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  • 13601.
    Zoerner, Frank
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrestManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

    Methods: Twenty-six immature male piglets were subjected to 12 min VF followed by 8 min CPR. The treatment group (n=13) received i.v. boluses vasopressin 0.4 U∙kg−1, esmolol 250 μg∙kg−1 and milrinone 25 μg∙kg−1 after 13 min, followed by i.v. boluses esmolol 375 μg∙kg−1 and milrinone 25 μg∙kg−1 after 18 min and continuous esmolol 15 μg∙kg−1∙h−1 infusion during 180 min reperfusion, while controls (n=13) received equal amounts of vasopressin and saline. A 200J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200J defibrillation and bolus vasopressin 0.4 U∙kg−1 were administered in both groups. DC shocks at 360J were applied as one shot min−1 over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

    Results: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (p<0.05). The treatment group received less norepinephrine (p<0.01) and had greater diuresis (p<0.01). There was no difference in survival between groups.

    Conclusions: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone. 

  • 13602.
    Zoerner, Frank
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest2015In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, no 4, p. 465-474Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Long-term survival after cardiac arrest (CA) due to shock-refractory ventricular fibrillation (VF) is low. Clearly, there is a need for new pharmacological interventions in the setting of cardiopulmonary resuscitation (CPR) to improve outcome. Here, hemodynamic parameters and cardiac damage are compared between the treatment group (milrinone, esmolol and vasopressin) and controls (vasopressin only) during resuscitation from prolonged CA in piglets.

    METHODS: A total of 26 immature male piglets were subjected to 12-min VF followed by 8-min CPR. The treatment group (n = 13) received i.v. (intravenous) boluses vasopressin 0.4 U/kg, esmolol 250 μg/kg and milrinone 25 μg/kg after 13 min, followed by i.v. boluses esmolol 375 μg/kg and milrinone 25 μg/kg after 18 min and continuous esmolol 15 μg/kg/h infusion during 180 min reperfusion, whereas controls (n = 13) received equal amounts of vasopressin and saline. A 200 J monophasic counter-shock was delivered to achieve resumption of spontaneous circulation (ROSC) after 8 min CPR. If ROSC was not achieved, another 200 J defibrillation and bolus vasopressin 0.4 U/kg would be administered in both groups. Direct current shocks at 360 J were applied as one shot per minute over maximally 5 min. Hemodynamic variables and troponin I as a marker of cardiac injury were recorded.

    RESULTS: Troponin I levels after 180 min reperfusion were lower in the treatment group than in controls (P < 0.05). The treatment group received less norepinephrine (P < 0.01) and had greater diuresis (P < 0.01). There was no difference in survival between groups.

    CONCLUSION: The combination of milrinone, esmolol and vasopressin decreased cardiac injury compared with vasopressin alone.

  • 13603. Zoerner, Frank
    et al.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs2014In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, Vol. 76, no 6, p. 1402-1408Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets. METHODS: Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation. RESULTS: Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group. CONCLUSION: Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

  • 13604.
    Zoerner, Frank
    et al.
    Department of Operative and Intensive Care Medicine, Hallands Hospital Halmstad, Halmstad, Sweden.
    Semenas, Egidijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs2014In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, E-ISSN 2163-0763, Vol. 76, no 6, p. 1402-1408Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets.

    METHODS:

    Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation.

    RESULTS:

    Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group.

    CONCLUSION:

    Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

  • 13605.
    Zoerner, Frank
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Miclescu, Adriana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cecile
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Therapeutic hypothermia activates the endothelin and nitric oxide systems after cardiac arrest in a pig model of cardiopulmonary resuscitation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e64792-Article in journal (Refereed)
    Abstract [en]

    Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32-34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

  • 13606. Zohari, Siamak
    et al.
    Gyarmati, Péter
    Ejdersund, Anneli
    Berglöf, Ulla
    Thorén, Peter
    Ehrenberg, Maria
    Czifra, György
    Belák, Sándor
    Waldenström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berg, Mikael
    Phylogenetic analysis of the non-structural (NS) gene of influenza A viruses isolated from mallards in Northern Europe in 20052008In: Virology Journal, ISSN 1743-422X, Vol. 5, p. 147-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although the important role of the non-structural 1 (NS) gene of influenza A in virulence of the virus is well established, our knowledge about the extent of variation in the NS gene pool of influenza A viruses in their natural reservoirs in Europe is incomplete. In this study we determined the subtypes and prevalence of influenza A viruses present in mallards in Northern Europe and further analysed the NS gene of these isolates in order to obtain a more detailed knowledge about the genetic variation of NS gene of influenza A virus in their natural hosts. RESULTS: A total number of 45 influenza A viruses of different subtypes were studied. Eleven haemagglutinin- and nine neuraminidase subtypes in twelve combinations were found among the isolated viruses. Each NS gene reported here consisted of 890 nucleotides; there were no deletions or insertions. Phylogenetic analysis clearly shows that two distinct gene pools, corresponding to both NS allele A and B, were present at the same time in the same geographic location in the mallard populations in Northern Europe. A comparison of nucleotide sequences of isolated viruses revealed a substantial number of silent mutations, which results in high degree of homology in amino acid sequences. The degree of variation within the alleles is very low. In our study allele A viruses displays a maximum of 5% amino acid divergence while allele B viruses display only 2% amino acid divergence. All the viruses isolated from mallards in Northern Europe possessed the typical avian ESEV amino acid sequence at the C-terminal end of the NS1 protein. CONCLUSION: Our finding indicates the existence of a large reservoir of different influenza A viruses in mallards population in Northern Europe. Although our phylogenetic analysis clearly shows that two distinct gene pools, corresponding to both NS allele A and B, were present in the mallards populations in Northern Europe, allele B viruses appear to be less common in natural host species than allele A, comprising only about 13% of the isolates sequenced in this study.

  • 13607. Zoltowska Nilsson, Anna Maria
    et al.
    Lei, Ying
    Adner, Mikael
    Nilsson, G P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden .
    Mast cell dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma2018In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 314, no 3, p. L484-L492Article in journal (Refereed)
    Abstract [en]

    Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated to the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM) induced asthma. Mast cell deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh+MC-WT) or ST2 deficient bone marrow derived mast cells (Wsh+MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh+MC-ST2KO compared to Wsh+MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in BALF and lung, the aggravated AHR in Wsh+MC-ST2KO mice, seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in bronchoalveolar lavage fluid. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role in the development of AHR.

  • 13608.
    Zorzan, Eleonora
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Sissi, Claudia
    Univ Padua, Dept Pharmaceut & Pharmacol Sci, Padua, Italy.
    Whole-Transcriptome Profiling of Canine and Human in Vitro Models Exposed to a G-Quadruplex Binding Small Molecule2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17107Article in journal (Refereed)
    Abstract [en]

    G-quadruplexes (G4) are secondary nucleic acid structures that have been associated with genomic instability and cancer progression. When present in the promoter of some oncogenes, G4 structures can affect gene regulation and, hence, represent a possible therapeutic target. In this study, RNA-Seq was used to explore the effect of a G4-binding anthraquinone derivative, named AQ1, on the whole-transcriptome profiles of two common cell models for the study of KIT pathways; the human mast cell leukemia (HMC1.2) and the canine mast cell tumor (C2). The highest non-cytotoxic dose of AQ1 (2 mu M) resulted in 5441 and 1201 differentially expressed genes in the HMC1.2 and C2 cells, respectively. In both cell lines, major pathways such as cell cycle progression, KIT- and MYC-related pathways were negatively enriched in the AQ1-treated group, while other pathways such as p53, apoptosis and hypoxia-related were positively enriched. These findings suggest that AQ1 treatment induces a similar functional response in the human and canine cell models, and provide news insights into using dogs as a reliable translational model for studying G4-binding compounds.

  • 13609.
    Zorzet, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersen, Jytte Mark
    Nilsson, Annika I
    Møller, Niels Frimodt
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Compensatory mutations in agrC partly restore fitness in vitro to peptide deformylase inhibitor-resistant Staphylococcus aureus2012In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 67, no 8, p. 1835-1842Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES

    To determine how the fitness cost of deformylase inhibitor resistance conferred by fmt mutations can be genetically compensated.

    METHODS

    Resistant mutants were isolated and characterized with regard to their growth rates in vitro and in neutropenic mice, MIC and DNA sequence. Faster-growing compensated mutants were isolated by serial passage in culture medium, and for a subset of the resistant and compensated mutants whole-genome sequencing was performed.

    RESULTS

    Staphylococcus aureus mutants resistant to the peptide deformylase inhibitor actinonin had mutations in the fmt gene that conferred high-level actinonin resistance and reduced bacterial growth rate. Compensated mutants that remained fully resistant to actinonin and showed increased growth rates appeared within 30-60 generations of growth. Whole-genome sequencing and localized DNA sequencing of mutated candidate genes showed that alterations in the gene agrC were present in the majority of compensated strains. Resistant and compensated mutants grew at similar rates as the wild-type in a mouse thigh infection model.

    CONCLUSIONS

    Resistance to deformylase inhibitors due to fmt mutations reduces bacterial growth rates, but these costs can be reduced by mutations in the agrC gene. Mutants defective in fmt (with or without compensatory agrC mutations) grew well in an animal model, implying that they can also cause infection in a host.

  • 13610.
    Zubarev, Roman Alexandrovich
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Physics, Department of Nuclear and Particle Physics.
    Mass spectrometry of biopolymers based on ion-induced desorption1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Various aspects of biopolymer molecular characterization by their molecular masses havebeen studied, with emphasis on ion-induced desorption and time-of-flight mass Spectrometry(TOF MS). Limitations of the average-isotopic mass concept, as well as the utility ofaccurate monoisotopic mass measurements for deriving amino-acid and elementalcompositions, are discussed. A new sufficiency criterion of mass accuracy for peptidecharacterization is formulated. Experimentally achievable mass accuracy in TOF MS basedon MeV-ion induced desorption is studied. A new method of deriving peptide structuralinformation using partial acid hydrolysis and accurately measured hydrolysis fragmentmasses is developed.

    Secondary ion formation mechanisms in ion-induced desorption have been studiedusing keV and MeV atomic and polyatomic projectiles. In the MeV-atomic-ion mode, kineticenergies and formation times of secondary ions have been investigated. The results suggestdelayed (10-10-10-9s) formation of target-specific ions in the gas phase. A concept ofexothermic matrices has been tested experimentally. A new effective matrix for peptides andproteins, HMX, has been found. In the keV-atomic-ion mode, target-specific ions are foundto possess kinetic energy distributions that are characteristic for gas-phase ion formation. Thissuggests that the ion-formation mechanisms may be similar in both MeV and keV modes.Polyatomic ion-induced desorption has been studied using multiply-charged proteinprojectiles. The total negative ion yield is found to depend primarily on the surface density ofthe deposited energy. The utility of these findings for mass determination of mixturecomponents from complicated electrospray-ionization spectra is demonstrated.

  • 13611.
    Zucca, Emanuele
    et al.
    Oncol Inst Southern Switzerland, Div Med Oncol, Bellinzona, Switzerland;Inst Oncol Res, Bellinzona, Switzerland;Bern Univ Hosp, Dept Med Oncol, Inselspital, Bern, Switzerland.
    Rondeau, Stephanie
    SAKK Coordinating Ctr, Bern, Switzerland.
    Vanazzi, Anna
    European Inst Oncol IRCCS, Clin Hematooncol, Milan, Italy.
    Ostenstad, Bjorn
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
    Mey, Ulrich J. M.
    Kantonsspital Graubunden, Med Oncol & Hematol, Chur, Switzerland.
    Rauch, Daniel
    Spital Thun Simmenthal, Div Oncol, Thun, Switzerland.
    Wahlin, Bjorn E.
    Karolinska Inst, Unit Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Hitz, Felicitas
    Kantonsspital St Gallen, Oncol Hematol, St Gallen, Switzerland.
    Hernberg, Micaela
    Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Oncol, Helsinki, Finland.
    Johansson, Ann-Sofie
    Norrlands Univ Sjukhus, Dept Oncol, Umea, Sweden.
    Brown, Peter de Nully
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ferreri, Andres J. M.
    IRCCS San Raffaele Sci Inst, Unit Lymphoid Malignancies, Milan, Italy.
    Lohri, Andreas
    Med Univ Clin, Dept Oncol Hematol, Liestal, Switzerland.
    Novak, Urban
    Bern Univ Hosp, Dept Med Oncol, Inselspital, Bern, Switzerland.
    Zander, Thilo
    Luzerner Kantonsspital, Dept Oncol, Luzern, Switzerland.
    Bersvendsen, Hanne
    Univ Hosp North Norway, Dept Oncol, Tromso, Norway.
    Bargetzi, Mario
    Kantonsspital Aarau, Div Hematol Oncol, Aarau, Switzerland.
    Mingrone, Walter
    Kantonsspital Olten, Dept Med Oncol, Olten, Switzerland.
    Krasniqi, Fatime
    Univ Hosp Basel, Dept Oncol, Basel, Switzerland.
    Dirnhofer, Stefan
    Univ Hosp Basel, Inst Pathol, Basel, Switzerland.
    Hayoz, Stefanie
    SAKK Coordinating Ctr, Bern, Switzerland.
    Hawle, Hanne
    SAKK Coordinating Ctr, Bern, Switzerland.
    Vilei, Simona Berardi
    SAKK Coordinating Ctr, Bern, Switzerland.
    Ghielmini, Michele
    Oncol Inst Southern Switzerland, Div Med Oncol, Bellinzona, Switzerland.
    Kimby, Eva
    Karolinska Inst, Unit Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Caspar, Clemens
    Koberle, Dieter
    Zenhausern, Reinhard
    Jost, Lorenz M.
    Mach, Nicolas
    Voegeli, Michele
    Tscherry, Georg
    Fischer, Natalie
    Burkhard, Roger
    Schmid, Mathias
    Panagiotis, Samaras
    Munksgaard, Lars
    Vasala, Kaija
    Lehtinen, Tuula
    Jyrkkio, Sirkku
    Ekanger, Roald
    Rolke, Jurgen
    Meyer, Peter
    Maisenholder, Martin
    Eidem, Monika
    Radlund, Anders
    Lagerlof, Ingemar
    Brandefors, Lena
    Ola, Linde Prime N.
    Arnljots, Kristina
    Strandberg, Maria
    Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy2019In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 134, no 4, p. 353-362Article in journal (Refereed)
    Abstract [en]

    The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m(2) IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (>= 90%). Toxicity grade >= 3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored.

  • 13612. Zucchelli, Giulio
    et al.
    Di Cori, Andrea
    Segreti, Luca
    Laroche, Cécile
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Kutarski, Andrzej
    Regoli, François
    Butter, Christian
    Defaye, Pascal
    Pasquié, Jean Luc
    Auricchio, Angelo
    Maggioni, Aldo P
    Bongiorni, Maria Grazia
    Major cardiac and vascular complications after transvenous lead extraction: acute outcome and predictive factors from the ESC-EHRA ELECTRa (European Lead Extraction ConTRolled) registry2019In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 21, no 5, p. 771-780Article in journal (Refereed)
    Abstract [en]

    Aims: We aimed at describing outcomes and predictors of cardiac avulsion or tear (CA/T) with tamponade and vascular avulsion or tear (VA/T) after transvenous lead extraction (TLE) in the ESC-EHRA European Lead Extraction ConTRolled (ELECTRa) registry.

    Methods and results: A total of 3555 consecutive patients of whom 3510 underwent TLE at 73 centres in 19 European countries were enrolled. Among 58 patients (1.7%) with procedure-related major complications, 49 (84.5%) patients (30 CA/T and 19 VA/T) presented cardiovascular complications requiring pericardiocentesis, chest tube positioning and/or surgical repair. The mortality was 20% in patients with tamponade due to CA/T and 31.6% in patients with VA/T. Pericardiocentesis as first manoeuvre followed by rescue surgical repair was highly effective in case of CA/T (93.8%). At multivariate analysis, CA/T with tamponade was more common in RIATA lead extraction, female patients, leads with a mean dwelling time more than 10 years, and when ≥3 leads were extracted or multiple sheaths required. Occlusion or critical stenosis of superior venous access and the leads mean dwelling time more than 10 years were independent predictors for VA/T, while mechanical dilatation was an independent predictor of a lower incidence of this complication as compared to the use of powered sheaths.

    Conclusions: In the ELECTRa registry, RIATA lead extraction and superior venous access occlusion/thrombosis are two new independent predictors for cardiac tamponade and major vascular complications, respectively. The use of mechanical sheaths seems to be associated with a lower incidence of VA/T. A strategy of pericardiocentesis followed by a rescue surgical approach seems to be reasonable in order to treat a CA/T with tamponade.

  • 13613.
    Zupancic, Tina
    et al.
    National Institute of Chemistry, Ljubljana.
    Sersa, Gregor
    Institute of Oncology, Ljubljana.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lane, Ellen Birgitte
    A*Star Institute of Medical Biology, Singapore.
    Herrmann, Harald
    German Cancer Research Center (DKFZ), B065 Functional Architecture of the Cell.
    Komel, Radovan
    University of Ljubljana, Faculty of Medicine, Medical Centre for Molecular Biology.
    Liovic, Mirjana
    University of Ljubljana, Faculty of Medicine, Medical Centre for Molecular Biology.
    Keratin gene mutations influence the keratinocyte response to DNA damage and cytokine induced apoptosis2017In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 309, no 7, p. 587-593Article in journal (Refereed)
    Abstract [en]

    The keratin filament cytoskeleton is vital to the normal function of epithelial cells. It provides structural support and regulates different aspects of cell metabolism. Mutations in keratins 5 and 14 cause a skin fragility disorder, epidermolysis bullosa simplex (EBS). Patients with severe EBS have an increased cumulative risk for basal cell carcinoma. In this study, we tested how keratin 5 and 14 mutant EBS patient-derived keratinocytes behave in the face of two different types of stressors that are able to induce cell death: ionizing radiation and cytokines TNF-alpha and TRAIL. The data point out to a substantial difference between how normal and keratin mutant keratinocytes deal with such stresses. When case of DNA damage, the ATM/Chk2-pathway is one of the two main tracks that can prevent the progression of mitosis and so allow repair. This was altered in all investigated keratin mutants with a particular down-regulation of the activated form of checkpoint kinase 2 (pChk2). Keratin mutants also appear less sensitive than normal cells to treatment with TNF-alpha or TRAIL, and this may be linked to the up-regulation of two pro-survival proteins, Bcl-2 and FLIP. Such changes are likely to have a profound effect on mutant keratinocytes ability to survive and withstand stress, and in theory this may be also a contributing factor to cell transformation.

  • 13614. Zwang, Julien
    et al.
    D'Alessandro, Umberto
    MRC Unit, Banjul, Gambia;London Sch Hyg & Trop Med, London, England;Inst Trop Med, Antwerp, Belgium.
    Ndiaye, Jean-Louis
    Cheikh Anta Diop Univ, Dept Parasitol, Fac Med, Dakar, Senegal.
    Djimde, Abdoulaye A.
    Univ Sci Tech & Technol Bamako, Fac Pharm, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali.
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Karema, Corine
    Swiss Trop & Publ Hlth Inst, Basel, Switzerland;Univ Basel, Basel, Switzerland.
    Olliaro, Piero L.
    Special Programme Res & Training Trop Dis WHO TDR, 20 Ave Appia, CH-1211 Geneva, Switzerland;Univ Oxford, Churchill Hosp, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford OX3 7LJ, England;Univ Basel, Basel, Switzerland.
    Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa2017In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 17, article id 443Article in journal (Refereed)
    Abstract [en]

    Background: Anaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity. Methods: Individual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models. Results: Eight thousand eight hundred ninety-seven patients (77.0% < 5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5' s had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 mu l) than older subjects (2784 mu l). Baseline anaemia increased the risk of parasitological recurrence. Hb began to fall after treatment start. In under 5' s the estimated nadir was similar to 35 h (range 29-48), with a drop of -12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15's, the mean Hb decline between day 0-3 was -4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach + 13.8% compared to baseline. Severe anaemia (< 5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28. There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia. Conclusion: On presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1-2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment.

  • 13615.
    Ängeby, Karin
    et al.
    Cty Council Varmland, Womens Dept, Karlstad, Sweden.;Cty Council Varmland, Clin Res Ctr, Karlstad, Sweden.;Karlstad Univ, Dept Hlth Sci, Fac Hlth Sci & Technol, Karlstad, Sweden..
    Wilde-Larsson, Bodil
    Karlstad Univ, Dept Hlth Sci, Fac Hlth Sci & Technol, Karlstad, Sweden.;Inland Norway Univ Appl Sci, Fac Publ Hlth, Dept Nursing, Elverum, Norway..
    Hildingsson, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Mid Sweden Univ, Dept Nursing Sci, Sundsvall, Sweden..
    Sandin-Bojo, Ann-Kristin
    Karlstad Univ, Dept Hlth Sci, Fac Hlth Sci & Technol, Karlstad, Sweden..
    Prevalence of Prolonged Latent Phase and Labor Outcomes: Review of Birth Records in a Swedish Population2018In: Journal of midwifery & women's health, ISSN 1526-9523, E-ISSN 1542-2011, Vol. 63, no 1, p. 33-44Article, review/survey (Refereed)
    Abstract [en]

    IntroductionThe prevalence of a prolonged latent phase of labor has been described as ranging from 5% to 6.5% in previous research. The aim of this study was to describe the prevalence of the prolonged latent phase of 18 hours or more, based on women's report, in women intending vaginal birth and who had spontaneous onset of labor. An additional aim was to compare the incidence of obstetric interventions, and the labor and neonatal outcomes in women with and without a prolonged latent phase. MethodsA descriptive and comparative study was performed in a mid-sized hospital in western Sweden. The sample consisted of 1343 birth records of women who intended vaginal births and who had spontaneous onset of labor at 37 or more weeks' gestation during a one-year period (2013-2014). Background characteristics, obstetric interventions, and labor and neonatal outcomes were compared between women with latent phases lasting less than 18 hours and 18 hours or more, based on women's self-report. Odds ratios with 95% confidence intervals were calculated for the different exposure variables. ResultsA prolonged latent phase lasting 18 hours or more occurred in 23% of all births analyzed (n = 1343). A prolonged latent phase was more common among nulliparous women (29.2%) but also common for multiparous women (17%). Nulliparous and multiparous women who experienced a prolonged latent phase were more often exposed to amniotomy during latent phase. For nulliparous women, the adjusted odds ratio (aOR) was 11.57 (95% confidence interval [CI], 5.25-25.51) and for multiparous women the aOR was 18.73 (95% CI, 9.06-38.69). Similarly, amniotomy during active phase was more common for both nulliparous and multiparous women who experienced a prolonged latent phase (aOR, 4.05; 95% CI, 2.53-6.47 and aOR, 3.93; 95% CI, 2.43-6.37, respectively). Women with latent phases of 18 hours or more, more often experienced augmentation of labor during all phases, especially during latent phase. For nulliparous women, the aOR was 10.13 (95% CI, 2.82-36.39) and for multiparous women, aOR was11.9 (95% CI, 3.69-38.71). A prolonged latent phase was associated with more instrumental vaginal births for multiparas (aOR, 2.58; 95% CI, 1.27-5.26) and emergency cesarean regardless of parity (nulliparous women: aOR, 3.21; 95% CI, 1.08-9.50 and multiparous women: aOR, 3.93; 95% CI, 1.67-9.26). DiscussionBased on women's self-report, the prevalence of a prolonged latent phase in women at term who planned a vaginal birth and had spontaneous onset of labor was higher than previously reported. Women with a prolonged latent phase were more likely to receive obstetric interventions. Assisted vaginal birth was more common for nulliparous women with prolonged latent phase and emergency cesarean occurred more frequently for both nulliparous women and multiparous women with a prolonged latent phase.

  • 13616.
    Ärfström, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Determining genetic relatedness in honey bees, Apis mellifera, using microsatellite analysis2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The world population is growing and becoming more connected whereby disease transmission is becoming an increasingly important issue. To learn more about disease spread, honey bees (Apis mellifera) could provide an animal-model system for network transmission. The honey bees have both an individual and a social defense against pathogens, their diseases are well studied and they enable studies on hundreds of individuals. The genetic relatedness is believed to be one of many important factors for disease transmission. A hypothesis is that the more closely related the honey bees are the more interactions will occur. In this study, the genetic relatedness in honey bees was analyzed by the use of microsatellite-DNA primers, in a multiplex PCR. Of the 18 microsatellite-DNA primers that were evaluated, the loci HB-C16-05, A007, AC006, HB-C16-02, AP043 and UN351 showed the highest variation. However, when applied on a larger material, the PCR-products did not yield any chromatograms that were possible to score. Many factors possibly affecting the result are discussed and further efforts will be made to improve the method and thereby determine genetic relatedness.

  • 13617. Ärlestig, Lisbeth
    et al.
    Mullazehi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kokkonen, Heidi
    Rocklöv, Joacim
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rantapää Dahlqvist, Solbritt
    Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 825-829Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years.

    OBJECTIVE:

    To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.'

    METHODS:

    51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.

    RESULTS:

    The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.

    CONCLUSIONS:

    All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.

  • 13618.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cathepsin S as a biomarker: where are we now and what are the future challenges?2012In: Biomarkers in medicine, ISSN 1752-0371, Vol. 6, no 1, p. 9-11Article in journal (Refereed)
  • 13619.
    Ärnlöv, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Left Ventricular Function in Elderly Men: Metabolic, Hormonal, Genetic and Prognostic Implications2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry.

    Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years.

    In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.

  • 13620.
    Ärnlöv, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ingelsson, Erik
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Tobias E
    Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community2013In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 83, no 1, p. 160-166Article in journal (Refereed)
    Abstract [en]

    Fibroblast growth factor-23 (FGF23), a regulator of mineral metabolism, has been linked to cardiovascular disease in chronic kidney disease. As community-based data of the longitudinal association between FGF23 and cardiovascular events are lacking, we investigated a possible relationship in 727 men of the Uppsala Longitudinal Study of Adult Men population-based cohort (mean age 77 years). During a median follow-up of 9.7 years, 110 participants died of cardiovascular causes. In Cox regression models adjusted for age and established cardiovascular risk factors, higher serum FGF23 was associated with a significantly increased risk for cardiovascular mortality (hazard ratio (HR) per increased s.d. of 1.36). This relationship remained significant, albeit attenuated, after adjustment for glomerular filtration rate (GFR) (HR 1.21). FGF23 was also associated with all-cause mortality, although the association was weaker than that with cardiovascular mortality, and it was nonsignificant in fully adjusted multivariate models. Spline analysis suggested a log-linear relationship between FGF23 and outcome. Participants with a combination of high FGF23 (>60 pg/ml), low GFR (<60 ml/min), and micro-/macro-albuminuria (albumin/creatinine ratio above 3 mg/ml) had an almost eightfold increased risk compared with participants without these abnormalities. Thus, a higher FGF23 level is associated with an increased cardiovascular mortality risk in the community. Clinical trials are needed to determine whether FGF23 is a modifiable risk factor.

  • 13621.
    Ärnlöv, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carrero, J. J.
    Karolinska Inst, Stockholm, Sweden..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stenemo, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Larsson, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carlsson, A. C.
    Karolinska Inst, Stockholm, Sweden..
    Discovery and replication of new risk markers for 5-year kidney function decline using a targeted multiplex proteomics chip2016Conference paper (Refereed)
  • 13622.
    Åberg, Anna Cristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gender comparisons of function-related dependence pain and insecurity in geriatric rehabilitation2006In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 38, no 1, p. 73-79Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate possible gender differences regarding the effect of intervention in geriatric rehabilitation, expressed in terms of change in function-related dependence, pain and insecurity. DESIGN: Comparative study. PARTICIPANTS: A total of 110 women and 44 men undergoing geriatric rehabilitation. METHODS: Performance-based assessments with use of the General Motor Function assessment scale. Non-parametric statistics were mainly used. RESULTS: The women showed higher degrees of function-related dependence, pain and insecurity on admission than the men. Both women and men displayed significant improvement in all 3 variables during the rehabilitation period. However, the positive changes regarding pain and insecurity were according to the analyses of systematic group changes, at a low degree among the men, probably because of the low levels on admission. Gender comparisons of proportions with positive intervention outcome indicated that a significantly larger proportion of the women showed a positive treatment effect after intervention, with a difference in recovery of 19% in dependence, 23% in pain and 33% in insecurity (p<0.05). CONCLUSIONS: Gender differences in disability, with higher degrees of function-related dependence, pain and insecurity among women on admission for geriatric rehabilitation, can be diminished during the rehabilitation period. These promising results may have relevance for the public health of the elderly population.

  • 13623.
    Åberg, Anna Cristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ehrenberg, Anna
    Dalarna Univ, Sch Educ Hlth & Social Studies, S-79188 Falun, Sweden.;Orebro Univ, Sch Hlth Sci, Orebro, Sweden..
    Inpatient geriatric care in Sweden-Important factors from an inter-disciplinary team perspective2017In: Archives of gerontology and geriatrics (Print), ISSN 0167-4943, E-ISSN 1872-6976, Vol. 72, p. 113-120Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to describe factors of importance for the quality of inpatient geriatric care from an inter-disciplinary team perspective, an area that has not been previously studied to our knowledge. The study design was qualitative descriptive with data being collected from focus-group interviews with members of geriatric care teams. The data collection was conducted at a Swedish university hospital with 69 beds for geriatric care. It comprised five group interviews with a total of 32 staff members, including representatives of all the seven professions working with geriatric care. Data was analysed using qualitative content analysis and a thematic framework approach. Three main themes were identified as being perceived as characterising important factors essential for quality geriatric care: Interactive assessment processes, A holistic care approach, and Proactive non-hierarchical interaction. Aspects of Time and Goal-Orientation were additionally running like common threads through these themes and informed them. Accessibility, open communication, and staff continuity were experienced as prerequisites for well-functioning teamwork. Including patients and relatives in care planning and implementation was seen as essential for good care, but was at risk due to budget cuts that imposed shortened hospital stays. To meet the care demands of the growing population of older frail people, more specialised team-based care according to the concept of Comprehensive Geriatric Assessment - which is possibly best provided by older-friendly hospitals - appears as a constructive solution for reaching high degrees of both staff and patient satisfaction in geriatric care. More research is needed in this area.

  • 13624.
    Åberg, Anna Cristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sidenvall, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Hepworth, Mike
    O'Reilly, Karen
    Lithell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    On loss of activity and independence, adaptation improves life satisfaction in old age: a qualitative study of patients' perceptions2005In: Quality of Life Research, ISSN 0962-9343, E-ISSN 1573-2649, Vol. 14, no 4, p. 1111-1125Article in journal (Refereed)
    Abstract [en]

    The purpose was to improve the understanding of factors are perceived by elderly people as important for their life satisfaction, during and after rehabilitation. Fifteen persons aged 80-94 years were interviewed while in hospital and on two follow-up occasions after discharge. Assessment of motor function using the General Motor Function assessment scale was used for descriptive purposes. Three themes emerged as important for life satisfaction: activity, independence and adaptation. Activity and independence were considered significant for life satisfaction. Basic activity preferences were related to care of one's own body and to social contacts. Control and influence over help and services were regarded as important. Different strategies for adaptation to the consequences of disease were used: reorganisation, interaction with caregivers, mental adaptation and mental activities (used as pastime and escape). Those with declined motor functions limited their activity preferences. A key finding was that pleasant past memories were actively recalled in an effort to achieve current life satisfaction. This adaptation strategy created a sense of life satisfaction, however with a potential risk for concealing dissatisfaction with conditions that might otherwise be correctable. Strategies for improving life satisfaction among old people in rehabilitation are suggested.

  • 13625.
    Åberg, Joakim
    et al.
    Orebro Univ, Sch Med Sci, S-70185 Orebro, Sweden.
    Hasselgren, Mikael
    Orebro Univ, Sch Med Sci, S-70185 Orebro, Sweden.
    Montgomery, Scott
    Orebro Univ, Clin Epidemiol & Biostat, S-70182 Orebro, Sweden;Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden;UCL, Dept Epidemiol & Publ Hlth, London, England.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Sundh, Josefin
    Orebro Univ, Sch Med Sci, Dept Resp Med, S-70185 Orebro, Sweden.
    Sex-related differences in management of Swedish patients with a clinical diagnosis of chronic obstructive pulmonary disease2019In: The International Journal of Chronic Obstructive Pulmonary Disease, ISSN 1176-9106, E-ISSN 1178-2005, Vol. 14, p. 961-969Article in journal (Refereed)
    Abstract [en]

    Purpose: Women with chronic obstructive pulmonary disease (COPD) have more symptoms, more exacerbations, lower health status scores, and more comorbidity. However, it is unclear whether management of COPD differs by sex. The aim of the study was to investigate differences by sex in the care of patients with COPD. Patients and methods: The population included 1329 primary and secondary care patients with a doctor ' s diagnosis of COPD in central Sweden. Data were obtained from patient questionnaires and included patient characteristics and data on achieved COPD care. Analyses included cross-tabulations, chi-squared test and multiple logistic regression using several measures in COPD management as dependent variables, female sex as independent variable, and with adjustment for age groups, previous exacerbations, COPD Assessment Test, level of dyspnea assessed by the modified Medical Research Council scale, comorbid conditions, self-rated moderate/severe disease, level of education and body mass index. Results: Women were more likely to receive triple therapy (OR 1.86 (95% CI 1.38-2.51)), to have any maintenance treatment (OR 1.82 (95% CI 1.31-2.55)), to be on sick leave (OR 2.16 (95% CI 1.19-3.93)), to have received smoking cessation support (OR 1.80 (95% CI 1.18-2.75)) and to have had pneumococcal vaccination (OR 1.82 (95% CI 1.37-2.43)), all independently of age, severity of disease or other potential confounders. Conclusion: Management of COPD differs by sex, with women being more actively managed than men. It is unclear whether this is due to patient-or care-related factors.

  • 13626.
    Åberg, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Pankotai, Eszter
    Weszl, Miklós
    Forster-Horváth, Casba
    Hulsart Billström, Gry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lacza, Zombor
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    In vivo evaluation of an injectable premixed radiopaque calcium phosphate cement2011In: EFORT, 2011Conference paper (Refereed)
  • 13627.
    Åberg, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Persson, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Hulsart Billström, Gry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Brisby, Helena
    Thomsen, Peter
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Evaluation of a radio-opaque premixed calcium phosphate cement2010In: Scandinavian Society or Biomaterials Annual Meeting, 2010Conference paper (Refereed)
  • 13628.
    Åberg, Mikael
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Tissue Factor Biological Functions: Coagulation Activity in Microparticles and Signaling with Focus On Migration and Apoptosis2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagulation. TF is over-expressed on many malignant cells and apart from increasing the risk of thrombosis, the presence of TF/FVIIa also promotes the progression of cancer and metastasis by intracellular signaling. TF expressing microparticles (MP) are, moreover, often found in the circulation of cancer patients.

    Aim: The aim of this thesis was to study different aspects of TF activity, e.g. the importance of procoagulant MP and TF-induced intracellular signaling pathways, with focus on cell migration (chemotaxis) and apoptosis.

    Results: The TF signaling complexes were shown to prevent apoptosis induced by serum starvation and TRAIL in cancer cells by reduced activation of caspase-8 in a PI3k/AKT-dependent manner. FVIIa also decreased transcription of pro-apoptotic genes in cancer cells treated with TRAIL. Simvastatin triggered apoptosis by transcriptional reduction of BCL-2 due to cytosolic retention of NFκB. Simvastatin also inactivated the PI3k/AKT pathway and reduced the production of the MP-like prostasomes which, respectively, impaired the anti-apoptotic signaling by TF and reduced the procoagulant activity in the vicinity of prostate cancer cells. Intracellular events conducted by the TF/FVIIa complex selectively enhanced PDGF-BB induced chemotaxis which was partly explained by the TF/FVIIa-induced transactivation of the PDGFβ-receptor. This was dependent on Src-family members and engagement of PAR2.

    Conclusions: The results presented in this thesis extend the current knowledge of TF-mediated signaling. We report the TF complexes to govern the extrinsic pathway of apoptosis, present data on FVIIa-dependent regulation of apoptosis-related genes, and exclude known surface proteins as transmitters of the anti-apoptotic signals. We moreover describe TF/FVIIa to transactivate the PDGFβ-receptor and play a decisive role in the potentiated chemotaxis toward PDGF-BB in a number of cell types. Finally, we explain the mechanism behind simvastatin-induced apoptosis in cancer cells and how statins interfere with TF-dependent signaling and coagulation.

    List of papers
    1. Simvastatin induces apoptosis in human breast cancer cells in a NFκB-dependent manner and abolishes the anti-apoptotic signaling of TF/FVIIa and TF/FVIIa/FXa
    Open this publication in new window or tab >>Simvastatin induces apoptosis in human breast cancer cells in a NFκB-dependent manner and abolishes the anti-apoptotic signaling of TF/FVIIa and TF/FVIIa/FXa
    2008 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 122, no 2, p. 191-202Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Statins have benefits independent of the plasma cholesterol properties among cancer patients and tissue factor (TF)/FVIIa induce PI3-kinase/AKT dependent anti-apoptosis during serum starvation. We analyzed how simvastatin induces apoptosis in human breast cancer cells and the influence of FVIIa and/or FXa on the proposed apoptosis. Materials and methods: MDA-MB-231 cells were serum starved or treated with 5 μM simvastatin and incubated with 10 and 100 nM FVIIa or 5/130 nM FVIIa/FX. RhoA was analyzed by confocal microscopy and caspase-3, nuclear fragmentation, and NFκB translocation were measured using the ArrayScan microscope. mRNA for BCL-2, AKT1 and TF were analyzed with RT-PCR or TaqMan. Protein levels and phosphorylation of PKB/AKT were determined by western blotting. Results and conclusions: Simvastatin-induced apoptosis was recorded at 48 h in the MDA-MB-231 cells. Addition of FVIIa to the cells induced PKB/AKT phosphorylation at 24 h and rescued serum-deprived cells from apoptosis. However, in the presence of simvastatin we were unable to report any phosphorylation of PKB/AKT or anti-apoptotic effect mediated by the TF/FVIIa or TF/FVIIa/FXa complexes. This was due to a RhoA-dependent retention of NFκB to the cytosol at 12 h which led to a transcriptional down-regulation of the anti-apoptotic protein BCL-2 as well as reduced AKT1 mRNA production at 24 h and thus diminished levels of PKB/AKT protein. A transcriptional down-regulation of TF at 12 h possibly also contributed to the absent anti-apoptotic signaling. These results thereby support a role for simvastatin in cancer treatment and emphasize the importance of PKB/AKT in TF-signaling.

    Keywords
    Statins, Apoptosis, NFκB, Tissue factor, FVIIa, Cell signaling
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97673 (URN)10.1016/j.thromres.2007.09.017 (DOI)000257282500008 ()18031796 (PubMedID)
    Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2017-12-14Bibliographically approved
    2. Simvastatin reduces the production of prothrombotic prostasomes in human prostate cancer cells
    Open this publication in new window or tab >>Simvastatin reduces the production of prothrombotic prostasomes in human prostate cancer cells
    Show others...
    2008 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 100, no 4, p. 655-662Article in journal (Refereed) Published
    Abstract [en]

    Cancer confers a prothrombotic state and statins are associated with a lowered risk for prostate cancer in vivo by unknown mechanisms. Prostate cancer cells release tissue factor (TF)- bearing, cholesterol-rich prostasomes which are pro-coagulant in vitro and a possible source for the blood-borne TF found in prostate cancer patients.We investigated the effect of cholesterol depletion on the production of prostasomes and on the TF activity in the conditioned medium of simvastatin-treated PC3 cells. Human PC3 prostate cancer cells were treated with high and low concentrations of simvastatin for different time periods. Caspase-3 was detected with theArrayScan microscope,whereas TF mRNA and protein were analyzed by TaqMan and flow cytometry. TF activity was assessed by measuring the cleavage of a chromogenic thrombin substrate.Prostasomes were isolated by repeated centrifugations and detected and quantified by flow cytometry. A micromolar dose of simvastatin caused reduction of TF expression and induction of apoptosis in the PC3 cells.The levels of TF on the prostasomes were also decreased but the TF activity in the conditioned medium of the simvastatin-treated PC3 cells was increased due to apoptosis-dependent release of prostasomes.Treatment with a nanomolar dose of simvastatin did not induce apoptosis or alter the expression of TF but instead decreased the production and release of the prostasomes. The TF activity was reduced in parity with the decline in prostasome release. In conclusion, in prostate cancer, a nanomolar dose of simvastatin may have an anti-thrombotic effect due to decreased levels of circulating TF-bearing prostasomes.

    Keywords
    Apoptosis, deep vein thrombosis, malignancy, microparticles, tissue factor
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97674 (URN)10.1160/TH08-03-0173 (DOI)000260216000022 ()18841289 (PubMedID)
    Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2017-12-14Bibliographically approved
    3. TF/FVIIa transactivate PDGFRbeta to regulate PDGF-BB-induced chemotaxis in different cell types: involvement of Src and PLC
    Open this publication in new window or tab >>TF/FVIIa transactivate PDGFRbeta to regulate PDGF-BB-induced chemotaxis in different cell types: involvement of Src and PLC
    Show others...
    2008 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, no 1, p. 135-41Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: We have previously reported the potentiation of PDGF-BB-induced chemotaxis of fibroblasts, vascular smooth muscle cells, and endothelial cells by FVIIa. Here we studied the role of TF/FVIIa and the induced signaling pathways in regulation of chemotaxis of human monocytes, fibroblasts, and porcine aorta endothelial cells. METHODS AND RESULTS: Human monocytes were obtained by using Ficoll-Paque gradient and the MACS system (for highly purified population), fibroblasts and PAE cells have been characterized previously. Inhibitors of selected signaling intermediates were used, and the effect of TF/FVIIa on the migratory response of all cells to chemotactic agents was analyzed. The induced signaling was studied by immunoprecipitation and Western blotting. TF/FVIIa complex selectively enhanced PDGF-BB-induced chemotaxis in a Src-family, PLC, and PAR-2-dependent manner. Using PAE cells we identified c-Src and c-Yes as the Src-family members activated by TF/FVIIa. We report for the first time the PAR-2 and Src family-dependent transactivation of PDGFRbeta by TF/FVIIa involving phosphorylation of a subset of PDGFRbeta tyrosines. CONCLUSIONS: The described transactivation is a likely mechanism of TF/FVIIa-mediated regulation of PDGF-BB-induced chemotaxis. Similar behavior of 3 principally different cell types in our experimental setup may reflect a general function of TF in regulation of cell migration.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97675 (URN)10.1161/ATVBAHA.107.155754 (DOI)000252159500020 ()17991872 (PubMedID)
    Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2017-12-14Bibliographically approved
    4. The tissue factor signaling complexes prevent caspase-8-induced apoptosis independently of PAR-1, PAR-2, and GRP78
    Open this publication in new window or tab >>The tissue factor signaling complexes prevent caspase-8-induced apoptosis independently of PAR-1, PAR-2, and GRP78
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97676 (URN)
    Available from: 2008-10-30 Created: 2008-10-30 Last updated: 2010-01-13Bibliographically approved
  • 13629.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edén, Desireé
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Activation of beta1-integrins and caveolin-1 by TF/FVIIa promotes cell survival2018In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S88-S88Article in journal (Other academic)
  • 13630.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Tissue factor/FVIIa transactivates the IGF-1R by a Src-dependent phosphorylation of caveolin-12016In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 111, p. S99-S99Article in journal (Other academic)
  • 13631.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tissue factor/FVIIA transactivates the IGF-1R in prostate cancer cells via inhibition of caveolin-12015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 707-707, article id PO552-TUEArticle in journal (Other academic)
  • 13632.
    Ågren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Monitoring fluid balance in the neonate2012In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 101, no 5, p. 444-445Article in journal (Refereed)
  • 13633.
    Ågren, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Water transport through perinatal skin: Barrier function and aquaporin water channels2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    While constituting a well functioning interface with the aqueous environment in utero, the skin offers a poor barrier after very preterm birth. As a result, transepidermal water loss (TEWL) is high, a fact which has important clinical consequences in these infants. To investigate the transport of water through perinatal skin and the potential role of aquaporin (AQP), a water channel protein, in this process, we determined TEWL in a group of extremely preterm infants, and in an experimental rat model we analyzed the expression and distribution of AQP in perinatal skin in relation to TEWL, skin surface hydration and water content. The effects of antenatal corticosteroids (ANS) and of restricted intake of fluids and nutrients on barrier characteristics of the perinatal skin and its AQP expression were also studied.

    In infants born at 24 and 25 weeks of gestation TEWL was very high in the first days after birth and decreased with increasing postnatal age. At a postnatal age of 4 weeks, TEWL was still twice as high as previously reported in infants born at a gestational age of 25-27 weeks and four times higher than in infants born at term. In the rat model, immunohistochemical analysis revealed that AQP1 and AQP3 are abundantly expressed in the skin. AQP1 was expressed exclusively in dermal capillaries and AQP3 in basal layers of the epidermis. AQP1 and AQP3 mRNA as assessed by semiquantitative RT-PCR was higher in fetal than in adult skin. As in infants, TEWL and skin surface hydration were inversely related to gestational age in the rat. In preterm rat pups exposed to ANS, TEWL and skin surface hydration were lower than in unexposed controls, and AQP3 expression was selectively induced by ANS. In term newborn rat pups, restriction of fluid and nutrient intake resulted in a higher skin water content and higher TEWL early after birth, while at an age of 7 days TEWL was lower in fasting rat pups than in controls, although skin water content was still higher.

    To conclude, TEWL is very high in extremely preterm infants early after birth and then decreases at a slower rate than previously reported for a group of slightly more mature infants.

    This is the first time that the distribution and gene expression of AQP1 and AQP3 have been demonstrated in perinatal skin. The localization and expression of AQP in the skin might indicate that these water channels are involved in the regulation of skin hydration and transepidermal water transport in the fetus and newborn infant.

    List of papers
    1. Transepidermal water loss in infants born at 24 and 25 weeks of gestation
    Open this publication in new window or tab >>Transepidermal water loss in infants born at 24 and 25 weeks of gestation
    1998 In: Acta Paediatrica, ISSN 0803-5253, Vol. 87, p. 1185-1190Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90229 (URN)
    Available from: 2003-04-16 Created: 2003-04-16Bibliographically approved
    2. Transepidermal water loss in developing rats: Role of aquaporins in the immature skin
    Open this publication in new window or tab >>Transepidermal water loss in developing rats: Role of aquaporins in the immature skin
    Show others...
    2003 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 53, no 4, p. 558-565Article in journal (Refereed) Published
    Abstract [en]

    In the extremely preterm infant, high transepidermal water loss (TEWL) can result in severe dehydration. TEWL has been attributed to the structural properties of the epidermis but might also be influenced by mechanisms that facilitate water transport. To investigate whether aquaporins (AQP) may be involved in the extreme losses of water through immature skin, we examined the presence and cellular distributions of AQP-1 and AQP-3 in embryonic and adult rat skin by immunohistochemistry. The expression of AQP mRNA in skin was analyzed with the use of semiquantitative reverse transcription-PCR. In rat pups of different embryonic (E) and postnatal (P) ages (days), TEWL and skin hydration were measured. AQP-1 was detected in dermal capillaries, and AQP-3 was abundant in basal epidermal layers. Both AQP displayed several times higher expression in embryonic than in adult skin. TEWL was highest at embryonic day 18 (E18) (133 +/- 18 g/m2h) and lower at E20 (25 +/- 1 g/m2h) and P4 (9 +/- 2 g/m2h). Skin hydration measured as skin electrical capacitance paralleled TEWL, being highest in fetal skin (794 +/- 15 pF at E18) and decreasing to 109 +/- 11 pF at E20 and to 0 +/- 0 pF at P4. We conclude that, as in infants, water loss through the skin of rats decreases markedly with maturation during the perinatal period. The expression and cellular localization of the AQP are such that they might influence skin hydration and water transport and contribute to the high losses of water through the immature skin.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90230 (URN)10.1203/01.PDR.0000055777.25933.98 (DOI)12612219 (PubMedID)
    Available from: 2003-04-16 Created: 2003-04-16 Last updated: 2017-12-14Bibliographically approved
    3. Antenatal steroids influence the skin barrier and epidermal aquaporin-3 expression in the preterm rat
    Open this publication in new window or tab >>Antenatal steroids influence the skin barrier and epidermal aquaporin-3 expression in the preterm rat
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90231 (URN)
    Available from: 2003-04-16 Created: 2003-04-16 Last updated: 2010-01-13Bibliographically approved
    4. Short-term restriction of fluids and nutrients increases transepidermal water loss in the newborn rat
    Open this publication in new window or tab >>Short-term restriction of fluids and nutrients increases transepidermal water loss in the newborn rat
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90232 (URN)
    Available from: 2003-04-16 Created: 2003-04-16Bibliographically approved
  • 13634.
    Åhlin, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ibrahim Elshafie, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nur, Musa A. M.
    Unit of Rheumatology, Alribat University Hospital, Khartoum, Sudan.
    Hassan El Safi, Sayda
    Department of Microbiology and Parasitology, Faculty of Medicine, University of Khartoum, Sudan.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Occurrence of rheumatoid arthritis-associated autoantibodies in Sudanese patients with Leishmania donovani infection Manuscript (preprint) (Other academic)
    Abstract [en]

    Objective

    Our aim with this investigation was to evaluate the occurrence of anti-cyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF) and circulating immune complexes (IC) in Sudanese patients infected with Leishmania donovani parasite.

    Methods

    Serum samples were collected from Leishmania infected patients and healthy Sudanese controls. Sudanese anti-CCP positive RA patients were included as positive controls. Data from all analyses were also compared with Swedish healthy control cohorts. Levels of circulating IC and anti-CCP were measured using ELISA and RF using nephelometry. A control plate with cyclic control peptides containing arginine instead of citrulline was used to evaluate citrulline specific reactivity.

    Results

    We demonstrate that sera from Leishmania infected patients are often RF positive, have elevated IC levels and that a substantial number exhibit antibody reactivity towards CCP. However, contrary to what was evident the in Sudanese RA sera, the CCP reactivity was not restricted to citrulline but reacted equally well with the arginine control peptide.

    Conclusions

    Our findings stress the importance to interpret a positive CCP test carefully when evaluated in non-rheumatic conditions.

  • 13635.
    Åhlin, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsdottir, Thorunn
    Unit of Rheumatology, Department of Medicine, Karolinska Institutet.
    Gunnarsson, Iva
    Unit of Rheumatology, Department of Medicine, Karolinska Institutet.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Autoantibodies associated with RNA are more enriched than anti-dsDNA antibodies in circulating immune complexes in SLE2012In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 21, no 6, p. 586-595Article in journal (Refereed)
    Abstract [en]

    To what extent different autoantibodies accumulate in systemic lupus erythematosus (SLE) immune complexes (ICs), and whether such accumulation is associated with disease activity has been investigated. ICs were isolated from SLE sera by both polyethylene glycol (PEG) precipitation and C1q-binding. Autoantibody specificities were determined using a lineblot assay quantified by densitometry. To compare the relative levels of autoantibodies, levels were normalized to the total levels of IgG measured by ELISA in sera and parallel ICs. Samples were investigated both in a cross-sectional design as well as in a paired design with samples obtained during both active and inactive SLE. All investigated autoantibody specificities except anti-dsDNA were enriched in circulating ICs as compared with parallel sera. The group of antibodies against RNA-associated antigens (anti-RNP/Sm, anti-Sm, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB/La) all exhibited higher median enrichment than the DNA-associated (anti-dsDNA, anti-histones, anti-nucleosomes) or cytoplasmic (anti-ribosomal P) antigens. In particular autoantibodies against RNP/Sm and SSA/Ro52 had the highest degree of enrichment in SLE PEG precipitates. These findings were corroborated by analysis of autoantibody content in C1q-bound ICs. There was no difference in degree of IC accumulation of the investigated autoantibodies during active and inactive SLE. Our findings demonstrate a difference in enrichment between autoantibodies against RNA- and DNA-associated autoantigens in isolated SLE IC, suggesting that the RNA-associated autoantibodies are more prone to form circulating ICs in SLE, in contrast to antibodies against DNA-associated autoantigens such as dsDNA. These finding have implications in understanding mechanisms of differential autoantibody accumulation in target organs in SLE.

  • 13636.
    Åhlund, Susanne
    et al.
    Karolinska Inst, Dept Womens & Childrens Hlth, Retzius Vag 13 B, S-17177 Solna, Sweden..
    Zwedberg, Sofia
    Karolinska Inst, Dept Womens & Childrens Hlth, Retzius Vag 13 B, S-17177 Solna, Sweden.;Karolinska Univ Hosp, Dept Obstet, Stockholm, Sweden..
    Hildingsson, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Mid Sweden Univ, Dept Nursing, Sundsvall, Sweden.
    Edqvist, Malin
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden..
    Lindgren, Helena
    Karolinska Inst, Dept Womens & Childrens Hlth, Retzius Vag 13 B, S-17177 Solna, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden..
    Midwives experiences of participating in a midwifery research project: A qualitative study2018In: Women and Birth, ISSN 1871-5192, E-ISSN 1878-1799, Vol. 31, no 2, p. E115-E121Article in journal (Refereed)
    Abstract [en]

    Problem and background: In an earlier research project midwives were asked to perform women-centered care focusing on the assumption that the physiological process in the second stage of labour could be trusted and that the midwives role should be encouraging and supportive rather than instructing. There is no knowledge about how midwives participating in such a research project, uses their skills and experience from the study in their daily work.

    Aim: The aim in this study was to investigate how midwives experienced implementing woman-centered care during second stage of labour.

    Methods: A qualitative study was designed. Three focus groups and two interviews were conducted. The material was analysed using content analysis.

    Findings: The participating midwives' experiences were understood as increased awareness of their role as midwives. The overarching theme covers three categories 1) establishing a new way of working, 2) developing as midwife, 3) being affected by the prevailing culture. The intervention was experienced as an opportunity to reflect and strengthen their professional role, and made the midwives see the women and the birth in a new perspective.

    Conclusions: Implementing woman-centered care during second stage of labour gave the midwives an opportunity to develop in their professional role, and to enhance their confidence in the birthing women and her ability to have a physiological birth. To promote participation in, as well as conduct midwifery research, can enhance the development of the midwives professional role as well as contribute new knowledge to the field.

  • 13637.
    Åhman, Annika
    et al.
    Umea Univ, Dept Clin Sci Obstet & Gynecol, S-90187 Umea, Sweden.
    Edvardsson, Kristina
    Umea Univ, Dept Clin Sci Obstet & Gynecol, S-90187 Umea, Sweden;La Trobe Univ, Judith Lumley Ctr, Melbourne, Vic, Australia.
    Fagerli, Tove Anita
    Trondheim Reg & Univ Hosp, Natl Ctr Fetal Med, St Olavs Hosp, Trondheim, Norway.
    Darj, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). St Olavs Hosp, Dept Obstet & Gynecol, Trondheim, Norway;Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, NTNU, Trondheim, Norway.
    Holmlund, Sophia
    Umea Univ, Dept Clin Sci Obstet & Gynecol, S-90187 Umea, Sweden.
    Small, Rhonda
    La Trobe Univ, Judith Lumley Ctr, Melbourne, Vic, Australia;Karolinska Inst, Reprod Hlth Womens & Childrens Hlth, Stockholm, Sweden.
    Mogren, Ingrid
    Umea Univ, Dept Clin Sci Obstet & Gynecol, S-90187 Umea, Sweden;La Trobe Univ, Judith Lumley Ctr, Melbourne, Vic, Australia.
    A much valued tool that also brings ethical dilemmas - a qualitative study of Norwegian midwives' experiences and views on the role of obstetric ultrasound2019In: BMC Pregnancy and Childbirth, ISSN 1471-2393, E-ISSN 1471-2393, Vol. 19, article id 33Article in journal (Refereed)
    Abstract [en]

    Background: Midwives are the main providers of routine antenatal care services including the routine ultrasound examination in Norway. The ultrasound examination can be perceived by expectant parents not only as a medical examination but also as a social event facilitating attachment to their fetus. This study explores Norwegian midwives' experiences and views on the role of ultrasound in clinical management of pregnancy.

    Methods: A qualitative study design was applied. Twenty-four midwives who all performed obstetric ultrasound examinations were recruited for focus group discussions and individual interviews. Data collection took place in 2015 in five hospitals in two different regions of Norway. Data were analyzed using qualitative content analysis.

    Results: Midwives described obstetric ultrasound examinations as very valuable although doing ultrasounds placed high demands on their operational and counselling skills. Increasing requests for ultrasound from pregnant women were mentioned. Advancements in ultrasound diagnosis were considered to have put the fetus in the position of a patient, and that pregnant women declining ultrasound could be viewed as irresponsible by some health professionals. Ethical concerns were raised regarding the possibility of pregnancy termination when fetal anomalies were detected. Fears were also expressed that prenatal diagnoses including those following ultrasound, might create a society where only perfect' children are valued. However, participants stressed that their intention in performing ultrasound was to optimize pregnancy outcome and thereby assist expectant couples and their unborn children.

    Conclusions: Midwives in Norwegian maternity care services describe obstetric ultrasound as very valuable, playing a central role in pregnancy management by optimizing pregnancy outcomes. Although high demands are placed on operators' technical skills and counseling, midwives described performing obstetric ultrasound as very satisfying work. However, midwives believed that expectant parents' approach to the ultrasound examination, both its medical value and the precious images obtained of the fetus, could put extra strain on the midwives performing ultrasounds. The potential of ultrasound to detect fetal anomalies and the possibility that this may lead to termination of pregnancy, seemed to create some ambivalent feelings in midwives towards its use.

  • 13638.
    Åhman, Annika
    et al.
    Umea Univ, Dept Clin Sci Obstet & Gynaecol, SE-90187 Umea, Sweden..
    Edvardsson, Kristina
    Umea Univ, Dept Clin Sci Obstet & Gynaecol, SE-90187 Umea, Sweden.;La Trobe Univ, Judith Lumley Ctr, Melbourne, Vic, Australia..
    Kidanto, Hussein L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Minist Hlth Social Welf Gender Children & Elderly, Reproduct Maternal & Child Hlth, Dar Es Salaam, Tanzania.
    Ngarina, Matilda
    Muhimbili Natl Hosp, Dept Obstet & Gynaecol, Dar Es Salaam, Tanzania..
    Small, Rhonda
    La Trobe Univ, Judith Lumley Ctr, Melbourne, Vic, Australia..
    Mogren, Ingrid
    Umea Univ, Dept Clin Sci Obstet & Gynaecol, SE-90187 Umea, Sweden..
    'Without ultrasound you can't reach the best decision': Midwives' experiences and views of the role of ultrasound in maternity care in Dar Es Salaam, Tanzania2018In: Sexual & Reproductive HealthCare, ISSN 1877-5756, E-ISSN 1877-5764, Vol. 15, p. 28-34Article in journal (Refereed)
    Abstract [en]

    Objective: To explore Tanzanian midwives' experiences and views of the role of obstetric ultrasound in relation to clinical management of pregnancy, and in situations where maternal and fetal health interests conflict.

    Method: In 2015, five focus group discussions were conducted with midwives (N = 31) at three public referral hospitals in the Dar es Salaam region as part of the CROss Country Ultrasound Study (CROCUS).

    Results: Ultrasound was described as decisive for proper management of pregnancy complications. Midwives noted an increasing interest in ultrasound among pregnant women. However, concerns were expressed about the lack of ultrasound equipment and staff capable of skilful operation. Further, counselling regarding medical management was perceived as difficult due to low levels of education among pregnant women.

    Conclusion: Ultrasound has an important role in management of pregnancy complications. However, lack of equipment and shortage of skilled healthcare professionals seem to hamper use of obstetric ultrasound in this particular low-resource setting. Increased availability of obstetric ultrasound seems warranted, but further investments need to be balanced with advanced clinical skills' training as barriers, including power outages and lack of functioning equipment, are likely to continue to limit the provision of pregnancy ultrasound in this setting.

  • 13639.
    Åhman, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sarkadi, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lindgren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    ‘It made you think about your opinion’ -Women's perception of a web-based decision aid concerning screening for fetal anomaliesManuscript (preprint) (Other academic)
    Abstract [en]

    Background:All pregnant women in Sweden are offered amid-trimester ultrasound examination as part of antenatal care. It is free ofcharge and very few women decline. Despite efforts to provide information,research shows that women’s choice of prenatal screening is often not based oninformed decisions. Objectives:To investigate the potential of a web-baseddecision aid (DA) concerning screening for fetal anomalies to initiate aprocess of reflection and conscious decision-making in pregnant women. Methods: Theweb-based DA consisted of four modules: ‘Facts about fetal diagnostics’,‘Likelihood of anomalies’, ‘Expectant parents’ stories’, and the interactive‘Worksheets’. Seventeen women with access to the DA were interviewed, eleven who opted to usethe DA and six who did not. Data were analysed by systematic text condensation. Results: Women appreciated the decisional aid for being easilyaccessible and emphasised the importance of a reliable source. The DA helpedthem to clarify their own standpoints and engaged their partner in the decision-makingprocess. Reading the expectant parents’ stories seemed especially instrumentalin making women more aware of their own standpoint. Women described that the DAenhanced their awareness that participating in prenatal screening anddiagnostics was a conscious choice. Women who chose not to use the web-based DAwhen offered believed they already had sufficient knowledge to make a decisionabout the different tests. Conclusions: TheDA was able to initiate a process of conscious decision-making in pregnantwomen as a result of their interaction with the tool. Practical Implications: A web-based DA has low costs, is convenientlyavailable to a population with Internet access and can be used on one’s ownterms. The DAs ability to improve awareness of the need to make a consciouschoice showed that this might be a feasible tool for sharing information duringpregnancy.

  • 13640.
    Åhman, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Sarkadi, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lindgren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Rubertsson, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    'It made you think twice': an interview study of women's perception of a web-based decision aid concerning screening and diagnostic testing for fetal anomalies2016In: BMC Pregnancy and Childbirth, ISSN 1471-2393, E-ISSN 1471-2393, Vol. 16, article id 267Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Enabling women to make informed decisions is a key objective in the guidelines governing prenatal screening and diagnostics. Despite efforts to provide information, research shows that women's choice of prenatal screening is often not based on informed decisions. The aim of this study was to investigate pregnant women's perceptions of the use of an interactive web-based DA, developed to initiate a process of reflection and deliberate decision-making concerning screening and testing for fetal anomalies.

    METHODS:

    A qualitative study was applied and individual interviews were conducted. Seventeen pregnant women attending antenatal healthcare in Uppsala County, Sweden, who had access to the decision aid were interviewed. Eleven opted to use the decision aid and six did not. Data were analysed by systematic text condensation.

    RESULTS:

    Women appreciated the decision aid, as it was easily accessible; moreover, they emphasised the importance of a reliable source. It helped them to clarify their own standpoints and engaged their partner in the decision-making process. Women described the decision aid as enhancing their awareness that participating in prenatal screening and diagnostics was a conscious choice. Those who chose not to use the web-based decision aid when offered reported that they already had sufficient knowledge.

    CONCLUSIONS:

    The decision aid was able to initiate a process of deliberate decision-making in pregnant women as a result of their interaction with the tool. Access to a web-based decision aid tool can be valuable to expectant parents in making quality decisions regarding screening for fetal anomalies.

  • 13641.
    Åhman, Hanna Bozkurt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cedervall, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lennhed, Bjorn
    Falu Lasarett, Dept Geriatr & Rehabil Med, Falun, Sweden.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    McKee, Kevin
    Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala Univ, Dept Publ Hlth & Caring Sci, Box 564, SE-75122 Uppsala, Sweden.
    Rosendahl, Erik
    Umea Univ, Dept Community Med & Rehabil, Umea, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala Univ, Dept Publ Hlth & Caring Sci, Box 564, SE-75122 Uppsala, Sweden.
    Åberg, Anna Cristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Dual-Task Performance and Neurodegeneration: Correlations Between Timed Up-and-Go Dual-Task Test Outcomes and Alzheimer's Disease Cerebrospinal Fluid Biomarkers2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 71, p. S75-S83Article in journal (Refereed)
    Abstract [en]

    Background: Tools to identify individuals at preclinical stages of dementia disorders are needed to enable early interventions. Alterations in dual-task performance have been detected early in progressive neurodegenerative disorders. Hence, dual-task testing may have the potential to screen for cognitive impairment caused by neurodegeneration. Exploring correlations between dual-task performance and biomarkers of neurodegeneration is therefore of interest. Objective: To investigate correlations between Timed Up-and-Go dual-task (TUGdt) outcomes and Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-beta 42 (A beta(42)), total tau (t-tau), and phosphorylated tau (p-tau). Methods: This cross-sectional cohort study included 90 participants (age range 49-84 years) undergoing memory assessment, who were subsequently diagnosed with AD, other dementia disorders, mild cognitive impairment, or subjective cognitive impairment. TUG combined with "Naming Animals" (TUGdt NA) and "Months Backwards" (TUGdt MB), respectively, were used to assess dual-task performance. The number of correct words and time taken to complete the tests were measured. The CSF biomarkers were analysed by ELISA. Spearman's rank correlation was used for analyses between TUGdt outcomes (TUGdt NA and TUGdt MB), and CSF biomarkers, adjusted for age, gender, and educational level. Results: The number of correct words, as well as the number of correct words/10 s during TUGdt NA correlated negatively to CSF t-tau and p-tau. No correlations were found between any time scores and CSF biomarkers. Conclusion: The correlations between TUGdt NA and t-tau and p-tau may indicate that neurodegeneration affects dual-task performance. Longitudinal studies are needed to further explore dual-task testing in screening for cognitive impairment due to neurodegeneration.

  • 13642.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Medial temporal lobe resection attenuates superior temporal sulcus response to faces2014In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 61, p. 291-298Article in journal (Refereed)
    Abstract [en]

    Face perception depends on activation of a core face processing network including the fusiform face area, the occipital face area and the superior temporal sulcus (STS). The medial temporal lobe (MTL) is also involved in decoding facial expression and damage to the anterior MTL, including the amygdala, generally interferes with emotion recognition. The impairment in emotion recognition following anterior MTL injury can be a direct result from injured MTL circuitry, as well as an indirect result from decreased MTL modulation of areas in the core face network. To test whether the MTL modulates activity in the core face network, we used functional magnetic resonance imaging to investigate activation in the core face processing network in patients with right or left anterior temporal lobe resections (ATR) due to intractable epilepsy. We found reductions of face-related activation in the right STS after both right and left ATR together with impaired recognition of facial expressions. Reduced activity in the fusiform and the occipital face areas was also observed in patients after right ATR suggesting widespread effects on activity in the core face network in this group. The reduction in face-related STS activity after both right and left ATR suggests that MTL modulation of the STS may facilitate recognition of facial expression.

  • 13643.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Within-session effect of repeated stress exposure on extinction circuitry function in social anxiety disorder2017In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 261, p. 85-90Article in journal (Refereed)
    Abstract [en]

    Anxiety reduction following repeated exposure to stressful experiences is generally held to depend on neural processes involved in extinction of conditioned fear. We predicted that repeated exposure to stressful experiences would change activity throughout the circuitry serving extinction, including ventromedial prefrontal cortex (vmPFC), the hippocampus and the amygdala. To test this prediction, 36 participants diagnosed with SAD performed two successive speeches in front of an observing audience while regional cerebral blood flow (rCBF) was recorded using positron emission tomography. To control for non-anxiolytic effects of repeated exposure, rCBF was also measured during repeated presentations of neutral and angry facial expressions. Results showed that anxiety ratings and heart rate decreased from the first to the second speech, indicating an anxiolytic effect of repeated exposure. Exposure attenuated rCBF in the amygdala whereas no change in rCBF was observed in the vmPFC or hippocampus. The rCBF-reductions in the amygdala were greater following repetition of the speech task than repetition of face exposure indicating that they were specific to anxiety attenuation and not due to a reduced novelty. Our findings suggest that amygdala-related attenuation processes are key to understanding the working mechanisms of exposure therapy.

  • 13644.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Duke Univ, Ctr Cognit Neurosci, Durham, NC 27708 USA.;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Kragel, Philip A.
    Duke Univ, Ctr Cognit Neurosci, Durham, NC 27708 USA..
    Zielinski, David J.
    Duke Univ, Pratt Sch Engn, Durham, NC 27708 USA..
    Brady, Rachael
    Duke Univ, Pratt Sch Engn, Durham, NC 27708 USA..
    LaBar, Kevin S.
    Duke Univ, Ctr Cognit Neurosci, Durham, NC 27708 USA..
    Medial prefrontal pathways for the contextual regulation of extinguished fear in humans2015In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 122, p. 262-271Article in journal (Refereed)
    Abstract [en]

    The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS + in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS -. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.

  • 13645.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Michelgård Palmquist, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Appel, Lieuwe
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Liberzon, Israel
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Arousal modulation of memory and amygdala-parahippocampal connectivity: A PET-psychophysiology study in specific phobia2011In: Psychophysiology, ISSN 0048-5772, E-ISSN 1469-8986, Vol. 48, no 11, p. 1463-1469Article in journal (Refereed)
    Abstract [en]

    Phobic fear is accompanied by intense bodily responses modulated by the amygdala. An amygdala moderated psychophysiological measure related to arousal is electrodermal activity. We evaluated the contributions of electrodermal activity to amygdala-parahippocampal regional cerebral blood flow (rCBF) during phobic memory encoding in subjects with spider or snake phobia. Recognition memory was increased for phobia-related slides and covaried with rCBF in the amygdala and the parahippocampal gyrus. The covariation between parahippocampal rCBF and recognition was related to electrodermal activity suggesting that parahippocampal memory processes were associated with sympathetic activity. Electrodermal activity further mediated the amygdala effect on parahippocampal activity. Memory encoding during phobic fear therefore seems contingent on amygdala's influence on arousal and parahippocampal activity.

  • 13646.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Biomarkers of Renal Function in Acute Coronary Syndromes2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The thesis aimed to investigate cystatin C and creatinine-based estimates of glomerular filtration rate (eGFR), both at admission and during follow-up, on the combined endpoint of cardiovascular death and myocardial infarction in patients with acute coronary syndrome (ACS). We also evaluated two cystatin C assays and assessed genetic determinants of cystatin C concentrations.

    We used the PLATelet inhibition and Patient Outcomes study, where all types of ACS patients (n=18624) were randomized to ticagrelor or clopidogrel treatment. Multivariable Cox regression models, including clinical variables and biomarkers (troponin and NT-proBNP), and c-statistics were calculated.

    Cystatin C and the creatinine-based CKD-EPI equation exhibited similar significant prognostic impact on the combined endpoint, with Area Under Curves (AUC) 0.6923 and 0.6941, respectively. Follow-up samples of renal biomarkers did not improve risk prediction.

    Patients randomized to ticagrelor treatment were associated with a non-sustained larger increase in renal markers at discharge, but neither the change nor the difference between the randomized groups affected cardiovascular risk.

    Two different cystatin C assays exhibited good correlation 0.86 (95% confidence interval 0.85-0.86), however moderate level of agreement. Risk prediction with a combination of creatinine and cystatin C did not outperform the creatinine-based CKD-EPI equation, AUC: 0.6913 and 0.6924, respectively (n=13050).

    The genetic polymorphism rs6048952 independently affected the cystatin C concentration with mean levels of 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G, and G/G genotypes, respectively.

    The genetic polymorphism did not affect outcome overall, however in the non-ST-elevation ACS subgroup a signal that genetic polymorphism may be associated with cardiovascular death was observed (p=0.002).

    In conclusion: cystatin C or eGFR, irrespective of equation or assay, are important cardiovascular risk factors in ACS patients. Nonetheless, the incremental value of adding any renal variable, to a multivariable risk model, is small. Further research on the impact of cystatin C genetic polymorphism is warranted.

    List of papers
    1. Cystatin C and Estimated Glomerular Filtration Rate as Predictors for Adverse Outcome in Patients with ST-Elevation and Non-ST-Elevation Acute Coronary Syndromes: Results from the Platelet Inhibition and Patient Outcomes Study
    Open this publication in new window or tab >>Cystatin C and Estimated Glomerular Filtration Rate as Predictors for Adverse Outcome in Patients with ST-Elevation and Non-ST-Elevation Acute Coronary Syndromes: Results from the Platelet Inhibition and Patient Outcomes Study
    Show others...
    2012 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 1, p. 190-199Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    We evaluated the predictive ability of cystatin C and creatinine-based estimations of glomerular filtration rate (eGFR), including the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, in acute coronary syndrome (ACS) patients with (STE-ACS) or without (NSTE-ACS) ST elevation in a large contemporary ACS population.

    METHODS:

    Concentrations of cystatin C and creatinine, as well as eGFR at randomization, were measured in 16 401 patients in the Platelet Inhibition and Patient Outcomes (PLATO) study and evaluated as predictors of the composite end point of cardiovascular death or myocardial infarction within 1 year. Two Cox proportional hazards models were used, the first adjusting for clinical characteristics and the second for clinical characteristics plus the biomarkers N-terminal pro-B-type natriuretic peptide, troponin I, and C-reactive protein.

    RESULTS:

    The median cystatin C value was 0.83 mg/L. Increasing quartiles of cystatin C were strongly associated with poor outcome (6.9%, 7.1%, 9.5%, and 16.2%). The fully adjusted hazard ratios per SD of cystatin C in the NSTE-ACS and STE-ACS populations were 1.12 (95% CI 1.04-1.20) (n = 8053) and 1.06 (95% CI 0.97-1.17) (n = 5278), respectively. There was no significant relationship of cystatin C with type of ACS (STE or NSTE). c Statistics ranged from 0.6923 (cystatin C) to 0.6941 (CKD-EPI).

    CONCLUSIONS:

    Cystatin C concentration contributes independently in predicting the risk of cardiovascular death or myocardial infarction in NSTE-ACS, with no interaction by type of ACS. CKD-EPI exhibited the largest predictive value of all renal markers. Nevertheless, the additive predictive value of cystatin C or creatinine-based eGFR measures in the unselected ACS patient is small.

    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-165398 (URN)10.1373/clinchem.2011.171520 (DOI)000299052700032 ()22126936 (PubMedID)
    Available from: 2012-01-05 Created: 2012-01-05 Last updated: 2017-12-08Bibliographically approved
    2. Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients: Results from the PLATelet inhibition and patient Outcomes (PLATO) study
    Open this publication in new window or tab >>Outcome and causes of renal deterioration evaluated by serial cystatin C measurements in acute coronary syndrome patients: Results from the PLATelet inhibition and patient Outcomes (PLATO) study
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    2012 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 164, no 5, p. 728-734Article in journal (Refereed) Published
    Abstract [en]

    Background: To investigate if ticagrelor treatment and other clinical characteristics were associated with increased cystatin C concentrations and if a deterioration in estimated renal function was associated with worse outcome in patients with acute coronary syndromes (ACS). Methods: Plasma cystatin C concentrations were determined within 24 hours of admission (baseline), at discharge, 1 month, and 6 months in the PLATO trial. The changes over time in relation to randomized treatment were analyzed by analysis of covariance. C-statistics and the relative Integrated Discrimination Improvement of the cystatin C concentrations regarding the primary outcome (cardiovascular death or myocardial infarction) was evaluated by multivariable analysis including background characteristics and biomarkers: N-terminal-pro-B-type natriuretic peptide and Troponin I. Results: Mean cystatin C concentrations in 2133 ticagrelor- and 2162 clopidogrel-treated patients were at baseline (0.86 mg/L and 0.86 mg/L), discharge (1.01 mg/L and 0.98 mg/L) (P <.0005), 1 month (1.00 mg/L and 0.98 mg/L) (P =.12), and 6 months (1.00 mg/L and 0.99 mg/L) (P =.17), respectively. Age, heart failure, and type of ACS were major determinants of the cystatin C concentration. c Statistics and the relative Integrated Discrimination Improvement of the primary outcome for the baseline cystatin C concentration were 0.687 and 5.2%, compared to 0.684 and 4.5% at discharge (n = 4034) and 0.693 and 5.1% at one month (n = 3096), respectively. Conclusions: Mean cystatin C concentrations increased in ACS patients, most importantly determined by age. The initial greater increase in ticagrelor-treated patients was not sustained over time. Risk prediction did not improve with serial measurements of renal markers.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-186226 (URN)10.1016/j.ahj.2012.08.017 (DOI)000310783100015 ()
    Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2017-12-07Bibliographically approved
    3. Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
    Open this publication in new window or tab >>Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
    Show others...
    2013 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 9, p. 1369-1375Article in journal (Refereed) Published
    Abstract [en]

    Background: The estimated glomerular filtration rate (eGFR) independently predicts cardiovascular (CV) death or myocardial infarction (MI), and can be estimated by creatinine and cystatin C concentrations. We evaluated two different cystatin C assays, alone or combined with creatinine, in patients with acute coronary syndromes.

    Methods: Plasma cystatin C, measured with assays from Gentian and Roche, and serum creatinine was analyzed in 16279 patients from the PLATelet inhibition and patient Outcomes trial. Pearson’s correlation and agreement (Bland–Altman) between methods was evaluated. Prognostic value in relation to CV death or MI during one year of follow up was evaluated by multivariable logistic regression analysis including clinical variables and biomarkers, c-statistics and relative Integrated Discrimination Improvement (IDI).

    Results: Median cystatin C concentrations (interquartile intervals) were 0.83 (0.68 - 1.01) mg/L (Gentian) and 0.94 (0.80 - 1.14) mg/L (Roche). Overall correlation was 0.86 (95% confidence interval 0.85-0.86). The level of agreement was ±0.39mg/L (±2 standard deviations) (n=16279).

    The area under curve (AUC) in the multivariable risk prediction model with cystatin C (Gentian, Roche) or Chronic Kidney Disease - Epidemiology (CKD-EPI) added was 0.6914, 0.6913 and 0.6932. Corresponding relative IDIs were 2.96%, 3.86% and 4.68%, respectively (n=13050). Addition of eGFR by the combined creatinine-cystatin C equation yielded AUC of 0.6923(Gentian) and 0.6924(Roche) with relative IDIs of 3.54% and 3.24% respectively.

    Conclusions: Despite differences in cystatin C concentrations, overall correlation between the Gentian and Roche assays was good while agreement was moderate.  The combined creatinine-cystatin C equation did not outperform risk prediction compared to CKD-EPI.

    Keywords
    cystatin C, creatinine, glomerular filtration rate, myocardial infarction, acute coronary, syndrome, death, assay
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-197704 (URN)10.1373/clinchem.2012.200709 (DOI)000325398600015 ()
    Available from: 2013-04-04 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved
    4. Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
    Open this publication in new window or tab >>Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study
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    2014 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 168, no 1, p. 96-102Article in journal (Other academic) Published
    Abstract [en]

    Purpose: Plasma cystatin C is independently associated with cardiovascular (CV) risk in non-ST-elevation acute coronary syndromes (NSTE-ACS). The effect of genetic variability on cystatin C concentrations and outcome is unclear.

    Methods: Plasma cystatin C concentrations were measured in blood, obtained within 24 hours of admission, in 16279 ACS patients from the PLATelet inhibition and patient Outcomes trial. 9978 patients were genome-wide genotyped with up to 2.5 million SNPs. The first occurrence of CV death or myocardial infarction (MI) within one year was evaluated by multivariable (clinical variables and biomarkers) Cox regression analysis and c-statistics both overall (all ACS) and in NSTE-ACS.

    Results: We observed SNPs association with cystatin C levels (up to p=7.82 x 10-16). The most significant SNP (rs6048952) was adjacent the CST3 gene with additive effect on cystatin C concentrations: 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G and G/G genotypes respectively. Multivariable c-statistics regarding the combined endpoint (CV death or MI) was 0.6619. Adding cystatin C concentrations or genetically adjusted cystatin C levels, exhibited c-statistics of 0.6705 and 0.6703, respectively.

    The overall hazard ratio for rs6048952 was 0.93 (95%CI 0.82-1.04) regarding the CV death or MI while 0.85 (95%CI 0.70-1.03) regarding CV death in all ACS patients. In the NSTE-ACS subgroup, the hazard ratio for rs6048952 was 0.72 (95%CI 0.54-0.95).

    Conclusions: Genetic polymorphism, independently of kidney function, affects cystatin C concentrations, but does not appear to influence ischemic outcome in an overall ACS population. However, genetic variation appears to affect cardiovascular mortality in moderate-to-high risk NSTE-ACS patients.

    Keywords
    genetics, rs6048952, CST3, CST, cystatin C, acute coronary syndrome, mortality, death, myocardial infarction
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-197712 (URN)10.1016/j.ahj.2014.03.010 (DOI)000338748800014 ()
    Note

    Published as Manuscript with the title: Genetic Polymorphism and Relationship to Cystatin C Concentrations and Outcome - Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study

    Available from: 2013-04-04 Created: 2013-04-02 Last updated: 2018-07-06Bibliographically approved
  • 13647.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Duke Clin Res Inst, Durham, NC USA..
    Clare, Robert M.
    Duke Clin Res Inst, Durham, NC USA..
    Lokhnygina, Yuliya
    Duke Clin Res Inst, Durham, NC USA..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Van de Werf, Frans
    Univ Leuven, Dept Cardiol, Leuven, Sweden..
    Moliterno, David J.
    Univ Kentucky, Gill Heart Inst, Lexington, KY USA.;Univ Kentucky, Div Cardiovasc Med, Lexington, KY USA..
    Patel, Uptal D.
    Duke Clin Res Inst, Durham, NC USA..
    Leonardi, Sergio
    Fdn IRCCS Policlin San Matteo, Pavia, Italy..
    Armstrong, Paul W.
    Univ Alberta, Div Cardiol, Edmonton, AB, Canada..
    Harrington, Robert A.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand..
    Aylward, Philip E.
    Flinders Univ & Med Ctr, South Australian Hlth & Med Res Inst, Adelaide, SA, Australia..
    Mahaffey, Kenneth W.
    Stanford Univ, Dept Med, Stanford, CA 94305 USA..
    Tricoci, Pierluigi
    Duke Clin Res Inst, Durham, NC USA..
    Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial2016In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 178, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Background Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes. Methods Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (>= 30 but <300 mg/dL), or macroalbuminuria (>= 300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute >= 0.3 mg/dL or relative >= 50%), was descriptively reported. Results Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98). Conclusions High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.

  • 13648.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Duke Clinical Research Institute, Durham, NC, USA.
    Budaj, Andrzej
    Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
    Himmelmann, Anders
    AstraZeneca Research and Development, Mölndal, Sweden.
    Husted, Steen
    Department of Cardiology, Århus University Hospital, Århus, Denmark.
    Storey, Robert F.
    Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study2014In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 168, no 1, p. 96-102Article in journal (Other academic)
    Abstract [en]

    Purpose: Plasma cystatin C is independently associated with cardiovascular (CV) risk in non-ST-elevation acute coronary syndromes (NSTE-ACS). The effect of genetic variability on cystatin C concentrations and outcome is unclear.

    Methods: Plasma cystatin C concentrations were measured in blood, obtained within 24 hours of admission, in 16279 ACS patients from the PLATelet inhibition and patient Outcomes trial. 9978 patients were genome-wide genotyped with up to 2.5 million SNPs. The first occurrence of CV death or myocardial infarction (MI) within one year was evaluated by multivariable (clinical variables and biomarkers) Cox regression analysis and c-statistics both overall (all ACS) and in NSTE-ACS.

    Results: We observed SNPs association with cystatin C levels (up to p=7.82 x 10-16). The most significant SNP (rs6048952) was adjacent the CST3 gene with additive effect on cystatin C concentrations: 0.85mg/L, 0.80mg/L and 0.73mg/L for the A/A, A/G and G/G genotypes respectively. Multivariable c-statistics regarding the combined endpoint (CV death or MI) was 0.6619. Adding cystatin C concentrations or genetically adjusted cystatin C levels, exhibited c-statistics of 0.6705 and 0.6703, respectively.

    The overall hazard ratio for rs6048952 was 0.93 (95%CI 0.82-1.04) regarding the CV death or MI while 0.85 (95%CI 0.70-1.03) regarding CV death in all ACS patients. In the NSTE-ACS subgroup, the hazard ratio for rs6048952 was 0.72 (95%CI 0.54-0.95).

    Conclusions: Genetic polymorphism, independently of kidney function, affects cystatin C concentrations, but does not appear to influence ischemic outcome in an overall ACS population. However, genetic variation appears to affect cardiovascular mortality in moderate-to-high risk NSTE-ACS patients.

  • 13649.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Helmersson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Weitoft, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Seasonal variations of urate in a Swedish adult population2017In: Clinical Rheumatology, ISSN 0770-3198, E-ISSN 1434-9949, Vol. 36, no 7, p. 1595-1598Article in journal (Refereed)
    Abstract [en]

    Seasonality in the incidence and prevalence of gout has previously been reported but the cause of this seasonality in gout is not explained. The aim of this study was to evaluate possible seasonal variations of urate in a large unselected Swedish adult population. We analyzed 170,915 urate test results from patients at a tertiary care hospital between 2000 and 2016. The results were divided according to sex and sampling month of the year. The median urate values were overall higher in males compared to females and both males and females had peak urate concentrations in the summer months (June-August). There is a seasonal pattern for urate concentrations in a large Swedish population similar to the previously reported seasonality for gout. This may be clinically important and could contribute to the circannual variation of gout. The seasonal pattern should be recognized when evaluating patient results both in clinical practice and in research studies.

  • 13650.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Flodin, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Comparison between cystatin C and creatinine estimated GFR in cardiology patients2015In: Cardiorenal medicine, ISSN 1664-5502, Vol. 5, no 4, p. 289-296Article in journal (Refereed)
    Abstract [en]

    Objective: Estimation of the glomerular filtration rate (GFR) is essential for identification, evaluation and risk prediction in patients with kidney disease. Estimated GFR (eGFR) is also needed for the correct dosing of drugs eliminated by the kidneys and to identify high-risk individuals in whom coronary angiography or other procedures may lead to kidney failure. Both cystatin C and creatinine are used for the determination of GFR, and we aimed to investigate if eGFR by the two methods differ in cardiology patients.

     Methods: We compared cystatin C and creatinine (CKD-EPI) eGFR calculated from the same request from a cardiology outpatient unit (n = 2,716), a cardiology ward (n = 980), a coronary care unit (n = 1,464), and an advanced coronary care unit (n = 518) in an observational, cross-sectional study. 

    Results: The median creatinine eGFR results are approximately 10 ml/min/1.73 m2 higher than the median cystatin C eGFR that is up to 90 ml/min/1.73 m2, irrespective of the level of care. Creatinine eGFR resulted in a less advanced eGFR category in the majority of patients with a cystatin C eGFR <60 ml/min/1.73 m2.

    Conclusions: Our study demonstrates a difference between creatinine and cystatin C eGFR in cardiology patients. It is important to be aware of which marker is used for the reported eGFR to minimize erroneous interpretations of the test results, as this could lead to under- or overmedication. Further studies are needed to determine the best method of estimating the GFR in cardiology units.

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