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  • 1.
    Abawi, Akram
    Örebro University, School of Medical Sciences.
    The effect of TGF-B1 and Fetal Bovine Serum on Sema 7A. Expression: An in Vitro study on Bone Marrow derived MSC from patients vith BCR-ABL negative Myeloproliferative neoplasms2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 2.
    Abdeldaim, Guma M. K.
    et al.
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Department of Clinical Mycobacteriology, National Center for Diseases Control, Benghazi, Libyan Arab Jamahiriya.
    Strålin, Kristoffer
    Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden; Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Olcén, Per
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Blomberg, Jonas
    Section of Clinical Virology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Mölling, Paula
    Örebro University Hospital. Department of Laboratory Medicine.
    Herrmann, Björn
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Quantitative fucK gene polymerase chain reaction on sputum and nasopharyngeal secretions to detect Haemophilus influenzae pneumonia2013In: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 76, no 2, p. 141-146Article in journal (Refereed)
    Abstract [en]

    A quantitative polymerase chain reaction (PCR) for the fucK gene was developed for specific detection of Haemophilus influenzae. The method was tested on sputum and nasopharyngeal aspirate (NPA) from 78 patients with community-acquired pneumonia (CAP). With a reference standard of sputum culture and/or serology against the patient's own nasopharyngeal isolate, H. influenzae etiology was detected in 20 patients. Compared with the reference standard, fucK PCR (using the detection limit 10(5) DNA copies/mL) on sputum and NPA showed a sensitivity of 95.0% (19/20) in both cases, and specificities of 87.9% (51/58) and 89.5% (52/58), respectively. In a receiver operating characteristic curve analysis, sputum fucK PCR was found to be significantly superior to sputum P6 PCR for detection of H. influenzae CAP. NPA fucK PCR was positive in 3 of 54 adult controls without respiratory symptoms. In conclusion, quantitative fucK real-time PCR provides a sensitive and specific identification of H. influenzae in respiratory secretions.

  • 3.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Department of Laboratory Medicine F68, Karolinska University Hospital, Stockholm, Sweden.
    Barqasho, Babilonia
    Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Nowak, Piotr
    Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Cuong, Do Duy
    Infectious Diseases Department, Bach Mai Hospital, Hanoi, Viet Nam .
    Amogné, Wondwossen
    Department of Medicine, Faculty of Medicine, University, Addis Abeba, Ethiopia .
    Larsson, Mattias
    Division of Global Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden; Oxford University Clinical Research Unit (OUCRU), Hanoi, Viet Nam .
    Lindquist, Lars
    Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden .
    Marrone, Gaetano
    Division of Global Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden .
    Sönnerborg, Anders
    Division of Clinical Microbiology, Department of Laboratory Medicine F68, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden2014In: Journal of the International AIDS Society, ISSN 1758-2652, E-ISSN 1758-2652, Vol. 17, p. 18841-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.

    METHODS: Cross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay.

    RESULTS: All three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection.

    CONCLUSIONS: Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.

  • 4.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Végvári, Akos
    Department of Electrical Measurements, Lund University, Lund, Sweden.
    Levi, Michael
    Tripep AB, Huddinge, Sweden.
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Högberg, Marita
    Chemilia AB, Huddinge, Sweden.
    Tong, Weimin
    Chemilia AB, Huddinge, Sweden.
    Romero, Ivan
    Chemilia AB, Huddinge, Sweden.
    Balzarini, Jan
    Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Isolation and characterization of a small antiretroviral molecule affecting HIV-1 capsid morphology2009In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 6, p. 34-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH2) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures.

    RESULTS: Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that displays antiviral activity. We show that conversion of G-NH2 to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH2 metabolite was alpha-hydroxy-glycineamide (alpha-HGA). Chemically synthesized alpha-HGA inhibited HIV-1 replication to the same degree as G-NH2, unlike a number of other synthesized analogues of G-NH2 which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized alpha-HGA further confirmed that the antiviral G-NH2-metabolite indeed was alpha-HGA.

    CONCLUSION: alpha-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, alpha-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.

  • 5.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Végvári, Akos
    Clinical Protein Science, Department of Electrical Measurements, Lund University, Lund, Sweden.
    Youssefi, Masoud
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Levi, Michael
    Tripep AB, Huddinge, Sweden .
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Andersson, Elin
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Horal, Peter
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Svennerholm, Bo
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Balzarini, Jan
    Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 6.
    Abedi, Mohammad R.
    et al.
    Örebro University Hospital. Department of Laboratory Medicine, Section for Transfusion Medicine.
    Doverud, Ann-Charlotte
    Department of Laboratory Medicine, Section for Transfusion Medicine, Örebro University Hospital. Örebro, Sweden.
    Preparation and Pathogen Inactivation of Double Dose Buffy Coat Platelet Products using the INTERCEPT Blood System2012In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 70, article id UNSP e4414Article in journal (Refereed)
    Abstract [en]

    Blood centers are faced with many challenges including maximizing production yield from the blood product donations they receive as well as ensuring the highest possible level of safety for transfusion patients, including protection from transfusion transmitted diseases. This must be accomplished in a fiscally responsible manner which minimizes operating expenses including consumables, equipment, waste, and personnel costs, among others.

    Several methods are available to produce platelet concentrates for transfusion. One of the most common is the buffy coat method in which a single therapeutic platelet unit (>= 2.0 x10(11) platelets per unit or per local regulations) is prepared by pooling the buffy coat layer from up to six whole blood donations. A procedure for producing "double dose" whole blood derived platelets has only recently been developed.

    Presented here is a novel method for preparing double dose whole blood derived platelet concentrates from pools of 7 buffy coats and subsequently treating the double dose units with the INTERCEPT Blood System for pathogen inactivation. INTERCEPT was developed to inactivate viruses, bacteria, parasites, and contaminating donor white cells which may be present in donated blood. Pairing INTERCEPT with the double dose buffy coat method by utilizing the INTERCEPT Processing Set with Dual Storage Containers (the "DS set"), allows blood centers to treat each of their double dose units in a single pathogen inactivation processing set, thereby maximizing patient safety while minimizing costs. The double dose buffy coat method requires fewer buffy coats and reduces the use of consumables by up to 50% (e.g. pooling sets, filter sets, platelet additive solution, and sterile connection wafers) compared to preparation and treatment of single dose buffy coat platelet units. Other cost savings include less waste, less equipment maintenance, lower power requirements, reduced personnel time, and lower collection cost compared to the apheresis technique.

  • 7.
    Acevedo, Reinaldo
    et al.
    Biologic Evaluation Department, Finlay Institute of Vaccines, Havana, Cuba.
    Bai, Xilian
    Meningococcal Reference Unit, Public Health England, Manchester, UK.
    Borrow, Ray
    Meningococcal Reference Unit, Public Health England, Manchester, UK.
    Caugant, Dominique A.
    Division of Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
    Carlos, Josefina
    Department of Pediatrics, College of Medicine, University of the East – Ramon Magsaysay Memorial Medical Center, Quezon City, Philippines.
    Ceyhan, Mehmet
    Faculty of Medicine, Department of Pediatric Infectious Diseases, Hacettepe University, Ankara, Turkey.
    Christensen, Hannah
    Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
    Climent, Yanet
    Biologic Evaluation Department, Finlay Institute of Vaccines, Havana, Cuba.
    De Wals, Philippe
    Department of Social and Preventive Medicine, Laval University, Quebec City QC, Canada.
    Dinleyici, Ener Cagri
    Department of Paediatrics, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey.
    Echaniz-Aviles, Gabriela
    Center for Research on Infectious Diseases, Instituto Nacional de Salud Pública, Cuernavaca, México.
    Hakawi, Ahmed
    Infectious Diseases Control, Ministry of Health, Riyadh, Saudi Arabia.
    Kamiya, Hajime
    Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan.
    Karachaliou, Andromachi
    Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
    Lucidarme, Jay
    Meningococcal Reference Unit, Public Health England, Manchester, UK.
    Meiring, Susan
    Division of Public Health Surveillance and Response, National Institute for Communicable Diseases, Johannesburg, South Africa.
    Mironov, Konstantin
    Central Research Institute of Epidemiology, Moscow, Russian Federation.
    Safadi, Marco A. P.
    Department of Pediatrics, FCM Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil.
    Shao, Zhujun
    National Institute for Communicable Disease Control and Prevention, Chinese Centre for Disease Control and Prevention, Beijing, China.
    Smith, Vinny
    Meningitis Research Foundation, Bristol, UK.
    Steffen, Robert
    Department of Epidemiology and Prevention of Infectious Diseases, WHO Collaborating Centre for Travellers’ Health, University of Zurich, Zurich, Switzerland.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Taha, Muhamed-Kheir
    Institut Pasteur, National Reference Centre for Meningococci, Paris, France.
    Trotter, Caroline
    Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
    Vazquez, Julio A.
    National Centre of Microbiology, Institute of Health Carlos III, Madrid, Spain.
    Zhu, Bingqing
    National Institute for Communicable Disease Control and Prevention, Chinese Centre for Disease Control and Prevention, Beijing, China.
    The Global Meningococcal Initiative meeting on prevention of meningococcal disease worldwide: Epidemiology, surveillance, hypervirulent strains, antibiotic resistance and high-risk populations2019In: Expert Review of Vaccines, ISSN 1476-0584, E-ISSN 1744-8395, Vol. 18, no 1, p. 15-30Article, review/survey (Refereed)
    Abstract [en]

    Introduction: The 2018 Global Meningococcal Initiative (GMI) meeting focused on evolving invasive meningococcal disease (IMD) epidemiology, surveillance, and protection strategies worldwide, with emphasis on emerging antibiotic resistance and protection of high-risk populations. The GMI is comprised of a multidisciplinary group of scientists and clinicians representing institutions from several continents.

    Areas covered: Given that the incidence and prevalence of IMD continually varies both geographically and temporally, and surveillance systems differ worldwide, the true burden of IMD remains unknown. Genomic alterations may increase the epidemic potential of meningococcal strains. Vaccination and (to a lesser extent) antimicrobial prophylaxis are the mainstays of IMD prevention. Experiences from across the globe advocate the use of conjugate vaccines, with promising evidence growing for protein vaccines. Multivalent vaccines can broaden protection against IMD. Application of protection strategies to high-risk groups, including individuals with asplenia, complement deficiencies and human immunodeficiency virus, laboratory workers, persons receiving eculizumab, and men who have sex with men, as well as attendees at mass gatherings, may prevent outbreaks. There was, however, evidence that reduced susceptibility to antibiotics was increasing worldwide.

    Expert commentary: The current GMI global recommendations were reinforced, with several other global initiatives underway to support IMD protection and prevention.

  • 8.
    Adolfsson, Peter
    et al.
    Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Endocrine and Diabetes Center, The hospital of Halland Kungsbacka, Kungsbacka, Sweden.
    Mattsson, Stig
    Faculty of Health Sciences and Medicine, Örebro University Hospital, Örebro, Sweden; Endocrine and Diabetes Center, Falun Hospital, Falun, Sweden.
    Jendle, Johan
    Faculty of Health Sciences and Medicine, Örebro University Hospital, Örebro, Sweden; Endocrine and Diabetes Center, Karlstad Hospital, Karlstad, Sweden.
    Evaluation of glucose control when a new strategy of increased carbohydrate supply is implemented during prolonged physical exercise in type 1 diabetes2015In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 115, no 12, p. 2599-2607Article in journal (Refereed)
    Abstract [en]

    Purpose: In healthy individuals, high carbohydrate intake is recommended during prolonged exercise for maximum performance. In type 1 diabetes (T1D), this would alter the insulin requirements. The aim of the study was to evaluate the safety of high glucose supplementation during prolonged exercise and the glucose control when a novel strategy of increased carbohydrate supply was implemented during prolonged exercise in T1D.

    Methods: Eight subjects with T1D participated in a sports camp including sessions of prolonged exercise and individualized feedback during three consecutive days. This was later followed by a 90 km cross-country skiing race. Large amounts of carbohydrates, 75 g/h, were supplied during exercise and the insulin requirements were registered. Glucose was measured before, during and after exercise aiming at euglycaemia, 4-8 mmol/L (72-144 mg/dL). During the race, continuous glucose monitoring (CGM) was used as an aspect of safety and to allow direct and individual adjustments.

    Results: Compared to ordinary carbohydrate supply during exercise, the high carbohydrate supplementation resulted in significantly increased insulin doses to maintain euglycaemia. During the cross-country skiing race, the participants succeeded to reach mean target glucose levels; 6.5 ± 1.9 mmol/L (117 ± 34 mg/dL) and 5.7 ± 1.5 mmol/L (103 ± 27 mg/dL) at the start and finish of the race, respectively. Episodes of documented hypoglycemia (<4 mmol/L/72 mg/dL) were rare. CGM was used for adjustments.

    Conclusion: In this study, large carbohydrate supplementation in T1D individuals during prolonged aerobic exercise is safe and allows the subjects to maintain glycaemic control and indicates the feasibility of CGM under these conditions.

  • 9.
    Aghanavesi, Somayeh
    et al.
    Computer Engineering, School of Technology and Business Studies, Borlänge, Dalarna University, Sweden.
    Bergquist, Filip
    Dept. of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Nyholm, Dag
    Dept. of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
    Senek, Marina
    Dept. of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
    Memedi, Mevludin
    Örebro University, Örebro University School of Business.
    Objective assessment of Parkinson’s disease motor symptoms during leg agility test using motion sensors2018Conference paper (Refereed)
    Abstract [en]

    Title: Objective assessment of Parkinson’s disease motor symptoms during leg agility test using motion sensors

    Objective: To develop and evaluate machine learning methods for assessment of Parkinson’s disease (PD) motor symptoms using leg agility (LA) data collected with motion sensors during a single dose experiment.

    Background: Nineteen advanced PD patients (Gender: 14 males and 5 females, mean age: 71.4, mean years with PD: 9.7, mean years with levodopa: 9.5) were recruited in a single center, open label, single dose clinical trial in Sweden [1].

    Methods: The patients performed up to 15 LA tasks while wearing motions sensors on their foot ankle. They performed tests at pre-defined time points starting from baseline, at the time they received a morning dose (150% of their levodopa equivalent morning dose), and at follow-up time points until the medication wore off. The patients were video recorded while performing the motor tasks. and three movement disorder experts rated the observed motor symptoms using 4 items from the Unified PD Rating Scale (UPDRS) motor section including UPDRS #26 (leg agility), UPDRS #27 (Arising from chair), UPDRS #29 (Gait), UPDRS #31 (Body Bradykinesia and Hypokinesia), and dyskinesia scale. In addition, they rated the overall mobility of the patients using Treatment Response Scale (TRS), ranging from -3 (very off) to 3 (very dyskinetic). Sensors data were processed and their quantitative measures were used to develop machine learning methods, which mapped them to the mean ratings of the three raters. The quality of measurements of the machine learning methods was assessed by convergence validity, test-retest reliability and sensitivity to treatment.

    Results: Results from the 10-fold cross validation showed good convergent validity of the machine learning methods (Support Vector Machines, SVM) with correlation coefficients of 0.81 for TRS, 0.78 for UPDRS #26, 0.69 for UPDRS #27, 0.78 for UPDRS #29, 0.83 for UPDRS #31, and 0.67 for dyskinesia scale (P<0.001). There were good correlations between scores produced by the methods during the first (baseline) and second tests with coefficients ranging from 0.58 to 0.96, indicating good test-retest reliability. The machine learning methods had lower sensitivity than mean clinical ratings (Figure. 1).

    Conclusions: The presented methodology was able to assess motor symptoms in PD well, comparable to movement disorder experts. The leg agility test did not reflect treatment related changes.

  • 10.
    Aghanavesi, Somayeh
    et al.
    Computer Engineering, School of Technology and Business Studies, Dalarna University, Borlänge, Sweden.
    Filip, Bergquist
    Dept. of Pharmacology, University of Gothenburg, Gothenbrug, Sweden.
    Nyholm, Dag
    Dept. of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
    Senek, Marina
    Dept. of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
    Memedi, Mevludin
    Örebro University, Örebro University School of Business.
    Feasibility of a multi-sensor data fusion method for assessment of Parkinson’s disease motor symptoms2018Conference paper (Other academic)
    Abstract [en]

    Title: Feasibility of a multi-sensor data fusion method for assessment of Parkinson’s disease motor symptoms

    Objective: To assess the feasibility of measuring Parkinson’s disease (PD) motor symptoms with a multi-sensor data fusion method. More specifically, the aim is to assess validity, reliability and sensitivity to treatment of the methods.

    Background: Data from 19 advanced PD patients (Gender: 14 males and 5 females, mean age: 71.4, mean years with PD: 9.7, mean years with levodopa: 9.5) were collected in a single center, open label, single dose clinical trial in Sweden [1].

    Methods: The patients performed leg agility and 2-5 meter straight walking tests while wearing motion sensors on their limbs. They performed the tests at baseline, at the time they received the morning dose, and at pre-specified time points until the medication wore off. While performing the tests the patients were video recorded. The videos were observed by three movement disorder specialists who rated the symptoms using a treatment response scale (TRS), ranging from -3 (very off) to 3 (very dyskinetic). The sensor data consisted of lower limb data during leg agility, upper limb data during walking, and lower limb data during walking. Time series analysis was performed on the raw sensor data extracted from 17 patients to derive a set of quantitative measures, which were then used during machine learning to be mapped to mean ratings of the three raters on the TRS scale. Combinations of data were tested during the machine learning procedure.

    Results: Using data from both tests, the Support Vector Machines (SVM) could predict the motor states of the patients on the TRS scale with a good agreement in relation to the mean ratings of the three raters (correlation coefficient = 0.92, root mean square error = 0.42, p<0.001). Additionally, there was good test-retest reliability of the SVM scores during baseline and second tests with intraclass-correlation coefficient of 0.84. Sensitivity to treatment for SVM was good (Figure 1), indicating its ability to detect changes in motor symptoms. The upper limb data during walking was more informative than lower limb data during walking since SVMs had higher correlation coefficient to mean ratings.  

    Conclusions: The methodology demonstrates good validity, reliability, and sensitivity to treatment. This indicates that it could be useful for individualized optimization of treatments among PD patients, leading to an improvement in health-related quality of life.

  • 11.
    Ahlstrand, Erik
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Medicine, Hematology, Örebro University Hospital, Örebro, Sweden.
    Bäckman, Anders
    Örebro University, School of Medical Sciences. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Persson, Lennart
    Örebro University Hospital. Department of Infectious diseases, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Infectious diseases & Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Evaluation of a PCR method to determine the clinical significance of blood cultures with Staphylococcus epidermidis in patients with hematological malignancies2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 6, p. 539-544Article in journal (Refereed)
    Abstract [en]

    The aim was to investigate whether the detection and quantification of Staphylococcus epidermidis DNA in blood could distinguish S. epidermidis blood stream infections (BSIs) from blood culture contaminations in patients with hematological malignancies. The hld gene was chosen to identify S. epidermidis DNA and DNA in blood samples was detected by real-time PCR. Blood samples were obtained simultaneously with blood cultures positive for S. epidermidis (n = 30), during blood culture-negative episodes (n = 10) and episodes of bacteremia with other bacteria than S. epidermidis (n = 4) and from healthy blood donors (n = 10). In addition, DNA from S. epidermidis and a selection of other bacterial species were analyzed. Three different sets of criteria were used to classify episodes with positive blood cultures with S. epidermidis as BSIs or contaminations. All DNA preparations from S. epidermidis (n = 48) were hld-positive, but other bacterial species (n = 13) were negative. Sixteen (53%) of 30 blood samples from patients with blood cultures positive for S. epidermidis were hld-positive, but none of the controls. There was no clear association between a positive hld PCR and episodes interpreted as BSIs. In conclusion, hld PCR failed to distinguish S. epidermidis BSIs from blood culture contaminations in patients with hematological malignancies.

  • 12.
    Ahmad, Abrar
    et al.
    Department of Clinical Research, Örebro University Hospital, Örebro, Sweden.
    Venizelos, Nikolaos
    Department of Clinical Research, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hahn-Strömberg, Victoria
    Department of Clinical Research, Örebro University Hospital, Örebro, Sweden; ; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Prognostic Effect of Vascular Endothelial Growth Factor +936C/T Polymorphism on Tumor Growth Pattern and Survival in Patients Diagnosed with Colon Carcinoma2016In: Journal of Tumor Research, Vol. 2, no 1, p. 1-6, article id 1000108Article in journal (Refereed)
    Abstract [en]

    Introduction: Vascular endothelial growth factor (VEGF) is considered as endothelial cell-specific mitogen that plays an important role in the process of angiogenesis, thereby affecting the prognosis of tumor as angiogenesis is a crucial phase in tumor growth and metastasis. Accordingly, we carried out a case-control study to assess whether VEGF rs3025039 polymorphism affects the growth pattern and susceptibility to colon carcinoma.

    Materials and methods: One hundred and fifty, formalin fixed paraffin embedded (FFPE) tissue samples from patients diagnosed with colon carcinoma and the same number of blood controls were used in the present study. VEGF +936 C>T (rs3025039) polymorphism was evaluated by pyrosequencing. Computer image analysis was used to analyse the growth pattern of the colon carcinoma tumor by using cytokeratin-8 stained slides.

    Results: A heterozygous genotype TC in rs3025039 polymorphism was found as a significantly protective genotype as compared to homozygous genotypes (CC and TT). However we found no significant correlation between investigated polymorphisms, tumor growth pattern, 5 years survival and other clinicopathological parameters.

    Conclusion: We concluded that the heterogenous genotype of VEGF rs3025039 polymorphism appears to be a protective factor for colon carcinoma that could be a useful marker in follow-up studies and may be a genetic determinant for colon carcinoma.

  • 13.
    AL HISHAN, ABDELKAREEM
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Aortic Valve Stenosis, Comparison of Peak Velocities Measured by Phase-Contrast MR versus Echocardiographic Doppler Measurements2013Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 14.
    Ali, Imran
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Julin, Bettina
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Glynn, Anders
    The National Food Agency, Uppsala, Sweden.
    Högberg, Johan
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Marika
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giovannucci, Edward
    Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston MA, United States; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Wolk, Alicja
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Stenius, Ulla
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Åkesson, Agneta
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Exposure to polychlorinated biphenyls and prostate cancer: population-based prospective cohort and experimental studies2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.

  • 15. Ali, Magdi M. M.
    et al.
    ElGhazali, Gehad
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Farouk, Salah E.
    Nasr, Amre
    Noori, Suzan I. A.
    Shamad, Mahdi M.
    Fadlelseed, Omar E.
    Berzins, Klavs
    Fc gamma RIIa (CD32) polymorphism and onchocercal skin disease: implications for the development of severe reactive onchodermatitis (ROD)2007In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 77, no 6, p. 1074-8Article in journal (Refereed)
    Abstract [en]

    The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the Fc gamma RIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. Fc gamma RIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). Fc gamma RIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

  • 16.
    Almon, Ricardo
    et al.
    Örebro University, Department of Clinical Medicine.
    Alvarez-Leon, Eva E.
    Engfeldt, Peter
    Örebro University, Department of Clinical Medicine.
    Serra-Majem, Lluis
    Magnuson, Anders
    Nilsson, Torbjörn K.
    Associations between lactase persistence and the metabolic syndrome: a Mendelian randomization study in the Canary Islands2009Conference paper (Refereed)
  • 17.
    Almon, Ricardo
    et al.
    Örebro University, Department of Clinical Medicine.
    Alvarez-Leon, Eva E.
    Univ Las Palmas Gran Canaria, Fac Hlth Sci, Dept Clin Sci, Canary Isl, Spain; Hosp Insular Gran Canaria, Canarian Hlth Serv, Serv Prevent Med, Canary Isl, Spain.
    Engfeldt, Peter
    Örebro University, Department of Clinical Medicine.
    Serra-Majem, Lluis
    Univ Las Palmas Gran Canaria, Fac Hlth Sci, Dept Clin Sci, Canary Isl, Spain; Hosp Insular Gran Canaria, Canarian Hlth Serv, Serv Prevent Med, Canary Isl, Spain.
    Magnuson, Anders
    Örebro University hospital, Örebro, Sweden.
    Nilsson, Torbjörn K.
    Örebro University hospital, Örebro, Sweden.
    Associations between lactase persistence and the metabolic syndrome in a cross-sectional study in the Canary Islands2009In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 49, no 3, p. 141-146Article in journal (Refereed)
    Abstract [en]

    Background: The single nucleotide polymorphism (SNP) LCT -13910 C>T, associated with genetically determined phenotypes of lactase persistence (LP) or non-persistence (LNP), was studied in relation to the metabolic syndrome (MS).

    AIim of the study: The aim was to determine if milk intake and MS are associated. We applied Mendelian randomization (MR). The SNP, LCT -13910 C>T, with the genotypes LP (TT/CT) and LNP (CC), was taken as a proxy for milk consumption.

    Methods: A representative sample of adults belonging to the Canary Islands Nutrition Survey (ENCA) in Spain aged 18-75 years (n = 551) was genotyped for the LCT -13910 C>T polymorphism. We used the International Diabetes Federation (IDF) criteria to define MS. RESULTS: 60% of the population was LP and 40% LNP. One hundred seven LP subjects (35.0%) and 53 LNP subjects (25.6%) showed MS (chi (2) = 5.04, p = 0.025). LP subjects showed a significantly higher odds ratio (OR) for MS than LNP subjects computed for the whole population: both the crude OR (1.56; 95% CI 1.06-2.31) and adjusted OR for sex, age, daily energy intake, physical activity and educational level (1.57; 95% CI 1.02-2.43). Adjusted OR for women with LP was 1.93; 95% CI 1.06-3.52.

    Conclusions: The T allele of the SNP might constitute a nutrigenetic factor increasing the susceptibility of LP subjects, especially women, to develop MS in the Canary Islands.

  • 18.
    Almroth, G.
    et al.
    Department of Nephrology, Institution of medicine and health sciences, Linköping University, Linköping, Sweden.
    Lönn, Johanna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Uhlin, F.
    Department of Nephrology, Institution of medicine and health sciences, Linköping University, Linköping, Sweden.
    Brudin, L.
    Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Department of Physiology, County Hospital, Kalmar, Sweden.
    Andersson, B.
    Department of Clinical Immunology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Hahn-Zoric, M.
    Department of Clinical Immunology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Sclerostin, TNF-alpha and Interleukin-18 Correlate and are Together with Klotho Related to Other Growth Factors and Cytokines in Haemodialysis Patients2016In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 83, no 1, p. 58-63Article in journal (Refereed)
    Abstract [en]

    Patients with chronic renal failure are known to have renal osteodystrophy (bone disease) and increased calcification of vessels. A new marker of bone disease, sclerostin, the two pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-18 (IL-18), and the fibroblast growth factor-23 (FGF-23) receptor-associated marker Klotho were tested in 84 haemodialysis (HD) patients and in healthy controls. The patients had significantly higher levels of the three former markers than of the controls while Klotho was significantly higher in the controls. Low level, but significant, correlations were observed in the patient group when the levels of these four markers were compared to each other and to those of 5 cytokines and growth factors tested earlier; high-sensitive CRP (hsCRP), interleukin-6 (IL-6), hepatocyte growth factor (HGF), fibroblast growth factor-23 (FGF-23) and soluble urokinase plasminogen activator (suPAR). Ln sclerostin correlated positively to Ln hsTNF-alpha, Ln HGF and Ln suPAR. Ln hsTNF-alpha correlated positively to Ln sclerostin, Ln hsCRP, Ln IL-6, Ln FGF-23, Ln suPAR and Ln IL-18. Ln IL-18 correlated positively to Ln suPAR and Ln TNF-alpha. Ln Klotho correlated negatively to Ln hsCRP but did not correlate to Ln FGF-23. The markers studied here may be involved in the calcification of vessels seen in HD patients due to a combination of inflammation and bone disease. The mechanisms are still not fully known but may be of importance for future therapeutic possibilities in this group of patients.

  • 19.
    Alpkvist, Helena
    et al.
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Athlin, Simon
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Naucler, Pontus
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Herrmann, Björn
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Abdeldaim, Guma
    Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Department of Medical Microbiology and Parasitology, Faculty of Medicine, Benghazi University, Benghazi, Libya.
    Slotved, Hans-Christian
    Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Hedlund, Jonas
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Strålin, Kristoffer
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Clinical and Microbiological Factors Associated with High Nasopharyngeal Pneumococcal Density in Patients with Pneumococcal Pneumonia2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, article id e0140112Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 20.
    Ambaye, Sisay
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Method development and improvement of Human papillomavirus (HPV) detection and genotyping2012Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 21. Ambrosio, Fabrisia
    et al.
    Kadi, Fawzi
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lexell, Jan
    Fitzgerald, G. Kelley
    Boninger, Michael L.
    Huard, Johnny
    The effect of muscle loading on skeletal muscle regenerative potential: an update of current research findings relating to aging and neuromuscular pathology2009In: American Journal of Physical Medicine & Rehabilitation, ISSN 0894-9115, E-ISSN 1537-7385, Vol. 88, no 2, p. 145-155Article in journal (Refereed)
    Abstract [en]

    Skeletal muscle is a dynamic tissue with a remarkable ability to continuously respond to environmental stimuli. Among its adaptive responses is the widely investigated ability of skeletal muscle to regenerate after loading or injury or both. Although significant basic science efforts have been dedicated to better understand the underlying mechanism controlling skeletal muscle regeneration, there has been relatively little impact in the clinical approaches used to treat skeletal muscle injuries and wasting. The purpose of this review article is to provide an overview of the basic biology of satellite cell function in response to muscle loading and to relate these findings in the context of aging and neuromuscular pathology for the rehabilitation medicine specialist.

  • 22. Ambrosio, Fabrisia
    et al.
    Tarabishy, Ayman
    Kadi, Fawzi
    Örebro University, School of Health and Medical Sciences.
    Brown, Elke H. P.
    Sowa, Gwendolyn
    Biological basis of exercise-based treatments for musculoskeletal conditions2011In: PM&R, ISSN 1934-1482, E-ISSN 1934-1563, Vol. 3, no 6 Suppl 1, p. S59-S63Article in journal (Refereed)
    Abstract [en]

    Exercise-based therapies are the cornerstone of rehabilitation programs. While the benefits of exercise on systemic and tissue function are generally accepted, mechanisms underlying these benefits are sometimes poorly understood. An improved understanding of the effects of mechanical loading on molecular and cellular processes has the potential to lead to more disease-specific and efficacious exercise-based therapies. The purpose of this paper is to review the current literature examining the role of mechanical signaling on muscle and cartilage biology.

  • 23. Amoudruz, Petra
    et al.
    Holmlund, Ulrika
    Schollin, Jens
    Örebro University, School of Health and Medical Sciences.
    Sverremark-Ekström, Eva
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Maternal country of birth and previous pregnancies are associated with breast milk characteristics2009In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 20, no 1, p. 19-29Article in journal (Refereed)
    Abstract [en]

    Populations in high infectious exposure countries are at low risk of some immune-mediated diseases such as Crohn's disease and allergy. This low risk is maintained upon immigration to an industrialized country, but the offspring of such immigrants have a higher immune-mediated disease risk than the indigenous population. We hypothesize that early life exposures in a developing country shape the maternal immune system, which could have implications for the offspring born in a developed country with a low infectious load. The aim of this study was to investigate if exposures in childhood (indicated by country of origin) and subsequent exposures influence immunologic characteristics relevant to stimulation of offspring. Breast milk components among 64 mothers resident in Sweden, 32 of whom immigrated from a developing country, were examined using the ELISA and Cytometric Bead Array methods. Immigrants from a developing country had statistically significantly higher levels of breast milk interleukin-6 (IL-6), IL-8 and transforming growth factor-beta1. A larger number of previous pregnancies were associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may influence adult immune characteristics, potentially relevant to disease risk in offspring. Such a mechanism may explain the higher immune-mediated disease risk among children of migrants from a developing to developed country. Older siblings may influence disease risk through the action of previous pregnancies on maternal immune characteristics.

  • 24. Andersson, Christin
    et al.
    Blennow, Kaj
    Almkvist, Ove
    Andreasen, Niels
    Engfeldt, Peter
    Örebro University, School of Health and Medical Sciences.
    Johansson, Sven-Erik
    Lindau, Maria
    Eriksdotter-Jönhagen, Maria
    Increasing CSF phospho-tau levels during cognitive decline and progression to dementia2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 10, p. 1466-1473Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression.

    OBJECTIVE: To investigate longitudinal changes in CSF biomarkers--total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (Abeta42)--during cognitive decline.

    METHODS: Forty memory clinic patients (47.5% females), aged 61.3+/-7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3+/-1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM).

    RESULTS: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Abeta42-levels did not change in any of the memory groups during follow-up.

    CONCLUSION: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.

  • 25.
    Angelison, L.
    et al.
    Helsingborg, Sweden.
    Almer, S.
    Stockholm, Sweden.
    Eriksson, A.
    Gothenburg, Sweden.
    Karling, P.
    Umeå, Sweden.
    Fagerberg, U.
    Västeras, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Thörn, M.
    Uppsala, Sweden.
    Björk, J.
    Stockholm, Sweden.
    Hindorf, U.
    Lund, Sweden.
    Löfberg, R.
    Stockholm, Sweden.
    Bajor, A.
    Gothenburg, Sweden.
    Hjortswang, H.
    Linköping, Sweden.
    Hammarlund, P.
    Ängelholm, Sweden.
    Grip, O.
    Malmö, Sweden.
    Torp, J.
    Kristianstad, Sweden.
    Marsal, J.
    Lund, Sweden.
    Hertervig, E.
    Lund, Sweden.
    Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients2017In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 45, no 4, p. 519-532Article in journal (Refereed)
    Abstract [en]

    Background: Real-life long-term data on infliximab treatment in ulcerative colitis are limited.

    Aim: To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined.

    Methods: A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age ≥18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant.

    Results: Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy.

    Conclusions: Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.

  • 26.
    Anselmius, Johan
    et al.
    Örebro University, School of Health and Medical Sciences.
    Milton, Ludvig
    Örebro University, School of Health and Medical Sciences.
    Expand A Lung: Ett träningsverktyg för andningsmuskulaturen?2011Independent thesis Advanced level (degree of Master (One Year)), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

     Abstrakt

     

    Syfte:

    Syftet var att undersöka om prestation och uthålligheten hade förbättrats vid användandet av Expand a lung.

     

    Metod:

    En intervention genomfördes på sju testpersoner (4 kvinnor & 3 män) som använde Expand a lung under fjorton dagar, som jämfördes mot en kontrollgrupp på fyra testpersoner (2 kvinnor & 2 män). Testpersonerna genomförde två tester, med en intervall på fjorton dagar. I undersökningen figurerade 4 kvinnor och 3 män (ålder: 22.7 ± 2, vikt: 68.5 ± 10, längd: 175.1 ± 8.5) i experimentgruppen. 2 kvinnor och 2 män (ålder: 22.5 ± 1.5, vikt: 69 ± 9, längd: 170.7 ± 5.5) ingick i kontrollgruppen. Hjärtfrekvens, respiratoriska kvoten och blodlaktat uppmättes med hjälp utav Jaeger Oxycon Pro och lungvolym (SVC & FEV1) uppmättes med hjälp av Spirare SPS 310.

     

    Resultat:

    Ingen signifikant skillnad existerade inom grupperna. Experimentgruppen: SVC före x 4.73, SVC efter x 4,77. FEV1 före x 4.31, FEV1 efter x 4.29, HF (vid OBLA) före x 156, HF efter 155, RQ (vid OBLA) före x 1.04, RQ efter 1.05. Kontrollgruppen: SVC före x 4.98, SVC efter x 4.95. FEV1 före 4.48, FEV1 efter x 4.49, HF (vid OBLA) före x 165, HF efter 163, RQ (vid OBLA) före x 0.99, RQ efter x 1.00. Det som gick att urskilja var att det fanns skillnader på individnivå.

     

    Diskussion:

    Vår undersökning visade ingen signifikant skillnad på gruppnivå efter 14 dagars användande av Expand a lung. Dock fanns det skillnader på individnivå. Detta resultat kan bland annat bero på för kort träningsperiod och för få deltagare. Om Expand a lung kan förbättra prestationen vid träning under längre tid kan vi inte uttala oss om utan krävs vidare forskning.

     

    Nyckelord:

    Expand a lung, andningsmuskulaturträning, laktat, lungvolym.

    Inledning:

    Det existerar träningsredskap som utlovar en ökning gällande prestation och uthållighet, i träningssammanhang, av människans andningsmuskulatur. Träningsredskapen isolerade träningen till att bara sätta andningsmuskulaturen i arbete. Expand a lung var en av dessa nya, mer obeprövade, träningsredskap som utlovade en förbättrad prestation och uthållighet vid ett frekvent användande. Samtidigt visade en befintlig del av forskning att det indirekt inte gick att träna andningsmuskulaturen. Vi påträffade aldrig granskade vetenskaplig forskning som kunde fastställa vad Expand a lung utlovade.

  • 27.
    Arinell, Karin
    et al.
    Örebro University, School of Medical Sciences. Department of Cardiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Acute Internal Medicine, Centralsjukhuset, Karlstad, Sweden.
    Blanc, Stéphane
    CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Université de Strasbourg, Strasbourg, France.
    Welinder, Karen Gjesing
    Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
    Støen, Ole Gunnar
    Norwegian Institute for Nature Research, Trondheim, Norway.
    Evans, Alina L.
    Department of Forestry and Wildlife Management, Inland Norway University of Applied Sciences, Koppang, Norway.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Physical inactivity and platelet function in humans and brown bears: A comparative study2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 1, p. 87-90Article in journal (Refereed)
    Abstract [en]

    Physical inactivity increases the risk of thromboembolism. However, good standardized human models on inactivity are in short supply and experimental models are few.

    Our objective was to investigate how standardized bed rest affects platelet aggregation in humans and to investigate if aggregation is altered in a translational model system - the hibernating brown bear (Ursus arctos). We collected blood from (1) healthy male volunteers participating in a 21-day bed rest study in head-down tilt position (-6°) 24 h a day; (2) free-ranging brown bears captured during winter hibernation and again during active state in summer. We analyzed platelet function using multiple electrode platelet aggregometry. In total, 9 healthy male volunteers (age 31.0 ± 6.4 years) and 13 brown bears (7 females and 6 males, age 2.8 ± 0.6 years) were included. In hibernating bears adenosine diphosphate, arachidonic acid, thrombin receptor activating peptide, and collagen impedance aggregometry tests were all halved compared to summer active state. In human volunteers no statistically significant changes were found between baseline and the end of bed rest. In human male volunteers 3 weeks of bed rest did not affect platelet function. In hibernating brown bears platelet aggregation was halved compared to summer and we hypothesize that this is a protective measure to avoid formation of thrombi under periods of low blood flow.

  • 28.
    Aronson, D.
    et al.
    Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
    Wojtaszewski, J.
    Copenhagen Muscle Research Center, August Krogh Institute, University of Copenhagen, Copenhagen, Denmark.
    Thorell, A.
    Department of Surgery, Karolinska Hospital and Institute, Stockholm, Sweden.
    Nygren, J.
    Department of Surgery, Karolinska Hospital and Institute, Stockholm, Sweden.
    Zangen, A.
    Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
    Richter, E. A.
    Copenhagen Muscle Research Center, August Krogh Institute, University of Copenhagen, Copenhagen, Denmark.
    Ljungqvist, Olle
    Department of Surgery, Karolinska Hospital and Institute, Stockholm, Sweden.
    Fielding, R. A.
    Department of Health Sciences, Sargent Coll. All. Hlth. Professions, Boston University, Boston, MA , United States.
    Goodyear, L. J.
    Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA, United States.
    Extracellular-regulated protein kinase cascades are activated in response to injury in human skeletal muscle1998In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 275, no 2, p. C555-C561Article in journal (Refereed)
    Abstract [en]

    The mitogen-activated protein (MAP) kinase signaling pathways are believed to act as critical signal transducers between stress stimuli and transcriptional responses in mammalian cells. However, it is not known whether these signaling cascades also participate in the response to injury in human tissues. To determine whether injury to the vastus lateralis muscle activates MAP kinase signaling in human subjects, two needle biopsies or open muscle biopsies were taken from the same incision site 30-60 min apart. The muscle biopsy procedures resulted in striking increases in dual phosphorylation of the extracellular-regulated kinases (ERK1 and ERK2) and in activity of the downstream substrate, the p90 ribosomal S6 kinase. Raf-1 kinase and MAP kinase kinase, upstream activators of ERK, were also markedly stimulated in all subjects. In addition, c-Jun NH2-terminal kinase and p38 kinase, components of two parallel MAP kinase pathways, were activated following muscle injury. The stimulation of the three MAP kinase cascades was present only in the immediate vicinity of the injury, a finding consistent with a local rather than systemic activation of these signaling cascades in response to injury. These data demonstrate that muscle injury induces the stimulation of the three MAP kinase cascades in human skeletal muscle, suggesting a physiological relevance of these protein kinases in the immediate response to tissue injury and possibly in the initiation of wound healing.

  • 29.
    Arvidsson Lindvall, Mialinn
    et al.
    Örebro University, School of Health Sciences. University Health Care Research Centre, Region Örebro County, Örebro, Sweden.
    Anderzen-Carlsson, Agneta
    Örebro University, School of Health Sciences. Örebro University Hospital. University Health Care Research Centre, Region Örebro County, Örebro, Sweden; Faculty of Health, Science, and Technology, Department of Health Sciences, Nursing, Karlstad University, Karlstad, Sweden.
    Appelros, Peter
    Faculty of Health, Science, and Technology, Department of Health Sciences, Nursing, Karlstad University, Karlstad, Sweden.
    Forsberg, Anette
    Örebro University, School of Health Sciences. Örebro University Hospital.
    Validity and test-retest reliability of the six-spot step test in persons after stroke2018In: Physiotherapy Theory and Practice, ISSN 0959-3985, E-ISSN 1532-5040Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: After stroke, asymmetric weight distribution is common with decreased balance control in standing and walking. The six-spot step test (SSST) includes a 5-m walk during which one leg shoves wooden blocks out of circles marked on the floor, thus assessing the ability to take load on each leg. The aim of the present study was to investigate the convergent and discriminant validity and test-retest reliability of the SSST in persons with stroke.

    METHODS: Eighty-one participants were included. A cross-sectional study was performed, in which the SSST was conducted twice, 3-7 days apart. Validity was investigated using measures of dynamic balance and walking. Reliability was assessed using intraclass correlation coefficient, standard error of the measurement (SEM), and smallest real difference (SRD).

    RESULTS: The convergent validity was strong to moderate, and the test-retest reliability was good. The SEM% was 14.7%, and the SRD% was 40.8% based on the mean of four walks shoving twice with the paretic and twice with the non-paretic leg.

    CONCLUSION: Values on random measurement error were high affecting the use of the SSST for follow-up evaluations but the SSST can be a complementary measure of gait and balance.

  • 30.
    Asfaw Idosa, Berhane
    Örebro University, School of Medical Sciences.
    Inflammasome polymorphisms and the Inflammatory Response to Bacterial Infections2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    NLRP3 inflammasome; a key component of the innate immune system, can be activated by a number of pathogens and other threats of the body. Activation of the NLRP3 inflammasome triggers caspase-1 mediated maturationof IL-1β and IL-18. Polymorphisms Q705K and C10X are two gene variants of the NLRP3 inflammasome that combined or per se have been associated with higher risk and severity of chronic inflammation and excessive production of IL-1β. Host genetic factors have been found an important determinants of susceptibility of infectious diseases and disease outcome. The aims of this thesis were to investigate the association between polymorphisms Q705K and C10X with bacterial infections and the inflammatory response, moreover to determine the inflammasome activation state in healthy carriers of these polymorphisms. The data of the thesis show higher levels of IL-1β and IL-33 in healthy carriers of combined polymorphisms of Q705K and C10X as compared to non-carrier controls. This may provide individuals with combined polymorphisms a more robust innate immune response against pathogens, but could also lead to the onset of chronic inflammation, and excessive inflammation during acute infection. In addition, individuals with C10X polymorphism per se showed association with the presence of bacteremia as compared withhealthy blood donors. No association was found in severely ill patients with negative blood culture bottle. In addition, the results show that LOS of N. meningitidis is responsible for the priming and activating steps of the inflammasome. The non-LOS components were found to contribute to the priming step. A higher inflammatory response to N. meningitidis was found in individuals who were non-carriers of the polymorphisms than individuals with the Q705K and C10X per se or combined regardless of the strain of bacteria. Taken together, the gene variations of the NLRP3 inflammasome are of importance in explaining inter-individual variation in susceptibility to infectious diseases.

    List of papers
    1. Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
    Open this publication in new window or tab >>Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
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    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed) Published
    Abstract [en]

    Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

    Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.

    Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

    Place, publisher, year, edition, pages
    Public Library of Science (PLoS), 2013
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-35447 (URN)10.1371/journal.pone.0075457 (DOI)000325483600018 ()24098386 (PubMedID)2-s2.0-84884894455 (Scopus ID)
    Funder
    Swedish Research Council, ES: K2010-57X-21435-01-3
    Note

    Funding Agencies:

    Research committee of the County Council of Örebro

    Nyckelfonden at Örebro University Hospital

    Sund's Foundation for Rheumatic Research

    King Gustaf V Memorial Foundation

    Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2019-06-14Bibliographically approved
    2. C10X polymorphism in the CARD8 gene is associated with bacteraemia
    Open this publication in new window or tab >>C10X polymorphism in the CARD8 gene is associated with bacteraemia
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    2014 (English)In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, p. 13-20Article in journal (Refereed) Published
    Abstract [en]

    The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

    Place, publisher, year, edition, pages
    West Sussex, UK: John Wiley & Sons, 2014
    Keywords
    Bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisims, sepsis
    National Category
    Clinical Laboratory Medicine Microbiology in the medical area Immunology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-42421 (URN)10.1002/iid3.14 (DOI)25400921 (PubMedID)
    Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2018-11-30Bibliographically approved
    3. LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophils
    Open this publication in new window or tab >>LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophils
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-51769 (URN)
    Available from: 2016-08-24 Created: 2016-08-23 Last updated: 2018-01-10Bibliographically approved
    4. Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18
    Open this publication in new window or tab >>Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-51776 (URN)
    Available from: 2016-08-24 Created: 2016-08-24 Last updated: 2018-01-10Bibliographically approved
  • 31.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18Manuscript (preprint) (Other academic)
  • 32.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Kelly, Anne
    iRiSC-Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Karolinska University Hospital, Solna, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Demirel, Isak
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Fredlund, Hans
    iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Persson, Alexander
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent2019In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 6193186Article in journal (Refereed)
    Abstract [en]

    Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1 (IL-1), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanismpriming and licensing of inflammasome activationbut there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1 release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.

  • 33.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophilsManuscript (preprint) (Other academic)
  • 34.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Sahdo, Berolla
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Balcha, Ermias
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Swedenital, Örebro, Sweden.
    Kelly, Anne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Särndahl, Eva
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    C10X polymorphism in the CARD8 gene is associated with bacteraemia2014In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, p. 13-20Article in journal (Refereed)
    Abstract [en]

    The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

  • 35.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences. School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden; iRiSC – Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Pettersson, John H-O
    Department of Infectious Disease Epidemiology and Modelling, Norwegian Institute of Public Health, Oslo, Norway; Department of Microbiology, National Veterinary Institute, Uppsala, Sweden; Department of Medical Biochemistry and Microbiology (IMBIM), Zoonosis Science Center, Uppsala University, Uppsala, Sweden.
    Dinnetz, Patrik
    School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden.
    Andreassen, Åshild
    Department of Virology, Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Deep sequencing analysis of tick-borne encephalitis virus from questing ticks at natural foci reveals similarities between quasispecies pools of the virus2017In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 98, no 3, p. 413-421Article in journal (Refereed)
    Abstract [en]

    Every year, tick-borne encephalitis virus (TBEV) causes severe central nervous system infection in 10,000 to 15,000 people in Europe and Asia. TBEV is maintained in the environment by an enzootic cycle that requires a tick vector and a vertebrate host, and the adaptation of TBEV to vertebrate and invertebrate environments is essential for TBEV persistence in nature. This adaptation is facilitated by the error-prone nature of the virus' RNA-dependent RNA polymerase that generates genetically distinct virus variants called quasispecies. TBEV shows a focal geographical distribution pattern where each focus represents a TBEV hotspot. Here we sequenced and characterized two TBEV genomes, JP-296 and JP-554, from questing Ixodes ricinus ticks at a TBEV focus in central Sweden. Phylogenetic analysis showed geographical clustering among the newly sequenced strains and three previously sequenced Scandinavian strains, Toro-2003, Saringe-2009, and Mandal-2009, which originated from same ancestor. Among these five Scandinavian TBEV strains, only Mandal-2009 showed a large deletion within the 3´ non-coding region (NCR) similar to the highly virulent TBEV strain Hypr. Deep sequencing of JP-296, JP-554, and Mandal-2009 revealed significantly high quasispecies diversity for JP-296 and JP-554, with intact 3´NCRs, compared to the low diversity in Mandal-2009, with a truncated 3´NCR. SNP analysis showed that 40% of the SNPs were common between quasispecies populations of JP-296 and JP-554, indicating a putative mechanism for how TBEV persists and is maintained within its natural foci.

  • 36.
    Asnake, Solomon
    et al.
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Kharlyngdoh, Joubert Banjop
    Örebro University, School of Science and Technology.
    Modig, Carina
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    The brominated flame retardants TBP-AE and TBP-DBPE antagonize the chicken androgen receptor and act as potential endocrine disrupters in chicken LMH cells2015In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 29, no 8, p. 1993-2000Article in journal (Refereed)
    Abstract [en]

    Increased exposure of birds to endocrine disrupting compounds has resulted in developmental and reproductive dysfunctions. We have recently identified the flame retardants, ally1-2,4,6-tribromophenyl ether (TBP-AE), 2-3-dibromopropy1-2,4,6-tribromophenyl ether (TBP-DBPE) and the TBP-DBPE metabolite 2-bromoallyI-2,4,6-tribromophenyl ether (TBP-BAE) as antagonists to both the human androgen receptor (AR) and the zebrafish AR. In the present study, we aimed at determining whether these compounds also interact with the chicken AR. In silico modeling studies showed that TBP-AE, TBP-BAE and TBP-DBPE were able to dock into to the chicken AR ligand-binding pocket. In vitro transfection assays revealed that all three brominated compounds acted as chicken AR antagonists, inhibiting testosterone induced AR activation. In addition, qRT-PCR studies confirmed that they act as AR antagonists and demonstrated that they also alter gene expression patterns of apoptotic, anti-apoptotic, drug metabolizing and amino acid transporter genes. These studies, using chicken LMH cells, suggest that TBP-AE, TBP-BAE and TBP-DBPE are potential endocrine disrupters in chicken.

  • 37. Aspholm, Marina
    et al.
    Kalia, Awdhesh
    Ruhl, Stefan
    Schedin, Staffan
    Arnqvist, Anna
    Lindén, Sara
    Sjöström, Rolf
    Gerhard, Markus
    Semino-Mora, Cristina
    Dubois, Andre
    Unemo, Magnus
    Örebro University, Department of Clinical Medicine.
    Danielsson, Dan
    Teneberg, Susann
    Lee, Woo-Kon
    Berg, Douglas E.
    Borén, Thomas
    Helicobacter pylori adhesion to carbohydrates2006In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 417, p. 293-339Article in journal (Refereed)
    Abstract [en]

    Adherence of bacterial pathogens to host tissues contributes to colonization and virulence and typically involves specific interactions between bacterial proteins called adhesins and cognate oligosaccharide (glycan) or protein motifs in the host that are used as receptors. A given pathogen may have multiple adhesins, each specific for a different set of receptors and, potentially, with different roles in infection and disease. This chapter provides strategies for identifying and analyzing host glycan receptors and the bacterial adhesins that exploit them as receptors, with particular reference to adherence of the gastric pathogen Helicobacter pylori.

  • 38.
    Assadi, G.
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Saleh, R.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Hadizadeh, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Vesterlund, L.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bonfiglio, F.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Törkvist, L.
    Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, A. S.
    Gatroenterology Unit, Department of Internal Medicine, Sahlgren's University Hospital/Östra, Göteborg, Sweden.
    Harris, H. E.
    Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Sundberg, E.
    Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    D'Amato, M.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
    LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis2016In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 17, no 4, p. 261-264Article in journal (Refereed)
    Abstract [en]

    The function of the Laccase domain-containing 1 (LACC1) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1's link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).

  • 39.
    Athlin, Simon
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Detection of polysaccharides and polysaccharide antibodies in pneumococcal pneumonia2015Doctoral thesis, comprehensive summary (Other academic)
    List of papers
    1. The Uni-Gold™ Streptococcus pneumoniae urinary antigen test: an inter-assay comparison with the BinaxNOW® Streptococcus pneumoniae test on consecutive urine samples and evaluation on patients with bacteremia
    Open this publication in new window or tab >>The Uni-Gold™ Streptococcus pneumoniae urinary antigen test: an inter-assay comparison with the BinaxNOW® Streptococcus pneumoniae test on consecutive urine samples and evaluation on patients with bacteremia
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:oru:diva-44401 (URN)
    Available from: 2015-04-22 Created: 2015-04-22 Last updated: 2019-04-24Bibliographically approved
    2. The Binax NOW Streptococcus pneumoniae test applied on nasopharyngeal aspirates to support pneumococcal aetiology in community-acquired pneumonia.
    Open this publication in new window or tab >>The Binax NOW Streptococcus pneumoniae test applied on nasopharyngeal aspirates to support pneumococcal aetiology in community-acquired pneumonia.
    2013 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 6, p. 425-31Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: The use of nasopharyngeal secretions to enhance diagnostic yields of pneumococcal aetiology in community-acquired pneumonia (CAP) is of interest. We evaluated the Binax NOW Streptococcus pneumoniae immunochromatographic test (ICT) on nasopharyngeal aspirates (NPA) in order to support pneumococcal aetiology in CAP.

    METHODS: The NPA ICT was applied on 180 adult CAP patients and 64 healthy controls. The rate of pneumococcal detection in the nasopharynx was compared to rates for lytA polymerase chain reaction (PCR) and culture on NPA.

    RESULTS: According to blood and sputum culture and urine ICT, the test sensitivity in 59 patients with a pneumococcal aetiology was 81%. The specificity was suboptimal, with 72% negative tests among CAP patients without a pneumococcal aetiology. However, the test was positive in only 11% of patients with atypical pneumonia and in 4.7% of healthy controls. The positivity rate was higher for NPA ICT compared to culture on NPA in all CAP patients, and to both PCR and culture on NPA in non-pneumococcal non-atypical CAP patients. In 113 (63%) patients with β-lactam monotherapy, cure without treatment alteration was noted more often in cases with positive compared to negative NPA ICT at admission (91% vs 69%; p < 0.01).

    CONCLUSIONS: The high sensitivity and the low positivity rates in patients with atypical pneumonia and healthy controls, in combination with the correlation between positive test results and clinical cure with β-lactam therapy, may support a pneumococcal aetiology in CAP in populations with low pneumococcal carriage rates.

    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:oru:diva-44372 (URN)10.3109/00365548.2012.760843 (DOI)000318940400002 ()23330980 (PubMedID)2-s2.0-84877917212 (Scopus ID)
    Note

    Funding Agency: Research Committee of Orebro County Council

    Available from: 2015-04-22 Created: 2015-04-20 Last updated: 2019-04-24Bibliographically approved
    3. Clinical and microbiological factors associated with high pneumococcal colonization density in pneumococcal pneumonia
    Open this publication in new window or tab >>Clinical and microbiological factors associated with high pneumococcal colonization density in pneumococcal pneumonia
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:oru:diva-44402 (URN)
    Available from: 2015-04-22 Created: 2015-04-22 Last updated: 2019-04-24Bibliographically approved
    4. Association between serotype-specific antibody response and serotype characteristics in patients with pneumococcal pneumonia, with special reference to degree of encapsulation and invasive potential
    Open this publication in new window or tab >>Association between serotype-specific antibody response and serotype characteristics in patients with pneumococcal pneumonia, with special reference to degree of encapsulation and invasive potential
    Show others...
    2014 (English)In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 21, no 11, p. 1541-1549Article in journal (Refereed) Published
    Abstract [en]

    We studied the immunoglobulin (Ig) response to causative serotype-specific capsular polysaccharides in adult pneumococcal pneumonia patients. The serotypes were grouped according to their degree of encapsulation and invasive potential. Seventy patients with pneumococcal pneumonia, 20 of whom were bacteremic, were prospectively studied. All pneumococcal isolates from the patients were serotyped, and the Ig titers to the homologous serotype were determined in acute- and convalescent-phase sera using a serotype-specific enzyme-linked immunosorbent assay. The Ig titers were lower in bacteremic cases than in nonbacteremic cases (P < 0.042). The Ig titer ratio (convalescent/acute titer) was ≥2 in 33 patients, 1 to 1.99 in 20 patients, and <1 in 17 patients. Patients ≥65 years old had a lower median Ig titer ratio than did younger patients (P < 0.031). The patients with serotypes with a thin capsule (1, 4, 7F, 9N, 9V, and 14) and medium/high invasive potential (1, 4, 7F, 9N, 9V, 14, and 18C) had higher Ig titer ratios than did patients with serotypes with a thick capsule (3, 6B, 11A, 18C, 19A, 19F, and 23F) and low invasive potential (3, 6B, 19A, 19F, and 23F) (P < 0.05 for both comparisons after adjustment for age). Ig titer ratios of <1 were predominantly noted in patients with serotypes with a thick capsule. In 8 patients with pneumococcal DNA detected in plasma, the three patients with the highest DNA load had the lowest Ig titer ratios. In conclusion, a high antibody response was associated with serotypes with a thin capsule and medium/high invasive potential, although a low antibody response was associated with serotypes with a thick capsule and a high pneumococcal plasma load.

    Place, publisher, year, edition, pages
    American Society for Microbiology, 2014
    National Category
    Infectious Medicine Immunology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-44373 (URN)10.1128/CVI.00259-14 (DOI)000344651200011 ()25230937 (PubMedID)2-s2.0-84914697787 (Scopus ID)
    Note

    Funding Agency: Research Committee of Orebro County Council OLL-137011

    Available from: 2015-04-22 Created: 2015-04-20 Last updated: 2019-04-24Bibliographically approved
  • 40.
    Athlin, Simon
    et al.
    Örebro University Hospital.
    Kaltoft, Margit
    Statens Serum Institut, Copenhagen, Denmark.
    Slotved, Hans-Christian
    Statens Serum Institut, Copenhagen, Denmark.
    Herrmann, Björn
    Uppsala University, Uppsala, Sweden.
    Holmberg, Hans
    Örebro University Hospital.
    Konradsen, Helle Bossen
    Statens Serum Institut, Copenhagen, Denmark.
    Strålin, Kristoffer
    Örebro University Hospital, Örebro, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Association between serotype-specific antibody response and serotype characteristics in patients with pneumococcal pneumonia, with special reference to degree of encapsulation and invasive potential2014In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 21, no 11, p. 1541-1549Article in journal (Refereed)
    Abstract [en]

    We studied the immunoglobulin (Ig) response to causative serotype-specific capsular polysaccharides in adult pneumococcal pneumonia patients. The serotypes were grouped according to their degree of encapsulation and invasive potential. Seventy patients with pneumococcal pneumonia, 20 of whom were bacteremic, were prospectively studied. All pneumococcal isolates from the patients were serotyped, and the Ig titers to the homologous serotype were determined in acute- and convalescent-phase sera using a serotype-specific enzyme-linked immunosorbent assay. The Ig titers were lower in bacteremic cases than in nonbacteremic cases (P < 0.042). The Ig titer ratio (convalescent/acute titer) was ≥2 in 33 patients, 1 to 1.99 in 20 patients, and <1 in 17 patients. Patients ≥65 years old had a lower median Ig titer ratio than did younger patients (P < 0.031). The patients with serotypes with a thin capsule (1, 4, 7F, 9N, 9V, and 14) and medium/high invasive potential (1, 4, 7F, 9N, 9V, 14, and 18C) had higher Ig titer ratios than did patients with serotypes with a thick capsule (3, 6B, 11A, 18C, 19A, 19F, and 23F) and low invasive potential (3, 6B, 19A, 19F, and 23F) (P < 0.05 for both comparisons after adjustment for age). Ig titer ratios of <1 were predominantly noted in patients with serotypes with a thick capsule. In 8 patients with pneumococcal DNA detected in plasma, the three patients with the highest DNA load had the lowest Ig titer ratios. In conclusion, a high antibody response was associated with serotypes with a thin capsule and medium/high invasive potential, although a low antibody response was associated with serotypes with a thick capsule and a high pneumococcal plasma load.

  • 41.
    Axelsson, Markus
    et al.
    University of Gothenburg, Gothenburg, Sweden .
    Malmeström, Clas
    University of Gothenburg, Gothenburg, Sweden .
    Gunnarsson, Martin
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Zetterberg, Henrik
    University of Gothenburg, Mölndal, Sweden; Institute of Neurology, The University College London (UCL), London, UK.
    Sundstrom, Peter
    Umeå University, Umeå, Sweden .
    Lycke, Jan
    University of Gothenburg, Gothenburg, Sweden .
    Svenningsson, Anders
    Umeå University, Umeå, Sweden .
    Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis2014In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, no 1, p. 43-50Article in journal (Refereed)
    Abstract [en]

    Background: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression.

    Objective: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13).

    Methods: CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays.

    Results: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline.

    Conclusions: Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.

  • 42.
    Axelsson, Therese
    Örebro University, School of Medical Sciences.
    Resultat efter Menisksutur på USÖ 2006-2016 - en retrospektiv uppföljningsstudie2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 43.
    Bala, Manju
    et al.
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Singh, Vikram
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Philipova, Ivva
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden; National Reference Laboratory for Mycology and Sexually Transmitted Infections (STIs), National Center of Infections and Parasitic Diseases, Sofia, Bulgaria.
    Bhargava, Aradhana
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Chandra Joshi, Naveen
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Gentamicin in vitro activity and tentative gentamicin interpretation criteria for the CLSI and calibrated dichotomous sensitivity disc diffusion methods for Neisseria gonorrhoeae2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 7, p. 1856-1859Article in journal (Refereed)
    Abstract [en]

    Objectives: XDR Neisseria gonorrhoeae imposes the threat of untreatable gonorrhoea. Gentamicin is considered for future treatment; however, no interpretation criteria for the CLSI and calibrated dichotomous sensitivity (CDS) disc diffusion (DD) techniques are available for N. gonorrhoeae. We investigated the in vitro gentamicin activity by MIC and DD methods, proposed DD breakpoints and determined DD ranges for 10 international quality control (QC) strains.

    Methods: Gentamicin susceptibility of 333 N. gonorrhoeae isolates, including 323 clinical isolates and 10 QC strains, was determined. MIC determination (Etest) and DD methods (CLSI and CDS) were performed. The relationship between MIC, inhibition zone diameter and annular radius was determined by linear regression analysis and the correlation coefficient (r) was calculated.

    Results: Gentamicin MICs for the QC strains were within published ranges. Of the 323 clinical isolates, according to published breakpoints 75.9%, 23.5% and 0.6% were susceptible, intermediately susceptible and resistant, respectively. Based on error minimization with MICs of ≤4, 8-16 and ≥32 mg/L, breakpoints proposed are susceptible ≥16 mm, intermediately susceptible 13-15 mm and resistant ≤12 mm for the CLSI method and susceptible ≥6 mm, less susceptible 3-5 mm and resistant ≤2 mm for the CDS technique.

    Conclusions: Low resistance to gentamicin was identified and gentamicin might be a future treatment option for gonorrhoea. Tentative gentamicin zone breakpoints were defined for two DD methods and QC ranges for 10 international reference strains were established. Our findings suggest that in resource-poor settings where MIC testing is not a feasible option, the DD methods can be used to indicate gentamicin resistance.

  • 44. Balagopal, P.
    et al.
    Ljungqvist, Olle
    Dept. of Surgery, Karolinska Institute and Hospital, Stockholm, Sweden.
    Nair, K. S.
    Endocrine Research Unit, Mayo Clinic and Foundation, Rochester, MN, United States.
    Skeletal muscle heavy-chain synthesis rate in healthy humans1997In: American Journal of Physiology, ISSN 0002-9513, E-ISSN 2163-5773, Vol. 272, no 1, p. 45-50Article in journal (Refereed)
    Abstract [en]

    Mixed muscle protein synthetic rate has been measured in humans. These measurements represent the average of synthetic rates of all muscle proteins with variable rates. We determined to what extent the synthesis rate of mixed muscle protein in humans reflects that of myosin heavy chain (MHC), the main contractile protein responsible for the conversion of ATP to mechanical energy as muscle contraction. Fractional synthetic rates of MHC and mixed muscle protein were measured from the increment of [C-13]leucine in these proteins in vastus lateralis biopsy samples taken at 5 and 10 h during a primed continuous infusion of L-[1-C-13]leucine in 10 young healthy subjects. Calculations were done by use of plasma [C-13]ketoisocaproate (KIC) and muscle tissue fluid [C-13]leucine as surrogate measures of leucyl-tRNA. Fractional synthetic rate of MHC with plasma KIC (0.0299 +/- 0.0043%/h) and tissue fluid leucine (0.0443 +/- 0.0056%/h) were only 72 +/- 3% of that of mixed muscle protein (0.0408 +/- 0.0032 and 0.0603 +/- 0.0059%/h, respectively, with KIC and tissue fluid leucine). Contribution of MHC (7 +/- 1 mg . kg(-1) . h(-1)) to synthetic rates of whole body mixed muscle protein (36 +/- 5 mg . kg(-1) . h(-1)) and whole body protein (127 +/- 4 mg . kg(-1) . h(-1)) is only 18 +/- 1 and 5 +/- 1%, respectively. This relatively low contribution of MHC to whole body and mixed muscle protein synthesis warrants direct measurement of synthesis rate of MHC in conditions involving abnormalities of muscle contractile function.

  • 45.
    Bang, Charlotte Sahlberg
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Önnberg, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Dept Lab Med, Örebro University Hospital, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Medicine, Örebro University, Sweden.
    Multiresistant uropathogenic extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are susceptible to the carbon monoxide releasing molecule-2 (CORM-2).2014In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 66, p. 29-35Article in journal (Refereed)
    Abstract [en]

    Carbon monoxide (CO) releasing molecules (CO-RMs) have been shown to inhibit growth of commensal Escherichia coli (E. coli). In the present study we examined the effect of CORM-2 on uropathogenic E. coli (UPEC) that produces extended-spectrum β-lactamase (ESBL). Viability experiments showed that CORM-2 inhibited the growth of several different ESBL-producing UPEC isolates and that 500 μM CORM-2 had a bactericidal effect within 4 h. The bactericidal effect of CORM-2 was significantly more pronounced than the effect of the antibiotic nitrofurantoin. CORM-2 demonstrated a low level of cytotoxicity in eukaryotic cells (human bladder epithelial cell line 5637) at the concentrations and time-points where the antibacterial effect was obtained. Real-time RT-PCR studies of different virulence genes showed that the expression of capsule group II kpsMT II and serum resistance traT was reduced and that some genes encoding iron acquisition systems were altered by CORM-2. Our results demonstrate that CORM-2 has a fast bactericidal effect against multiresistant ESBL-producing UPEC isolates, and also identify some putative UPEC virulence factors as targets for CORM-2. CO-RMs may be candidate drugs for further studies in the field of finding new therapeutic approaches for treatment of uropathogenic ESBLproducing E. coli.

  • 46.
    Barbarroja, Nuria
    et al.
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Camargo, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Pirraco, Ana
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
    Relat, Joana
    Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
    Cuadrado, Irene
    Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
    Pellegrinelli, Vanessa
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lopez-Pedrera, Chary
    Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Tinahones, Francisco J.
    CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Biomédica de Málaga, Hospital Virgen de la Victoria, Malaga, Spain.
    Symons, J. David
    College of Health, University of Utah, Salt Lake City UT, United States; Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City UT, United States.
    Summers, Scott A.
    Program in Cardiovascular and Metabolic Disorders, Duke-National University, Singapore Graduate Medical School, Singapore, Singapore.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1180-1192Article in journal (Refereed)
    Abstract [en]

    Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

  • 47.
    Bark, Tor
    et al.
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Katouli, Mohammad
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Ljungqvist, Olle
    Örebro University, School of Medical Sciences. Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Möllby, R.
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Svenberg, Torgny E.
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Glutamine supplementation does not prevent bacterial translocation after non-lethal haemorrhage in rats1995In: European Journal of Surgery, ISSN 1102-4151, E-ISSN 1741-9271, Vol. 161, no 1, p. 3-8Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To find out whether supplementation of an enteral diet with glutamine would reduce translocation of bacteria to mesenteric lymph nodes or blood after major haemorrhage in rats.

    DESIGN:

    Open randomised study.

    SETTING:

    University departments of surgery and microbiology, Sweden.

    MATERIAL:

    49 Sprague-Dawley rats.

    INTERVENTIONS:

    Rats were fed enterally for 7 days on diets supplemented with either glutamine or an isonitrogenous amount of non-essential amino acids. After feeding, 8 experimental and 8 control rats underwent sham operation; 9 and 7, respectively, underwent moderate haemorrhage (to 65 mm Hg); and 9 and 8, respectively, underwent severe haemorrhage (50 mm Hg) without reinfusion.

    MAIN OUTCOME MEASURES:

    Microbiological analyses of samples of blood and mesenteric lymph nodes taken 24 hours after haemorrhage.

    RESULTS:

    The median (interquartile) number of colony forming units/mesenteric lymph nodes after moderate haemorrhage in animals who were given glutamine supplementation was 11 (0-34) and in control animals 20 (0-178). After severe haemorrhage the corresponding figures were 199 (10-310) and 22 (0-187). No pathogens were isolated from blood cultures.

    CONCLUSION:

    Glutamine supplementation before haemorrhage did not reduce bacterial translocation to mesenteric lymph nodes in this rat model.

  • 48.
    Bark, Tor
    et al.
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Katouli, Mohammad
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Svenberg, Torgny E.
    Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Ljungqvist, Olle
    Örebro University, School of Medical Sciences. Department of Surgery, Karolinska Hospital, Stockholm, Sweden.
    Food deprivation increases bacterial translocation after non-lethal haemorrhage in rats1995In: European Journal of Surgery, ISSN 1102-4151, E-ISSN 1741-9271, Vol. 161, no 2, p. 67-71Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To investigate whether brief fasting before the induction of hypotension by non-lethal haemorrhage may induce translocation of enteric bacteria to mesenteric lymph nodes or blood in rats.

    DESIGN:

    Laboratory experiment.

    SETTING:

    University departments of surgery and microbiology, Sweden.

    MATERIAL:

    39 Male Sprague-Dawley rats.

    INTERVENTIONS:

    20 animals were fasted for 24 hours, all 39 then underwent controlled haemorrhage for 60 minutes that reduced the blood pressure to 55 mm Hg.

    MAIN OUTCOME MEASURES:

    Differences in blood loss, blood glucose concentrations, and packed cell volume; and aerobic cultures of mesenteric lymph nodes and blood.

    RESULTS:

    Fasted rats (n = 20) lost 2.3% of blood volume compared with 2.8% in fed rats(p < 0.001). Packed cell volume dropped by 11.3% in fasted rats and 16.5% in fed rats (p < 0.001). Glucose concentrations rose by 7.0 mmol/l in fasted rats compared with 21.0 mmol/l in fed rats (p < 0.001). Mesenteric lymph nodes contained enteric bacteria in 14/20 fasted rats compared with 6/19 fed rats (p < 0.05). In 4 fasted rats blood cultures grew pathogenic bacteria compared with no fed rats (p = 0.11). The number of bacteria found in mesenteric lymph nodes was significantly greater in fasted than in fed rats (p = 0.01).

    CONCLUSIONS:

    Brief fasting before hypotension caused by non-lethal haemorrhage was associated with significantly increased bacterial translocation compared with fed animals. Increases in blood glucose concentrations and plasma refill may have had a protective effect in fed rats. These experiments may be of clinical relevance as elective operations are usually preceded by overnight fasting.

  • 49.
    Barqasho, Babilonia
    et al.
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Nowak, Piotr
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Abdurahman, Samir
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden .
    Walther-Jallow, Lillian
    Center for Infectious Medicine, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden .
    Sönnerborg, Anders
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden; Division of Infectious Diseases, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Implications of the release of high-mobility group box 1 protein from dying cells during human immunodeficiency virus type 1 infection in vitro2010In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 91, no Pt 7, p. 1800-1809Article in journal (Refereed)
    Abstract [en]

    Plasma levels of high-mobility group box 1 protein (HMGB1) are elevated during the course of human immunodeficiency virus type 1 (HIV-1) infection and the molecule has an impact on virus replication. This study investigated the mode of cell death and release of HMGB1 during HIV-1 infection in vitro. MT4 cells and primary CD4(+) T cells were infected with HIV-1 isolates, and HMGB1 release was monitored in relation to cytopathic effects (CPE) and apoptosis. HMGB1 release from cells was analysed by Western blotting. For MT4 cells, an enzyme-linked immunosorbent spot (ELISPOT) assay was adapted to measure the release during necrosis. Lactate dehydrogenase (LDH) activity was quantified using a commercial assay. Flow cytometry was used to determine the level of infection and apoptosis. MT4 cells were > or =90 % infected at 48 h post-infection (p.i.). CPE was first observed at 60 h and correlated with release of HMGB1, LDH activity and caspase-3 (C3) activation. HMGB1 spots were clearly detected by ELISPOT assay at 72 h p.i. Annexin V and C3 staining showed that apoptosis was substantially involved in HIV-1-related cell death. Addition of Z-VAD (a caspase inhibitor) in a single dose at 24 or 40 h p.i. decreased both the number of caspase-positive cells and the release of HMGB1. Infection of primary CD4(+) T cells showed a 22 % (median) infection rate at 96 h. Related CPE corresponded to LDH and HMGB1 release. Both necrosis and apoptosis contributed to HMGB1 liberation during HIV-1-induced cell death and the protein could induce tumour necrosis factor-alpha release from peripheral mononuclear blood cells. These data imply that passive HMGB1 release contributes to the excessive immune activation characteristic of HIV-1 pathogenesis.

  • 50.
    Basic, Vladimir
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Molecular mechanisms mediating development of pulmonary cachexia in COPD2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cigarette smoking (CS) represents the main causative agent underlying development and progress of COPD. Recently, involvement of CS in the pathogenesis of COPDassociated muscle abnormalities is becoming increasingly evident. Nevertheless, involved triggers and underlying mechanisms remain largely unknown. This study was conceived in order to examine effects of cigarette smoke exposure on skeletal muscle morphology, vascular supply and function. For this purpose, we have specifically designed murine COPD/emphysema model and gastrocnemius muscle was examined, while in vitro experiments were conducted using murine C2C12 skeletal muscle myocytes.

    In addition to the mild emphysematous changes present in the lungs of CS-exposed mice, our results demonstrated evident signs of muscle atrophy reflected by decreased fiber cross-sectional area, profound fiber size variation and reduced body mass. Furthermore, we have observed impairment in terminal myogenesis and lower number of myonuclei in skeletal muscles of CS-exposed animals despite evident activation of muscle repair process. Additionally, our results demonstrate capillary rarefaction in skeletal muscles of CS-exposed animals which was associated with deregulation of hypoxia-angiogenesis signaling, reduced levels of angiogenic factors such as HIF1-α and VEGF and enhanced expression of VHL and its partner proteins PHD2 and Ube2D1. The results of our in-vitro experiments demonstrated that VHL and its ubiquitination machinery can be synergistically regulated by TNF and hypoxia consequentially impairing angiogenic potential of skeletal muscle myocytes. Finally, we have shown that CS elicits chronic ER stress in murine skeletal muscles which is associated with activation of ERAD and apoptotic pathways as mirrored by elevated expression of Usp19, caspase 12 and caspase 3 in skeletal muscles of CSexposed animals. Moreover, molecular and morphological alterations in CS-exposed mice resulted in impairment of muscle function as reflected by their impaired exercise capacity.

    Taken together, from our results it is evident that cigarette smoke exposure elicits set of morphological, vascular and functional changes highly resembling those observed in COPD. Additionally, CS induces wide range of molecular alterations and signaling pathway deregulations suggesting profound effects of cigarette smoke exposure on skeletal muscle cell homeostasis.

    List of papers
    1. Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle
    Open this publication in new window or tab >>Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle
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    2012 (English)In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 303, no 6, p. L519-L527Article in journal (Refereed) Published
    Abstract [en]

    Cigarette smoke (CS) is a well established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance a mouse model of CS exposure was used. The129/SvJ mice were exposed to CS for 6 months, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1) and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1 (HIF1-α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading towards impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area and decreased exercise tolerance.

    Place, publisher, year, edition, pages
    Bethesda, USA: American Physiological Society, 2012
    Keywords
    Capillaries, chronic obstructive pulmonary disease, hypoxia inducible factor-1 alpha, pulmonary cachexia syndrome, vascular endothelial growth factor
    National Category
    Medical and Health Sciences Physiotherapy
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-24177 (URN)10.1152/ajplung.00007.2012 (DOI)000309109300005 ()22842216 (PubMedID)2-s2.0-84866418091 (Scopus ID)
    Funder
    NIH (National Institute of Health)
    Note

    Funding Agencies:

    Olle Engkvist Byggmastare Fund, Sweden

    NIEHS Environmental Health Science Center grant 

    Available from: 2012-07-31 Created: 2012-07-31 Last updated: 2018-05-09Bibliographically approved
    2. Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.
    Open this publication in new window or tab >>Chronic cigarette smoke exposureimpairs skeletal muscle regenerative capacity in murineCOPD/emphysema model.
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Cigarette smoke (CS) is a well established risk factor in the development of COPD and irreversible airflow limitation. In contrast, the extent to which CS exposure contributes to development of peripheral skeletal muscle dysfunction and wasting remains largely unknown. Decline in skeletal muscle regenerative capacity has been previously reported in COPD patients.

    Methods: To investigate effects of chronic CS exposure on skeletal muscle regenerative capacity, 129/SvJ mice were exposed to CS for 6 months. The expression levels of myogenin, Jarid2, Znf496, Notch1, Pax7, Fgf1 and Myh3, which are known to regulate skeletal muscle myogenesis, were studied. Additionally, number of fibers with central nuclei, myonuclei number and mean fiber cross-sectional area were assessed.

    Results: Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly decreased expression of Jarid2, coupled with enhanced expression of Znf496, Notch1, Pax7, Fgf1 and Myh3. Expression of myogenin, a marker of terminally differentiated myofibers, was reduced. Furthermore, reduced muscle fiber crosssectional area, increased number of fibers with central nuclei and reduced myonuclei number were also observed in CS-exposed animals.

    Conclusions: Taken together, current results provide evidence linking chronic CS exposure and an ongoing damage/repair process as well as impaired regenerative capacity in skeletal muscles of CS-exposed mice.

    Keywords
    cigarette smoke, chronic obstructive pulmonary disease, skeletal muscle dysfunction, skeletal muscle regeneration
    National Category
    Otorhinolaryngology
    Research subject
    Oto-Rhino-Laryngology
    Identifiers
    urn:nbn:se:oru:diva-38189 (URN)
    Note

    Funding and support:

    Olle Engkvist Byggmästare Fund,

    Åke WibergFoundation, Sweden

    and the research funds of the Department of Medicine,Danderyd Hospital, Stockholm(to S.M.A-H),

    Örebro university grant to doctoralsstudents (We thank the Developmental Studies Hybridoma Bank (DSHB, Universityof Iowa, IA, USA)) for antibody against Pax7

    Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-10-17Bibliographically approved
    3. TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
    Open this publication in new window or tab >>TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
    2014 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, no 1, p. 228-236Article in journal (Refereed) Published
    Abstract [en]

    Decreased skeletal muscle capillarization is considered to significantly contribute to the development of pulmonary cachexia syndrome (PCS) and progressive muscle wasting in several chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). It is unclear to which extent the concurrent presence of systemic inflammation contributes to decreased skeletal muscle capillarization under these conditions. The present study was designed to examine in vitro the effects of the pro-inflammatory cytokine, tumor necrosis factor (TNF), on the regulation of hypoxia-angiogenesis signal transduction and capillarization in skeletal muscles. For this purpose, fully differentiated C2C12 skeletal muscle myocytes were stimulated with TNF and maintained under normoxic or hypoxic conditions. The expression levels of the putative elements of the hypoxia-angiogenesis signaling cascade were examined using qPCR, western blot analysis and immunofluorescence. Under normoxic conditinos, TNF stimulation increased the protein expression of anti-angiogenic von-Hippel Lindau (VHL), prolyl hydroxylase (PHD)2 and ubiquitin conjugating enzyme 2D1 (Ube2D1), as well as the total ubiquitin content in the skeletal muscle myocytes. By contrast, the expression levels of hypoxia-inducible factor 1‑α (HIF1-α) and those of its transcriptional targets, vascular endothelial growth factor (VEGF)A and glucose transporter 1 (Glut1), were markedly reduced. In addition, hypoxia increased the expression of the VHL transcript and further elevated the VHL protein expression levels in C2C12 myocytes following TNF stimulation. Consequently, an impaired angiogenic potential was observed in the TNF-stimulated myocytes during hypoxia. In conclusion, TNF increases VHL expression and disturbs hypoxia-angiogenesis signal transduction in skeletal muscle myocytes. The current findings provide a mechanism linking systemic inflammation and impaired angiogenesis in skeletal muscle. This is particularly relevant to further understanding the mechanisms mediating muscle wasting and cachexia in patients with chronic inflammatory diseases, such as COPD.

    Place, publisher, year, edition, pages
    Spandidos Publications, 2014
    National Category
    Medical Biotechnology
    Research subject
    Medical Disability Research
    Identifiers
    urn:nbn:se:oru:diva-35141 (URN)10.3892/ijmm.2014.1776 (DOI)000338178000027 ()24820910 (PubMedID)2-s2.0-84902649801 (Scopus ID)
    Available from: 2014-05-25 Created: 2014-05-25 Last updated: 2018-06-07Bibliographically approved
    4. Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
    Open this publication in new window or tab >>Cigarette smoke exposure up-regulates Ubiquitin specific protease 19 in murine skeletal muscles as an adaptive response to prolonged ER stress
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Enhanced protein degradation via ubiquitin proteolytic system (UPS) was demonstrated to play an important role in the pathogenesis of cachexia syndrome and muscle wasting in patients with COPD and animal models of the disease. The role of cigarette smoke (CS) exposure in eliciting these abnormalities remains largely unknown. Usp19 is a member of UPS suggested to be involved in progressive muscle wasting in different catabolic conditions. However, factors regulating Usp19 expression, activity and correlation/s with CS-induced muscle atrophy remainunclear.

    Methods: To address these questions, 129 SvJ mice were exposed to cigarette smoke for 6 months and the gastrocnemius muscles were collected. Expression levels of Usp19 as well as pivotal mediators of ER stress response have been studied using PCR, qPCR, western blot and immunofluorescence. Factors regulating muscle Usp19 expression were studied using in-silico analysis of Usp19 promoter as well as by stimulating C2C12 myocytes with different inducers of ER stress including hypoxia, TNF and tunicamycin. Finally, Usp19 expression was depleted in C2C12 myocytes using specific Usp19 siRNA quadriplex and the expression of pivotal myogenic regulators were analyzed.

    Results: Usp19 mRNA expression was enhanced in skeletal muscles of CS-exposed mice. Concurrently, ER stress-associated Caspase 12 and Caspase 3 were activated in the CS-exposed group. Analysis of Usp19 promoter sequence revealed binding sites for ER stress response transcription factors such as HSF, STRE1 and AML1-α. Exposure of C2C12 myocytes to tunicamycin but not hypoxia elevated expression levels of Usp19. TNFstimulation elevated Usp19 protein expression but inhibited its RNA transcription in a dose- and time-dependent manner. Finally, Usp19 overexpression in tunicamycin-treated myocytes was accompanied by reduced expression of myosin heavy chain and tropomyosin and their levels were increased after knocking down Usp19 in C2C12 myocytes.

    Conclusions: In summary, our data demonstrated elevated expression of Usp19 in skeletal muscles of CS-exposed 129 SvJ mice. Moreover, Usp19 overexpression was associated with muscle adaptations to ER stress and suppression of myogenesis. Taken together; our results might provide further insight into molecular mechanisms underlying development and progression of skeletal muscle abnormalities in response to chronic cigarette smoke exposure.

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-38194 (URN)
    Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-10-17Bibliographically approved
    5. The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
    Open this publication in new window or tab >>The periodontal pathogen Porphyromonas gingivalis changes the gene expression in vascular smooth muscle cells involving the TGFbeta/Notch signalling pathway and increased cell proliferation
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    2013 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 770-Article in journal (Refereed) Published
    Abstract [en]

    Background: Porphyromonas gingivalis is a gram-negative bacterium that causes destructive chronic periodontitis. In addition, this bacterium is also involved in the development of cardiovascular disease. The aim of this study was to investigate the effects of P. gingivalis infection on gene and protein expression in human aortic smooth muscle cells (AoSMCs) and its relation to cellular function.

    Results: AoSMCs were exposed to viable P. gingivalis for 24 h, whereafter confocal fluorescence microscopy was used to study P. gingivalis invasion of AoSMCs. AoSMCs proliferation was evaluated by neutral red assay. Human genome microarray, western blot and ELISA were used to investigate how P. gingivalis changes the gene and protein expression of AoSMCs. We found that viable P. gingivalis invades AoSMCs, disrupts stress fiber structures and significantly increases cell proliferation. Microarray results showed that, a total of 982 genes were identified as differentially expressed with the threshold log2 fold change >|1| (adjust p-value <0.05). Using bioinformatic data mining, we demonstrated that up-regulated genes are enriched in gene ontology function of positive control of cell proliferation and down-regulated genes are enriched in the function of negative control of cell proliferation. The results from pathway analysis revealed that all the genes belonging to these two categories induced by P. gingivalis were enriched in 25 pathways, including genes of Notch and TGF-beta pathways.

    Conclusions: This study demonstrates that P. gingivalis is able to invade AoSMCs and stimulate their proliferation. The activation of TGF-beta and Notch signaling pathways may be involved in the bacteria-mediated proliferation of AoSMCs. These findings further support the association between periodontitis and cardiovascular diseases.

    Keywords
    Porphyromonas gingivalis, Aortic smooth muscle cells, Proliferation, Gene expression profiling
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:oru:diva-33287 (URN)10.1186/1471-2164-14-770 (DOI)000328639800002 ()24209892 (PubMedID)2-s2.0-84887327838 (Scopus ID)
    Funder
    Swedish Research Council, 2008-2459Swedish Heart Lung Foundation, 2011-0632
    Note

    Funding Agency: Foundation of Olle Engkvist; Foundation of Mats Kleberg (se även Forskningsfinansiär)

    Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2018-01-11Bibliographically approved
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