties. Genetic assessment, cascade screening, risk estimation, treatment and follow-up is difficult to cover. Fourteen years ago, a center for cardiovascular diseases was created in our hospital, to improve the care of families with monogenic cardiovascular diseases. At our center, clinical geneticists, cardiologists, angiologists, pediatric cardiologists and genetic counselors work together in a seamless organization, while still having different clinic affiliations. A key feature of this organization are the family outpatient clinics, where the proband and his/her relatives at genetic risk are invited to take part. When the family or relatives live in other parts of the country, they are invited to participate through video conference.  In this paper we report our experiences and working routines from more than 300 families and 2000 individuals.

  • 42.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kazzam, Elsadig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Amyloid heart disease mimicking hypertrophic cardiomyopathy.2005In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 258, no 3, p. 225-230Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the importance of transthyretin (TTR) gene mutations in explaining the phenotypic expression in patients diagnosed with hypertrophic cardiomyopathy (HCM) in northern Sweden. BACKGROUND: Hypertrophic cardiomyopathy is relatively common and often caused by mutations in sarcomeric protein genes. Mutations in the TTR gene are also common, one of which causes familial amyloid polyneuropathy (FAP), with peripheral polyneuropathy and frequently, cardiac hypertrophy. These circumstances were highlighted by the finding of an index case with amyloidosis, presenting itself as HCM. Initial rectal and fat biopsies did not show amyloid deposits. Later on, the patient was shown to carry a TTR gene mutation, and cardiac amyloidosis was confirmed by myocardial biopsy. Only then was a repeated fat biopsy positive for amyloid deposits. DESIGN: Cross-sectional study. SETTING: Cardiology tertiary referral centre. SUBJECTS: Forty-six unrelated individuals with HCM and the index case were included. Common diagnostic criteria for HCM were used. The 46 patients with HCM were previously analysed for mutations in eight sarcomeric protein genes and the TTR gene was now analysed by denaturing high-performance liquid chromatography and direct sequencing. RESULTS: One mutation in the TTR gene (Val30Met) was found in three individuals and the index case. CONCLUSIONS: Three of the 46 cases with HCM carried the Val30Met mutation, and were considered likely to have cardiac amyloidosis, like the index case. As a correct diagnosis of cardiac amyloidosis is mandatory for a potentially life-saving treatment, TTR mutation analysis should be considered in cases of HCM not explained by mutations in sarcomeric protein genes.

  • 43.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Richard, Pascale
    Kazzam, Elsadig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hainque, Bernard
    Schwartz, Ketty
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden2003In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 35, no 7, p. 841-849Article in journal (Refereed)
    Abstract [en]

    Hypertrophic cardiomyopathy (HCM) is a heterogenous disease, with variable genotypic and phenotypic expressions, often caused by mutations in sarcomeric protein genes. The aim of this study was to identify the genotypes and associated phenotypes related to HCM in northern Sweden. In 46 unrelated individuals with familial or sporadic HCM, mutation analysis of eight sarcomeric protein genes was performed; the cardiac beta-myosin heavy chain, cardiac myosin-binding protein C, cardiac troponin T, alpha-tropomyosin, cardiac essential and regulatory myosin light chains, cardiac troponin I and cardiac alpha-actin. A total of 11 mutations, of which six were novel ones, were found in 13 individuals. Seven mutations were located in the myosin-binding protein C gene, two in the beta-myosin heavy chain gene and one in the regulatory myosin light chain and troponin I genes, respectively. This is the first Swedish study, where a population with HCM has been genotyped. Mutations in the cardiac myosin-binding protein C gene were the most common ones found in northern Sweden, whereas mutations in the beta-myosin heavy chain gene were less frequent than previously described. There are differences in the phenotypes mediated by these genes characterised by a more late-onset disease for the myosin-binding protein C gene mutations. This should be taken into consideration, when evaluating clinical findings in the diagnosis of the disease, especially in young adults in families with HCM, where penetrance can be expected to be incomplete in the presence of a myosin-binding protein C gene mutation.

  • 44.
    Norgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ericzon, Bo Göran
    Division of Transplantation Surgery, Karolinska Institutet, Stockholm, Sweden.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Allele specific expression of the transthyretin gene in Swedish patients with hereditary transthyretin amyloidosis (ATTR V30M) is similar between the two alleles2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 11, p. e49981-Article in journal (Refereed)
    Abstract [en]

    Background: Hereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease characterized by extracellular deposits of amyloid fibrils composed of misfolded TTR. The differences in penetrance and age at onset are vast, both between and within populations, with a generally late onset for Swedish carriers. In a recent study the entire TTR gene including the 3' UTR in Swedish, French and Japanese ATTR patients was sequenced. The study disclosed a SNP in the V30M TTR 3' UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C > T). This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR's mRNA thus decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression.

    Methodology/Principal Findings: Allele-specific expression was measured on nine liver biopsies from Swedish ATTR patients using SNaPshot Multiplex assay. Luciferase activity was measured on cell lines transfected with constructs containing the TTR 3' UTR. Allele-specific expression measured on liver biopsies from Swedish ATTR patients showed no difference in expression between the two alleles. Neither was there any difference in expression between cell lines co-transfected with two constructs with or without the TTR 3' UTR SNP regardless of added miRNA.

    Conclusions/Significance: The SNP found in the 3' UTR of the TTR gene has no effect on degrading the variant allele's expression and thus has no impact on the diminished penetrance of the trait in the Swedish population. However, the 3' UTR SNP is unique for patients descending from the Swedish founder, and this SNP could be utilized to identify ATTR patients of Swedish descent.

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  • 45.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Planté-Bordeneuve, V
    Jonasson, J
    Lång, K
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mitochondrial haplogroup is associated with the phenotype of familial amyloidosis with polyneuropathy in Swedish and French patients2009In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 75, no 2, p. 163-168Article in journal (Refereed)
    Abstract [en]

    Familial amyloidotic polyneuropathy (FAP) is a monogenic disease caused by mutations in the transthyretin (TTR) gene. The phenotype of the most common TTR mutation, V30M, varies within and between populations. Oxidative stress and protein misfolding are cellular processes involved in the development of FAP. Because the mitochondria are important for both these processes, we investigated if mitochondrial haplogroups are related to age at onset of the disease in Swedish and French FAP patients. Mitochondrial haplogroup analysis was performed on 25 early-onset (below 40 years) and 29 late-onset (above 51 years) Swedish FAP patients. DNA from 249 Swedish individuals served as controls. In addition, 6 early-onset and 17 late-onset French FAP patients were examined with 25 French controls. The haplogroup distribution among late-onset Swedish and French cases was similar to that found in the general populations, whereas among early-onset cases a different haplogroup distribution was seen. The relatively rare haplogroup K was significantly more common among early-onset cases. Our findings substantiate the suggestion that a genetic component, still to be found, affecting mitochondrial function has an impact on the amyloid generating process in transthyretin amyloidosis.

  • 46.
    Olsson, Malin
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Metabolomics analysis for diagnosis and biomarker discovery of transthyretin amyloidosis2021In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 28, no 4, p. 234-242Article in journal (Refereed)
    Abstract [en]

    Untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis (ATTRv) is a disabling and fatal disease with different clinical features such as polyneuropathy, cardiomyopathy, different gastrointestinal symptoms and renal failure. Plasma specimens collected from 27 patients with ATTRv (ATTRV30M), 26 asymptomatic TTRV30M carriers and 26 control individuals were subjected to gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS)-based metabolomics analysis. Partial least squares discriminant and univariate analysis was used to analyse the data. The models constructed by Partial least squares-discriminant analysis (PLS-DA) could clearly discriminate ATTRV30M patients from controls and asymptomatic TTRV30M carriers. In total, 24 plasma metabolites (VIP > 1.0 and p <.05) were significantly altered in ATTRV30M patient group (6 increased and 18 decreased). Eleven of these distinguished the ATTRV30M group from both controls and TTRV30M carriers. Plasma metabolomics analysis revealed marked changes in several pathways in patients with ATTRV30M amyloidosis. Statistical analysis identified a panel of biomarkers that could effectively separate controls/TTRV30M carriers from ATTRV30M patients. These biomarkers can potentially be used to diagnose patients at an early stage of the disease.

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  • 47. Opheim, Leif Runar
    et al.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Laurent, Claude
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Speech/Language Pathology and Audiology, University of Pretoria, Pretoria, South Africa.
    Hyaluronan in Human Vocal Folds in Smokers and Nonsmokers: A Histochemical Study2016In: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588, Vol. 30, no 3, p. 255-262Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES/HYPOTHESIS: To study the hyaluronan occurrence in human vocal folds, with special regards to gender and smoking and to discuss the implications of findings.

    STUDY DESIGN: This is a descriptive/morphologic study.

    METHODS: Sixteen cadaveric vocal folds from eight individuals between 58 and 90 years old (six women and two men) were removed and studied morphologically. Three of the individuals had been cigarette smokers. A direct method for hyaluronan histochemistry using a hyaluronan-binding protein probe (HABP) was used to visualize the polysaccharide. Five examiners performed an analysis of the intensities of hyaluronan staining, independently.

    RESULTS: We observed intense hyaluronan staining of the vocal folds of which those from women stained considerably stronger than those from men. Stratified squamous epithelium stained for hyaluronan in all sections, whereas respiratory epithelium only stained weakly or not at all. The highest accumulation of hyaluronan occurred subepithelially in the lamina propria, corresponding to Reinke's space. It was observed that vocal folds from smokers were more intensively stained than those from nonsmokers.

    CONCLUSIONS: Hyaluronan is found in all layers of the human vocal fold. Contradictory to earlier studies, hyaluronan was visualized in squamous epithelium, where it may function as an impact protector. The occurrence of hyaluronan in smokers may have implications in the development of vocal fold inflammation and tumor initiation as hyaluronan is an important molecule in these processes.

  • 48. Svennerholm, Kristina
    et al.
    Rodsand, Pouria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Biber, Björn
    Ronquist, Gunnar
    Haney, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Myocardial ischemic preconditioning in a porcine model leads to rapid changes in cardiac extracellular vesicle messenger RNA content2015In: International Journal of Cardiology Heart and Vasculature, ISSN 2352-9067, Vol. 8, p. 62-67Article in journal (Refereed)
    Abstract [en]

    Background: Extracellular vesicles (EVs) are thought to exert protective effects after ischemic and remote ischemic preconditioning. It is not well understood which EV content factors are most relevant for protective effects. We hypothesize that ischemic preconditioning leads to qualitative changes in EV mRNA content and quantitative changes in EV size and number.

    Methods: Using an in vivo porcine ischemic preconditioning model, EVs were collected from coronary venous blood, and isolated by differential ultracentrifugations. The presence and purity of EV were verified by electron microscopy and Western blot, and EV number was assessed by nanoparticle tracking analysis. The mRNA EV was identified by microarray.

    Results: Gene ontology analysis showed enrichment of EV mRNA coding for proteins associated with regulation of transcription, translation, extracellular matrix, morphogenic development and feeding behavior. There were 11,678 different mRNA transcripts detected in EV, where a total of 1103 was significantly increased or decreased after preconditioning, of which 638 mRNA sequences were up-regulated and/or emerged due to preconditioning. Several of them have known association with ischemic preconditioning. There was no significant difference in EV quantity or size before and after preconditioning.

    Conclusions: These findings demonstrate in an in vivo model that myocardial ischemic preconditioning influences the composition of mRNA in EV, including gene transcripts for proteins associated with the protective effect of ischemic preconditioning. The finding that preconditioned parental cells release EV containing mRNA that is qualitatively different from those released by non-preconditioned cells shows the importance of the external milieu on parental cell EV production.

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  • 49. Svennerholm, Kristina
    et al.
    Rodsand, Pouria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ahrén, Dag
    Biber, Björn
    Ronquist, Gunnar
    Haney, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    DNA content in extracellular vesicles isolated from porcine coronary venous blood directly after myocardial ischemic preconditioning2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159105Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Extracellular vesicles (EV) are nano-sized membranous structures released from most cells. They have the capacity to carry bioactive molecules and gene expression signals between cells, thus mediating intercellular communication. It is believed that EV confer protection after ischemic preconditioning (IPC). We hypothesize that myocardial ischemic preconditioning will lead to rapid alteration of EV DNA content in EV collected from coronary venous effluent.

    MATERIALS AND METHODS: In a porcine myocardial ischemic preconditioning model, EV were isolated from coronary venous blood before and after IPC by differential centrifugation steps culminating in preparative ultracentrifugation combined with density gradient ultracentrifugation. The EV preparation was validated, the DNA was extracted and further characterized by DNA sequencing followed by bioinformatics analysis.

    RESULTS: Porcine genomic DNA fragments representing each chromosome, including mitochondrial DNA sequences, were detected in EV isolated before and after IPC. There was no difference detected in the number of sequenced gene fragments (reads) or in the genomic coverage of the sequenced DNA fragments in EV isolated before and after IPC. Gene ontology analysis showed an enrichment of genes coding for ion channels, enzymes and proteins for basal metabolism and vesicle biogenesis and specific cardiac proteins.

    CONCLUSIONS: This study demonstrates that porcine EV isolated from coronary venous blood plasma contain fragments of DNA from the entire genome, including the mitochondria. In this model we did not find specific qualitative or quantitative changes of the DNA content in EV collected immediately after an in vivo myocardial IPC provocation. This does not rule out the possibility that EV DNA content changes in response to myocardial IPC which could occur in a later time frame.

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  • 50.
    Tjust, Anton Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences. Department of Medical Sciences, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Giannopoulos, Antonios
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Winsnes, Annika
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Strigård, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Gunnarsson, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Evaluation of extracellular matrix remodeling in full-thickness skin grafts in mice2024In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 72, no 2, p. 79-94Article in journal (Refereed)
    Abstract [en]

    Abdominal hernia is a protruding weakness in the abdominal wall. It affects abdominal strength and life quality and can lead to complications due to intestinal entrapment. Autologous full-thickness skin graft (FTSG) has recently become an alternative material for reinforcement in the surgical repair of large abdominal hernias instead of synthetic mesh. FTSG eventually integrates with the abdominal wall, but the long-term fate of the graft itself is not fully understood. This has implications as to how these grafts should be optimally used and handled intraoperatively. This study investigates the remodeling of FTSG in either the onlay or the intraperitoneal position 8 weeks after FTSG transplantation in an experimental mouse model. There was a significant presence of fibroblasts, indicated by vimentin and S100A4 staining, but there were significant variations among animals as to how much of the graft had been remodeled into dense connective tissue. This correlated significantly with the proportion of vimentin-positive cells in the dense connective tissue. We also found that collagen hybridizing peptide staining intensity, a marker of active remodeling, was significantly associated with the proportion of S100A4-positive cells in the dense connective tissue of the FTSG.

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