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  • 1.
    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, 3737-3744 p.Article 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.

  • 2.
    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, 519-532 p.Article 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.

  • 3.
    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, 1993-2000 p.Article 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.

  • 4.
    Bastami, Salumeh
    et al.
    Unit for Development and Patient Safety, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Gupta, Anil
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Anesthesia and Intensive Care, Örebro University, Örebro, Sweden.
    Zackrisson, Anna-Lena
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Ahlner, Johan
    Unit for Development and Patient Safety, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden .
    Osman, Abdimajid
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Uppugunduri, Srinivas
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Influence of UGT2B7, OPRM1 and ABCB1 Gene Polymorphisms on Postoperative Morphine Consumption2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 5, 423-431 p.Article in journal (Refereed)
    Abstract [en]

    Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in both effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7,OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine-induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsies as morphine is also a very commonly abused drug. Blood samples were collected from 40 patients following abdominal hysterectomy, 24hr after initiation of analgesia through a patient-controlled analgesia (PCA) pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsies found positive for morphine in routine forensic analysis. Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. The dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood. Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients. We conclude that gene polymorphisms contribute significantly to the variation in morphine concentrations observed in individual patients.

  • 5.
    Burkill, Sarah
    et al.
    Centre for Pharmocoepodemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
    Iacobaeus, Ellen
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, Shahram
    Centre for Pharmocoepodemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
    Brundin, Lou
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Fored, Michael
    Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Clinical Epidemology and Biostatistics .
    Pharmacological Treatments Preceding Diagnosis Of Progressive Multifocal Leukencephalopathy2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, 496-497 p.Article in journal (Other academic)
    Abstract [en]

    Background: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, which is present in most people and is usually harm-less. For immunocompromised persons, such as those who are taking immunosuppressive treatments, the risk of JC virus causing PML is increased, although still rare. As PML diagnosis is not always accurate, epidemiology of PML, including the true incidence and patient characteristics, is incompletely described.

    Objectives: To identify pharmacological treatments preceding diagnosis of definitive, probable and possible PML, after excluding incorrect PML diagnoses by medical record review.

    Methods: Patients with a PML diagnosis in Sweden between 1988 and 2013 were identified through the Patient register using ICD 9 code 046D and ICD 10code A81.2 (n = 281). Medical records were reviewed and information on clinical characteristics and pharmacological treatments were collected. Each of the diagnoses was determined as definite PML, possible PML, probable PML or non-PML based on the consensus statement for the AAN neuroinfectious disease section published in 2013. (PMCID: 3662270).

    Results: Medical records for 251 patients (89%) were available and examined. In total, 84 (33%) of the 251 PML diagnoses were confirmed. For those with a record of being exposed to immunosuppressant drugs, 60 (65%) of the 92 records were confirmed as being definite PML. Among 12 patients exposed to rituximab 11 (92%) had definite and 1 (8%) had probable PML. For the 9 natalizumab users, 8 (89%) had definite PML and 1 (11%) was diagnosed incorrectly.

    Conclusions: A substantial proportion of PML diagnoses recorded in Sweden are incorrect, however amongst those exposed to immunosuppressants such as rituximab and natalizumab the majority of diagnoses are correct. Assessing immunosuppressive drug history could be an important part of the diagnostic processes for PML.

  • 6.
    Chen, Shao-Chun
    et al.
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    Yin, Yue-Ping
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    Dai, Xiu-Qin
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology.
    Chen, Xiang-Sheng
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    First nationwide study regarding ceftriaxone resistance and molecular epidemiology of Neisseria gonorrhoeae in China2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 1, 92-99 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern worldwide. This is the first nationwide study, performed within the China Gonococcal Antimicrobial Susceptibility Programme (China-GASP), regarding AMR, including ceftriaxone genetic resistance determinants, and molecular epidemiology of gonococci in China.

    Methods: Gonococcal isolates (naEuroS=aEuroS1257) from consecutive patients were collected at 11 sentinel sites distributed across China during 2012-13. Susceptibility to ceftriaxone, spectinomycin, ciprofloxacin and tetracycline was determined using the agar dilution method. Ceftriaxone resistance determinants penA and penB were examined using sequencing. N. gonorrhoeae multiantigen sequence typing (NG-MAST) was performed for molecular epidemiology.

    Results: Among isolates, 0.2% were resistant to spectinomycin, 4.4% to ceftriaxone, 42.9% to tetracyclines (high-level resistance) and 99.8% to ciprofloxacin. Among 890 sequenced isolates, 16 (1.8%) possessed a penA mosaic allele; 4 of these isolates belonged to the MDR internationally spread NG-MAST genogroup G1407 (first description in China). Non-mosaic penA alleles with an A501T mutation and an A102D alteration in porB1b were statistically associated with decreased susceptibility/resistance to ceftriaxone. NG-MAST G10339, G1424 and G1053 were associated with decreased susceptibility/resistance to ceftriaxone.

    Conclusions: In China, ceftriaxone and spectinomycin can continue to be recommended for gonorrhoea treatment, with the possible exception of Hainan and Sichuan provinces where ceftriaxone resistance exceeded 5% and AMR surveillance needs to be strengthened. Molecular approaches including genotyping and AMR determinant analysis can be valuable to supplement and enhance conventional surveillance of gonococcal AMR in China.

  • 7.
    Elvers, Margitta
    et al.
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Grenegård, Magnus
    University of Linköping, Faculty of Health Sciences, Department of Medicine and Health, Division of Drug Research/Pharmacology.
    Khoshjabinzadeh, Hanieh
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping.
    Münzer, Patrick
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Borst, Oliver
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany; Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Tian, Huasong
    Columbia University Medical Center, Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, USA.
    Di Paolo, Gilbert
    Columbia University Medical Center, Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, USA.
    Lang, Florian
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Gawaz, Meinrad
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Lindahl, Tomas L
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping.
    Fälker, Knut
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping.
    A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity2012In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, no 9, 1743-52 p.Article in journal (Refereed)
    Abstract [en]

    Platelet aggregation, secretion and thrombus formation play a critical role in primary hemostasis to prevent excessive blood loss. On the other hand, uncontrolled platelet activation leads to pathological thrombus formation resulting in myocardial infarction or stroke. Stimulation of heterotrimeric G-proteins by soluble agonists or immunoreceptor tyrosine based activation motif-coupled receptors that interact with immobilized ligands such as the collagen receptor glycoprotein (GP) VI lead to the activation of phospholipases that cleave membrane phospholipids to generate soluble second messengers. Platelets contain the phospholipases (PL) D1 and D2 which catalyze the hydrolysis of phosphatidylcholine to generate the second messenger phosphatidic acid (PA). The production of PA is abrogated by primary alcohols that have been widely used for the analysis of PLD-mediated processes. However, it is not clear if primary alcohols effectively reduce PA generation or if they induce PLD-independent cellular effects. In the present study we made use of the specific PLD inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) and show for the first time, that FIPI enhances platelet dense granule secretion and aggregation of human platelets. Further, FIPI has no effect on cytosolic Ca(2+) activity but needs proper Rho kinase signaling to mediate FIPI-induced effects on platelet activation. Upon FIPI treatment the phosphorylation of the PKC substrate pleckstrin was prominently enhanced suggesting that FIPI affects PKC-mediated secretion and aggregation in platelets. Similar effects of FIPI were observed in platelets from mouse wild-type and Pld1(-/-) mice pointing to a new role for PLD2 as a negative regulator of platelet sensitivity.

  • 8.
    Ericsson, Elisabeth
    et al.
    Avd. f omvårdnad, Institutionen för medicin och hälsa, Linköpings universitet, Linköping.
    Brattwall, Metha
    Anestesi och intensivvårdskliniken, Sahlgrenska Universitetssjukhuset/Mölndal, Mölndal.
    Lundeberg, Stefan
    Smärtbehandlingsenheten, Astrid Lindgrens Barnsjukhus, Stockholm.
    Farmakologisk behandling av smärta och illamående i samband med tonsillotomi och tonsillektomi på barn och ungdomar2013In: Nationellt kvalitetsregister Öron-, Näs- och Halssjukvård: Årsrapport 2012, Hisings Backa: Nationellt kvalitetsregister för öron-, näs- och halssjukvård , 2013, 64-71 p.Chapter in book (Other academic)
    Abstract [sv]

    Premedicinering kan göras enligt sjukhusets vanliga rutiner. En möjlig kombination som oral premedicinering (= start av multimodal smärtbehandling) är paracetamol (40 mg/kg), klonidin (2–3 mikrog/kg) och betametason (0,2 mg/kg, max 8 mg) enligt kroppsvikt eller 4 mg vid vikt under 50 kg, 8 mg vid vikt över 50 kg som ges cirka 90 minuter innan anestesistart.

    Alternativt ges ovanstående läkemedel i samband med inledningen av anestesin men med doseringsförslag som anges under smärtbehandling per operativt nedan.

    Smärtbehandling peroperativt

    Paracetamol bör ges intravenöst (20 mg/kg) och intravenöst betametason (0,2 mg(kg) om inte det ingått i premedicineringen. Vid slutet av operationen ges en dos av COX hämmare (diklofenak 1 mg/kg rektalt eller intravenöst, alternativt ibuprofen 5–7 mg/kg rektalt). Om klonidin inte givits som premedicinering kan en intravenös dos ges vid inledningen av anestesin, 1 mikrog/kg intravenöst. Med klonidin kan övriga underhållsanestetika ofta reduceras med cirka 25%. För att minska den tidiga smärtan kan också kompresser indränkta med bupivacain 5 mg/ml läggas på sårområdet i cirka 5 minuter.

    Initial postoperativ smärta behandlas med intravenösa opioider, paracetamol och klonidin titrerat till för individen acceptabel smärtnivå. Smärtskattning ska göras med ålderadekvat instrument.

    Illamående, profylax och behandling

    I samband med anestesiinledningen ges betametason samt vid indikation ondansetron 0,1 mg/kg för att förbygga postoperativt illamående. Behandling kan ske med ondansetron 0,1 mg/kg, prometazin 0,1 mg/kg (licenspreparat) eller droperidol 30 mikrog/kg. En kombination av antiemetika ger bättre effekt. En fördel är att inducera anestesin med propofol om intravenös infart finns.

    Smärtbehandling i hemmet

    Paracetamol 24 mg/kg x 4 i tre dygn och därefter minska till 18 mg/kg x 4 (paracetamolmixturen är 24 mg/ml vilket innebär att den initiala behandlingen blir 1 ml/kg x 4 om mixturen används). Kombinera paracetamol med COXhämmare ibuprofen 5–7mg/kg x 4 eller diklofenak 1–1,5 mg/kg x 3. Vid blödningsrisk kan selektiv COX-2 hämmare användas, celecoxib 2 mg/kg x 2, som alternativ till ibuprofen och diklofenak. COX hämmare och paracetamol utgör basen i analgetikabehandlingen och ska ges regelbundet.

    För ytterligare smärtbehandling kan t. ex klonidin ges i dosen 1–2 mikrog/kg x 3 per os. Opioider kan behövas i vissa fall men insättning bör göras efter kontakt med ÖNH kliniken. Ur praktisk synvinkel rekommenderas att doser av klonidin- eller opioidmixtur (oxikodon eller morfin) dras upp i sprutor med engångsdoser när analgetika skickas med vid utskrivningen. Antalet doser som skickas hem med patienten bestäms av behovet och lokala rutiner. När smärtan avklingar kan man börja sätta ut analgetika: först opioider, därefter klonidin, paracetamol och sist COX hämmare. (Enstaka doser av COX hämmare ger en bättre analgetisk effekt än enstaka doser av paracetamol).

    Smärtbehandling kan behövas upp till 2–3 veckor efter tonsillektomi, och drygt en vecka efter tonsillotomi. Vid tonsillotomi räcker det oftast med paracetamol kombinerat med COX-hämmare. Som förslag i nationella riktlinjer föreslås en behandlingslängd med COX-hämmare i kombination med paracetamol i 3–5 dygn vid tonsillotomi och 5–8 dygn vid tonsillektomi.

  • 9.
    Eriksson, Carl
    et al.
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Cao, Yang
    Örebro University, School of Medical Sciences. Örebro University Hospital. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden; Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Rundquist, Sara
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Zhulina, Yaroslava
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Gastroenterology.
    Henriksson, I.
    Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Editorial: do thiopurines and biologics decrease the risk of colectomy? Authors' reply2017In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 46, no 9, 897-898 p.Article in journal (Other academic)
  • 10.
    Everhov, A. H.
    et al.
    Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Olén, O.
    Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of paediatric gastroenterology and nutrition, Sachs’ Children and Youth Hospital, Stockholm, Sweden.
    Ludvigsson, Jonas F
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York NY, United States.
    Editorial: importance of definition of inflammatory bowel disease and an increased incidence in children2017In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 45, no 10, 1369-1370 p.Article in journal (Refereed)
    Abstract [en]

    No abstract is available for this article.

  • 11.
    Foerster, Sunniva
    et al.
    Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University, Örebro, Sweden; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
    Desilvestro, Valentino
    World Trade Institute (WTI), University of Bern, Bern, Switzerland.
    Hathaway, Lucy J
    Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
    Althaus, Christian L
    Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University, Örebro, Sweden.
    A new rapid resazurin-based microdilution assay for antimicrobial susceptibility testing of Neisseria gonorrhoeae2017In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 7, 1961-1968 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: Rapid, cost-effective and objective methods for antimicrobial susceptibility testing of Neisseria gonorrhoeae would greatly enhance surveillance of antimicrobial resistance. Etest, disc diffusion and agar dilution methods are subjective, mostly laborious for large-scale testing and take ∼24 h. We aimed to develop a rapid broth microdilution assay using resazurin (blue), which is converted into resorufin (pink fluorescence) in the presence of viable bacteria.

    Methods: The resazurin-based broth microdilution assay was established using 132 N. gonorrhoeae strains and the antimicrobials ceftriaxone, cefixime, azithromycin, spectinomycin, ciprofloxacin, tetracycline and penicillin. A regression model was used to estimate the MICs. Assay results were obtained in ∼7.5 h.

    Results: The EC 50 of the dose-response curves correlated well with Etest MIC values (Pearson's r  = 0.93). Minor errors resulting from misclassifications of intermediate strains were found for 9% of the samples. Major errors (susceptible strains misclassified as resistant) occurred for ceftriaxone (4.6%), cefixime (3.3%), azithromycin (0.6%) and tetracycline (0.2%). Only one very major error was found (a ceftriaxone-resistant strain misclassified as susceptible). Overall the sensitivity of the assay was 97.1% (95% CI 95.2-98.4) and the specificity 78.5% (95% CI 74.5-82.9).

    Conclusions: A rapid, objective, high-throughput, quantitative and cost-effective broth microdilution assay was established for gonococci. For use in routine diagnostics without confirmatory testing, the specificity might remain suboptimal for ceftriaxone and cefixime. However, the assay is an effective low-cost method to evaluate novel antimicrobials and for high-throughput screening, and expands the currently available methodologies for surveillance of antimicrobial resistance in gonococci.

  • 12.
    Fälker, Knut
    et al.
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Haglund, Linda
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Gunnarsson, Peter
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Nylander, Martina
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Lindahl, Tomas L
    Department of Clinical and Experimental Medicine, University of Linköping, University Hospital, Linköping, Sweden.
    Grenegård, Magnus
    Department of Medical and Health Sciences, University of Linköping, University Hospital, Linköping, Sweden.
    Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets2011In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 436, no 2, 469-480 p.Article in journal (Refereed)
    Abstract [en]

    PARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both G(α12/13) and G(αq) signalling. By applying the specific PAR1- and PAR4-activating hexapeptides, SFLLRN and AYPGKF respectively, we found that aggregation of isolated human platelets mediated via PAR1, but not via PAR4, is abolished upon homologous receptor activation in a concentration- and time-dependent fashion. This effect was not due to receptor internalization, but to a decrease in Ca²⁺ mobilization, PKC (protein kinase C) signalling and α-granule secretion, as well as to a complete lack of dense granule secretion. Interestingly, subthreshold PAR4 activation rapidly abrogated PAR1 signalling desensitization by differentially reconstituting these affected signalling events and functional responses, which was sufficient to re-establish aggregation. The lack of ADP release and P2Y₁₂ receptor-induced G(αi) signalling accounted for the loss of the aggregation response, as mimicking G(αi/z) signalling with 2-MeS-ADP (2-methylthioadenosine-5'-O-diphosphate) or epinephrine (adrenaline) could substitute for intermediate PAR4 activation. Finally, we found that the re-sensitization of PAR1 signalling-induced aggregation via PAR4 relied on PKC-mediated release of both ADP from dense granules and fibrinogen from α-granules. The present study elucidates further differences in human platelet PAR signalling regulation and provides evidence for a cross-talk in which PAR4 signalling counteracts mechanisms involved in PAR1 signalling down-regulation.

  • 13.
    Fälker, Knut
    et al.
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    Lange, Danica
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    Presek, Peter
    Martin-Luther-University, Halle-Wittenberg, Halle, Germany .
    ADP secretion and subsequent P2Y12 receptor signalling play a crucial role in thrombin-induced ERK2 activation in human platelets2004In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 92, no 1, 114-23 p.Article in journal (Refereed)
    Abstract [en]

    Stimulating human platelets with thrombin induces the activation of the extracellular signal-regulated kinase 2 (ERK2). We demonstrate that this effect is highly dependent on ADP secretion and P2Y12 receptor signalling. AR-C69931MX (10 microM), a specific antagonist of the Gi-coupled P2Y12 ADP receptor, inhibits ERK2 activation induced by thrombin. Antagonists of the Gq-coupled P2Y1 ADP receptor, A3P5P (500 microM) and MRS2179 (100 microM), have no effect. ADP and its more potent analogue 2-methylthio-ADP alone (both up to 100 microM) do not induce ERK2 activation. Furthermore, we show that the inhibitory effect of AR-C69931MX on ERK2 activation induced by 0.1 U/ml thrombin as well as on platelet aggregation can be bypassed by epinephrine (1 and 10 microM), whereas epinephrine alone has no effect. Epinephrine acts on platelets mainly via alpha(2A)-adrenergic receptors, which, like P2Y12 receptors, couple to inhibitory G proteins. In addition, 2-methylthio-ADP as well as epinephrine provoke ERK2 activation at a thrombin concentration that alone has no detectable effect (0.05 U/ml). Thromboxane A2 (TXA2), which, like ADP, is released by activated platelets, acts as a positive feedback mediator. Stimulating the Gq-coupled TXA2 -receptor with U46619 (10 microM), which leads to ADP secretion and P2Y12 receptor-dependent platelet aggregation, also induces P2Y12-related ERK2 activation. The inhibition of U46619-induced ERK2 activation and platelet aggregation by AR-C69931MX are also rescued by epinephrine. Pretreatment with aspirin inhibits ERK2 activation induced by 0.1 U/ml thrombin, but has no effect at high concentrations of thrombin. The combination of U46619 and thrombin, at concentrations which alone have no effect, provokes ERK2 activation, suggesting that thrombin and released TXA2 act synergistically. Our data indicate that both primary signalling through Gq, which evokes ADP secretion, as well as subsequent coupling via Gi by the P2Y12 receptor are required for ERK2 activation.

  • 14.
    Fälker, Knut
    et al.
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    Lange, Danica
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    Presek, Peter
    Martin-Luther-University Halle-Wittenberg, Faculty of Medicine, Department of Pharmacology and Toxicology, Halle, Germany .
    P2Y12 ADP receptor-dependent tyrosine phosphorylation of proteins of 27 and 31 kDa in thrombin-stimulated human platelets2005In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 93, no 5, 880-888 p.Article in journal (Refereed)
    Abstract [en]

    In thrombin-stimulated human platelets several proteins undergo rapid and transient changes in tyrosine phosphorylation. We demonstrate that a set of proteins of 27, 29, 31, 34, and 39 kDa is affected by released ADP and P2Y12 receptor signaling during platelet activation. AR-C69931MX, an antagonist of the Gi(2)-coupled P2Y12 ADP receptor, inhibits initial tyrosine phosphorylation of p27 and p31 and prevents subsequent dephosphorylation of p29, p34, and p39. Antagonists of the Gq-coupled P2Y1 ADP receptor have no effect. Precluding integrin alpha(IIb)beta(3) outside-in signaling with RGDS or S1197 does not affect the increase in tyrosine phosphorylation of the set of proteins but inhibits their subsequent dephosphorylation. Besides the ADP analogue 2-MeS-ADP, other platelet agonists such as collagen and the TXA(2)-mimetic U46619 also induce p27 and p31 tyrosine phosphorylation in a P2Y12 receptor-dependent manner. Tyrosine phosphorylation of p27 and p31 in response to collagen, but not thrombin, is prevented by aspirin and the TXA(2) receptor antagonist SQ29548, indicating that the effect of collagen strongly relies on TXA(2) signaling. Furthermore, epinephrine, acting via inhibitory Gz-coupled alpha(2A)-adrenoceptors, bypasses the inhibitory effect of AR-C69931MX on thrombin-induced p27 and p31 tyrosine phosphorylation. Finally, we demonstrate that tyrosine phosphorylation of p27 and p31 downstream of P2Y12 receptors is due to the inhibition of adenylyl cyclase but not phosphoinositide 3-kinase (PI 3-K) activation. Elevating cAMP levels with PGI(2) or forskolin precludes thrombin-induced p27 and p31 tyrosine phosphorylation. Moreover, direct inhibition of adenylyl cyclase by SQ22536 reverses the effect of AR-C69931MX. Our data indicate that the observed changes in tyrosine phosphorylation are the result of both primary Gq signaling, initiating the release of ADP, as well as subsequent P2Y12 receptor-mediated Gi coupling.

  • 15.
    Ginsberg, Ylva
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    ADHD and criminality: could treatment benefit prisoners with ADHD who are at higher risk of reoffending?2013In: Expert Review of Neurotherapeutics, ISSN 1473-7175, E-ISSN 1744-8360, Vol. 13, no 4, 345-348 p.Article in journal (Refereed)
  • 16.
    Ginsberg, Ylva
    et al.
    Division of Psychiatry, Department of Clinical Neuroscience, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lindefors, Nils
    Division of Psychiatry, Department of Clinical Neuroscience, Stockholm, Sweden.
    Long-Term Treatment Outcome in Adult Male Prisoners With Attention-Deficit/Hyperactivity Disorder: Three-Year Naturalistic Follow-Up of a 52-Week Methylphenidate Trial2015In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 35, no 5, 535-543 p.Article in journal (Refereed)
    Abstract [en]

    Despite high rates of attention-deficit/hyperactivity disorder (ADHD) among adult lawbreakers, particularly the long-term effects of ADHD pharmacotherapy remain unclear, not the least because of ethical challenges with preventing control subjects in randomized controlled trials from receiving medication over prolonged time. We followed up adult male prisoners with ADHD who completed a 5-week randomized, double-blind, placebo-controlled trial followed by a 47-week open-label extension of osmotic-release oral system methylphenidate in a Swedish high-security prison from 2007 to 2010 (ClinicalTrials.gov: NCT00482313). Twenty-five trial completers were prospectively followed up clinically 1 year (24/25, 96% participated fully or in part) and 3 years (20/25, 80% participation) after trial regarding ADHD symptoms (observer and self-reports), psychosocial functioning, substance misuse, and criminal reoffending. Methylphenidate-related improvements in ADHD symptoms and psychosocial functioning obtained during the 52-week trial were maintained at 1- and 3-year follow-ups. Specifically, after 3 years, 75% (15/20) of the respondents had been released from prison, and 67% of these (10/15) had employment, usually full time. In contrast, nonmedicated respondents at the 3-year follow-up (5/20) reported more ADHD symptoms, functional impairment, and substance misuse compared with currently medicated respondents (15/20). Further, 40% of the respondents self-reported reoffending, indicating a substantially lower relapse rate than expected (70%-80%).In summary, although these observations need validation from new and larger samples, positive effects were maintained after 4 years of methylphenidate treatment. Most study completers were employed and had no relapse in substance misuse or criminality. These results suggest that motivational support and continued medication are important for improved outcome in adult criminal offenders with ADHD.

  • 17.
    Golparian, Daniel
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fernandes, Prabhavathi
    Cempra Pharmaceuticals, Inc., Chapel Hill NC, United States.
    Ohnishi, Makoto
    National Institute of Infectious Diseases, Tokyo, Japan.
    Jensen, Jörgen S
    Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology.
    In vitro activity of the new fluoroketolide solithromycin (CEM-101) against a large collection of clinical Neisseria gonorrhoeae isolates and international reference strains, including those with high-level antimicrobial resistance: potential treatment option for gonorrhea?2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 5, 2739-2742 p.Article in journal (Refereed)
    Abstract [en]

    Gonorrhea may become untreatable, and new treatment options are essential. We investigated the in vitro activity of the first fluoroketolide, solithromycin. Clinical Neisseria gonorrhoeae isolates and reference strains (n = 246), including the two extensively drug-resistant strains H041 and F89 and additional isolates with clinical cephalosporin resistance and multidrug resistance, were examined. The activity of solithromycin was mainly superior to that of other antimicrobials (n = 10) currently or previously recommended for gonorrhea treatment. Solithromycin might be an effective treatment option for gonorrhea.

  • 18.
    Goswami, Manish
    et al.
    Molecular Biology Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India; The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden .
    Subramanian, Mahesh
    Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India.
    Kumar, Ranjeet
    The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Jass, Jana
    Örebro University, School of Science and Technology. The Life Science Center.
    Jawali, Narendra
    Molecular Biology Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India.
    Involvement of Antibiotic Efflux Machinery in Glutathione-Mediated Decreased Ciprofloxacin Activity in Escherichia coli2016In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 60, no 7, 4369-4374 p.Article in journal (Refereed)
    Abstract [en]

    We have analyzed the contribution of different efflux components to glutathione-mediated abrogation of ciprofloxacin's activity in Escherichia coli and the underlying potential mechanism(s) behind this phenomenon. The results indicated that glutathione increased the total active efflux, thereby partially contributing to glutathione-mediated neutralization of ciprofloxacin's antibacterial action in E. coli However, the role of glutathione-mediated increased efflux becomes evident in the absence of a functional TolC-AcrAB efflux pump.

  • 19.
    Hadad, Ronza
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology.
    Pizza, Mariagrazia
    Novartis V&D, Siena, Italy.
    Rappuoli, Rino
    Novartis V&D, Siena, Italy.
    Fredlund, Hans
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology.
    Olcén, Per
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology.
    Novel meningococcal 4CMenB vaccine antigens - prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 9, 750-760 p.Article in journal (Refereed)
    Abstract [en]

    The first cross-protective Neisseria meningitidis vaccine (focus on serogroup B), the protein-based 4 component meningococcus serogroup B (4CMenB), includes the New Zealand outer membrane vesicle and three main genome-derived neisserial antigens (GNAs). These GNAs are fHbp (fused to GNA2091), NHBA (fused to GNA1030) and NadA. In this study, the prevalence and polymorphisms of the nucleotide and amino acid sequences of the 4CMenB antigens in a temporally and geographically diverse collection of N. gonorrhoeae isolates (n similar to=similar to 111) were investigated. All the examined GNA genes, except the nadA gene, were present in all gonococcal isolates. However, 25 isolates contained premature stop codons in the fHbp gene and/or the nhba gene, resulting in truncated proteins. Compared with the 4CMenB antigen sequences in reference strain MC58, the gonococcal strains displayed 67.095.4% and 60.994.9% identity in nucleotide sequence and amino acid sequence, respectively, in the equivalent GNA antigens. The absence of NadA, lack of universal expression of fHbp and NHBA and the uncertainty regarding the surface exposure of fHbp as well as the function of NHBA in N. gonorrhoeae will likely limit the use of the identical 4CMenB antigens in a gonococcal vaccine. However, possible cross-immunity of 4CMenB with gonococci and expression and function of the equivalent gonococcal GNAs, as well as of more appropriate GNAs for a gonococcal vaccine, need to be further examined.

  • 20.
    Hallberg, Pär
    et al.
    Uppsala University, Uppsala, Sweden .
    Nagy, Julia
    The Ryhov County Hospital, Jönköping, Sweden.
    Karawajczyk, Malgorzata
    Uppsala University, Uppsala, Sweden .
    Nordang, Leif
    Uppsala University, Uppsala, Sweden .
    Islander, Gunilla
    Skåne University Hospital, Lund, Sweden.
    Norling, Pia
    Sickla Health Centre, Nacka, Sweden.
    Johansson, Hans-Erik
    Uppsala University, Uppsala, Sweden .
    Kämpe, Mary
    Uppsala University, Uppsala, Sweden .
    Hugosson, Svante
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden .
    Wadelius, Mia
    Uppsala University, Uppsala, Sweden .
    Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough2017In: The Annals of Pharmacotherapy, ISSN 1060-0280, E-ISSN 1542-6270, Vol. 51, no 4, 293-300 p.Article in journal (Refereed)
    Abstract [en]

    Background: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema.

    Objective: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events.

    Methods: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons.

    Results: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10(-5), and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10(-5) Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10(-4)) and had longer time to onset and higher doses than those with cough (P = 3.2 × 10(-10) and P = 2.6 × 10(-4)). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups.

    Conclusion: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

  • 21.
    Hedegaard, E. R.
    et al.
    Univ Aarhus, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus, Denmark..
    Nielsen, B. D.
    Univ Aarhus, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus, Denmark.;Aarhus Univ Hosp, Dept Rheumatol, DK-8000 Aarhus, Denmark..
    Kun, A.
    Univ Aarhus, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus, Denmark..
    Hughes, A. D.
    Univ London Imperial Coll Sci Technol & Med, Fac Med, Natl Heart & Lung Inst, London SW7 2AZ, England..
    Kroigaard, C.
    Univ Aarhus, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus, Denmark..
    Mogensen, S.
    Univ Aarhus, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus, Denmark..
    Matchkov, V. V.
    Univ Aarhus, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus, Denmark..
    Fröbert, Ole
    Örebro University Hospital. Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, University of Aarhus, Aarhus, Denmark; Department of Cardiology.
    Simonsen, U.
    Univ Aarhus, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus, Denmark..
    K(V)7 channels are involved in hypoxia-induced vasodilatation of porcine coronary arteries2014In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 171, no 1, 69-82 p.Article in journal (Refereed)
    Abstract [en]

    Background and PurposeHypoxia causes vasodilatation of coronary arteries, but the underlying mechanisms are poorly understood. We hypothesized that hypoxia reduces intracellular Ca2+ concentration ([Ca2+](i)) by opening of K channels and release of H2S. Experimental ApproachPorcine coronary arteries without endothelium were mounted for measurement of isometric tension and [Ca2+](i), and the expression of voltage-gated K channels K(V)7 channels (encoded by KCNQ genes) and large-conductance calcium-activated K channels (K(Ca)1.1) was examined. Voltage clamp assessed the role of K(V)7 channels in hypoxia. Key ResultsGradual reduction of oxygen concentration from 95 to 1% dilated the precontracted coronary arteries and this was associated with reduced [Ca2+](i) in PGF(2) (10M)-contracted arteries whereas no fall in [Ca2+](i) was observed in 30mM K-contracted arteries. Blockers of ATP-sensitive voltage-gated potassium channels and K(Ca)1.1 inhibited hypoxia-induced dilatation in PGF(2)-contracted arteries; this inhibition was more marked in the presence of the K(v)7 channel blockers, XE991 and linopirdine, while a K(V)7.1 blocker, failed to change hypoxic vasodilatation. XE991 also inhibited H2S- and adenosine-induced vasodilatation. PCR revealed the expression of K(V)7.1, K(V)7.4, K(V)7.5 and K(Ca)1.1 channels, and K(Ca)1.1, K(V)7.4 and K(V)7.5 were also identified by immunoblotting. Voltage clamp studies showed the XE991-sensitive current was more marked in hypoxic conditions. ConclusionThe K(V)7.4 and K(V)7.5 channels, which we identified in the coronary arteries, appear to have a major role in hypoxia-induced vasodilatation. The voltage clamp results further support the involvement of K(V)7 channels in this vasodilatation. Activation of these K(V)7 channels may be induced by H2S and adenosine.

  • 22.
    Hedegaard, Elise R.
    et al.
    Aarhus Univ, Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, DK-8000 Aarhus C, Denmark..
    Nielsen, Berit D.
    Aarhus Univ, Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, DK-8000 Aarhus C, Denmark.;Aarhus Univ Hosp, Dept Rheumatol, Aarhus, Denmark..
    Mogensen, Susie
    Aarhus Univ, Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, DK-8000 Aarhus C, Denmark..
    Rembold, Christopher M.
    Univ Virginia Hlth Syst, Dept Internal Med, Div Cardiovasc, Charlottesville, VA USA..
    Fröbert, Ole
    Örebro University Hospital. Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, University of Aarhus, Aarhus, Denmark; Department of Cardiology.
    Simonsen, Ulf
    Aarhus Univ, Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, DK-8000 Aarhus C, Denmark..
    Mechanisms involved in increased sensitivity to adenosine A(2A) receptor activation and hypoxia-induced vasodilatation in porcine coronary arteries2014In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 723, 216-226 p.Article in journal (Refereed)
    Abstract [en]

    Hypoxia-induced coronary vasorelaxation is a compensatory mechanism increasing blood flow. We hypothesized that hypoxia shares pathways with adenosine and causes vasorelaxation through the adenosine A(2A) receptor and force suppression by increasing cAMP and phosphorylated heat shock protein (HSP)20. Adenosine receptors in porcine left anterior descending coronary arteries (LAD) were examined by RT-PCR and isometric tension recording in myographs. Vasorelaxation was induced by adenosine, 1% oxygen, or both in the absence or presence of ZM241385, an adenosine A(2A) receptor antagonist, cAMP was determined by ELISA and p-HSP20/1-ISP20 and p-MLC/MLC were determined by immunoblotting and densitometric analyses. In coronary arteries exposed to 1% oxygen, there was increased sensitivity to adenosine, the adenosine 112 selective agonist NECA, and the adenosine A(2A) selective receptor agonist CGS21680. ZM241385 shifted concentration-response curves for CGS21680 to the right, whereas the adenosine A(1) antagonist DPCPX, the adenosine A(2B) receptor antagonist MRS1754 and the adenosine A(3) receptor antagonist MRS1523 failed to reduce vasodilatation induced by CGS21680. 1% oxygen or adenosine increased cAMP accumulation and HSP20 phosphorylation without changing T850-MYPT1 and MLC phosphorylation. ZM241385 failed to change 1% oxygen-induced vasodilation, cAMP accumulation, HSP20 phosphorylation and MLC phosphorylation. The PKA inhibitor Rp-8-CPT-cAMPS significantly reduced vasorelaxation induced by 1% oxygen or CGS21680. Our findings suggest that the increased sensitivity to adenosine, NECA, and CGS21680 at 1% oxygen involves adenosine A(2A) receptors. Adenosine and 1% oxygen induce vasorelaxation in PGF(2 alpha)-contracted porcine coronary arteries partly by force suppression caused by increased cAMP and phosphorylation of HSP20.

  • 23.
    Hess, David
    et al.
    Department of Biology, Santa Clara University, Santa Clara, CA, United States.
    Wu, Abel
    San Francisco Public Health Laboratory, San Francisco, CA, United States.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University Hospital, Örebro, Sweden.
    Esmaili, Sarah
    Department of Biology, Santa Clara University, Santa Clara, CA, United States.
    Pandori, Will
    Department of Biology, Santa Clara University, Santa Clara, CA, United States.
    Sena, Emilee
    Department of Biology, Santa Clara University, Santa Clara, CA, United States.
    Klausner, Jeffrey D.
    Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
    Barry, Pennan
    San Francisco Department of Public Health, San Francisco, CA, United States.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University Hospital, Örebro, Sweden.
    Pandori, Mark
    San Francisco Public Health Laboratory, San Francisco, CA, United States.
    Genome Sequencing of a Neisseria gonorrhoeae Isolate of a Successful International Clone with Decreased Susceptibility and Resistance to Extended-Spectrum Cephalosporins2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 11, 5633-5641 p.Article in journal (Refereed)
  • 24.
    Heymans, Raymond
    et al.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Netherlands.
    Bruisten, Sylvia M.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Netherlands; University of Amsterdam, Department of Experimental Virology, Amsterdam, Netherlands.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    de Vries, Henry J. C.
    STI Outpatient Clinic, Cluster of Infectious Diseases, Health Service of Amsterdam, Amsterdam, Netherlands; Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands; Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
    van Dam, Alje P.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Netherlands; Department of Medical Microbiology, Onze Lieve Vrouwe Gasthuis General Hospital, Amsterdam, Netherlands.
    Clonally Related Neisseria gonorrhoeae Isolates with Decreased Susceptibility to the Extended-Spectrum Cephalosporin Cefotaxime in Amsterdam, the Netherlands2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 3, 1516-1522 p.Article in journal (Refereed)
    Abstract [en]

    From 2006 to 2008, Neisseria gonorrhoeae isolates were identified with decreased susceptibility to the extended-spectrum cephalosporin (ESC) cefotaxime among visitors of the Amsterdam sexually transmitted infections (STI) clinic, the Netherlands. Spread, clonality, and characteristics of 202 isolates were examined using antibiograms, conventional penA mosaic gene PCR, and N. gonorrhoeae multiple-locus variable-number tandem repeat analysis (NG-MLVA). A strictly defined subset was further characterized by N. gonorrhoeae multiantigen sequence typing (NG-MAST) and sequencing of ESC resistance determinants (penA, mtrR, and porB1b). Seventy-four N. gonorrhoeae isolates with a cefotaxime MIC of >0.125 mu g/ml (group A), 54 with a cefotaxime MIC of 0.125 mu g/ml (group B), and a control group of 74 with a cefotaxime MIC of <0.125 mu g/ml (group C) were included. Fifty-three clonally related penA mosaic-positive isolates (penicillin-binding protein 2 type XXXIV) were identified in group A (n = 47 isolates; 64%) and B (n = 6 isolates; 11%). The 53 penA mosaic-positive isolates were predominantly NG-MAST ST1407 (87%) and contained an mtrR promoter A deletion (98%) and porB1b alterations G101K/A102N. All were assigned to the same NG-MLVA cluster that comprised in total 56 isolates. A correlation was found between decreased cefotaxime susceptibility and ST1407 that was highly prevalent among visitors of the Amsterdam STI clinic. The rapid spread of this strain, which also has been identified in many other countries, might be facilitated by high-risk sexual behavior and should be monitored closely to identify potential treatment failure. Quality-assured surveillance of ESC susceptibility on the national and international levels and exploration of new drugs and/or strategies for treatment of gonorrhea are crucial.

  • 25.
    Hussain, Rashida
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Shahror, Rami
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Karpati, Ferenc
    3Stockholm CF-centre, Department of Pediatrics, Karolinska University Hospital, Huddinge, Stockholm.
    Roomans, Godfried M.
    Örebro University, School of Medicine, Örebro University, Sweden.
    Effect of IL-6, IL-8 and glucocorticoids on the internalization of Pseudomonas aeruginosa (ATCC 27853) in cystic fibrosis bronchial epithelial cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Pseudomonas aeruginosa infection is common in cystic fibrosis (CF). Uptake of P. aeruginosa by the cell and the subsequent apoptosis may prevent colonization of P. aeruginosa in CF airways. CF airways have elevated levels of IL-6 and IL-8. Glucocorticoids (GCs) are anti-inflammatory but their use in CF is controversial. We studied the effect of IL- 6, IL-8 and GCs on bacterial internalization, apoptosis, and intracellular Ca2+concentration in CF bronchial epithelial (CFBE) cells and found that increased levels of IL-6 and IL-8 can increase the susceptibility of P. aeruginosa infected cells to apoptosis and/or internalization of these bacteria in CF cells. GCs decreased the extent of apoptosis in CFBE cells infected with P. aeruginosa, but may improve airway hydration by increasing the intracellular Ca2+ concentration. None of the GCs and cytokines affected apoptosis in cells not exposed to Pseudomonas. We conclude that increased levels of IL-6 and IL-8 may have important roles in the pathology of P. aeruginosa infection in CF airways. If internalization is beneficial for the host then GCs are not beneficial for the treatment of CF patients. Whether the benefits of GC treatment outweigh the negative effects is questionable, and further clinical studies need to be carried out. 

  • 26.
    Iacobaeus, Ellen
    et al.
    Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
    Burkill, Sarah
    Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Bahmanyar, Shahram
    Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Brundin, Lou
    Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
    Fored, Mikael
    Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Olsson, Tomas
    Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Comorbid Diseases Preceding Diagnosis of Progressive Multifocal Leukencephalopathy2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no S3, 99-99 p.Article in journal (Other academic)
  • 27.
    Isomura, Kayoko
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Nordsletten, Ashley E
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Rück, Christian
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ljung, Rickard
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ivarsson, Tord
    Centre for Child and Adolescent Mental Health, Oslo, Norway.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mataix-Cols, David
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Pharmacoepidemiology of obsessive-compulsive disorder: A Swedish nationwide cohort study2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, no 4, 693-704 p.Article in journal (Refereed)
    Abstract [en]

    The extent to which clinicians adhere to international guidelines for the pharmacological management of obsessive-compulsive disorder (OCD) is unknown. We aimed to comprehensively map the patterns of prescription of psychotropic drugs for OCD patients (adults and children) at the Swedish national level and to compare these prescription patterns to best-practice recommendations in international guidelines. We linked the Swedish National Patient Register and the Swedish Prescribed Drug Register, which includes a record for all medications prescribed and dispensed in Sweden since July 2005. Of all active OCD cases in the Swedish National Patient Register between July 1st, 2005, and December 31st 2008 (N=10,523), 85% received at least one psychotropic drug. Most of the medicated adults and children with OCD (88%) received serotonin reuptake inhibitors (SRIs). Of all adults and children prescribed SRIs, 16% received sub-optimal doses. An additional 12% of all medicated patients were prescribed drugs that never included an SRI. Approximately 75% of the patients on SRIs received additional drugs (67% anxiolytics/hypnotics, 27% antipsychotics, 17% serotonin and norepinephrine reuptake inhibitors, 24% other antidepressants). Twelve percent of all medicated patients were at least 'regular' users, and 3% 'heavy' users of benzodiazepines. We also observed important variations in prescription practices according to patient's gender, age, and comorbidity status. We conclude that a substantial number of OCD patients might benefit from changes in their prescriptions. Dissemination of best-practice prescription guidelines for OCD is a major educational goal for the future. Monitoring of these prescription patterns over time is warranted.

  • 28.
    Ito, Teruyo
    et al.
    Juntendo Univ, Dept Bacteriol, Tokyo, Japan .
    Hiramatsu, Keiichi
    Rockefeller Univ, New York, NY 10021 USA .
    Tomasz, Alexander
    Rockefeller Univ, New York, NY 10021 USA .
    de Lencastre, Herminia
    Rockefeller Univ, New York, NY 10021 USA;. Univ Nova Lisboa, Inst Tecnol Quim & Biol, Oeiras, Portugal.
    Perreten, Vincent
    Univ Bern, Inst Vet Bacteriol, Bern, Switzerland.
    Holden, Matthew T. G.
    Wellcome Trust Sanger Inst, Hinxton, Cambs, England.
    Coleman, David C.
    Univ Dublin, Dublin Dent Univ Hosp, Trinity Coll Dublin, Dublin, Ireland.
    Goering, Richard
    Creighton Univ, Med Ctr, Omaha, NE USA.
    Giffard, Philip M.
    Charles Darwin Univ, Menzies Sch Hlth Res, Darwin, NT 0909, Australia.
    Skov, Robert L.
    Statens Serum Inst, DK-2300 Copenhagen, Denmark .
    Zhang, Kunyan
    Univ Calgary, Calgary, AB, Canada.
    Westh, Henrik
    Univ Copenhagen, Fac Hlth, Copenhagen, Denmark; Univ Copenhagen, Hvidovre Hosp, Copenhagen, Denmark.
    O'Brien, Frances
    Curtin Univ Technol, Perth, WA, Australia.
    Tenover, Fred C.
    Cepheid, Sunnyvale, CA USA.
    Oliveira, Duarte C.
    Univ Nova Lisboa, Inst Tecnol Quim & Biol, Oeiras, Portugal; Univ Nova Lisboa, Fac Ciencias & Tecnol, Dept Life Sci, CREM, Caparica, Portugal .
    Boyle-Vavra, Susan
    Univ Nova Lisboa, Fac Ciencias & Tecnol, Dept Life Sci, CREM, Caparica, Portugal .
    Laurent, Frederic
    Hosp Civils Lyon, French Natl Reference Ctr Staphylococci, Lyon, France.
    Kearns, Angela M.
    Hlth Protect Agcy, Staphylococcus Reference Unit, London, England.
    Kreiswirth, Barry
    Publ Hlth Res Inst, New York, NY USA .
    Ko, Kwan Soo
    Sungkyunkwan Univ, Sch Med, Seoul, South Korea .
    Grundmann, Hajo
    Natl Inst Publ Hlth & Environm, Utrecht, Netherlands .
    Sollid, Johanna E.
    Univ Tromso, Tromso, Norway .
    John, Joseph F. Jr.
    Ralph H Johnson VA Med Ctr, Charleston, SC USA.
    Daum, Robert
    Univ Chicago, Chicago, IL 60637 USA.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden.
    Buist, Girbe
    Guidelines for Reporting Novel mecA Gene Homologues2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 10, 4997-4999 p.Article in journal (Other academic)
  • 29.
    Jacobsson, Susanne
    et al.
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine.
    Golparian, Daniel
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Alm, Richard A.
    Infection IMed, AstraZeneca RandD Boston, Waltham, MA, United States.
    Huband, Michael
    Infection IMed, AstraZeneca RandD Boston, Waltham, MA, United States.
    Mueller, John
    Infection IMed, AstraZeneca RandD Boston, Waltham, MA, United States.
    Jensen, Jorgen Skov
    Statens Serum Institut, Copenhagen, Denmark.
    Ohnishi, Makoto
    National Institute of Infectious Diseases, Tokyo, Japan.
    Unemo, Magnus
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine.
    High In Vitro Activity of the Novel Spiropyrimidinetrione AZD0914, a DNA Gyrase Inhibitor, against Multidrug-Resistant Neisseria gonorrhoeae Isolates Suggests a New Effective Option for Oral Treatment of Gonorrhea2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 9, 5585-5588 p.Article in journal (Refereed)
    Abstract [en]

    We evaluated the activity of the novel spiropyrimidinetrione AZD0914 (DNA gyrase inhibitor) against clinical gonococcal isolates and international reference strains (n = 250), including strains with diverse multidrug resistance and extensive drug resistance. The AZD0914 MICs were substantially lower than those of most other currently or previously recommended antimicrobials. AZD0914 should be further evaluated, including in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans, optimal dosing, and performance, in appropriate randomized and controlled clinical trials.

  • 30.
    Jeverica, Samo
    et al.
    Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia..
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Lab. Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hanzelka, Brian
    Vertex Pharmaceut Inc, Boston, MA USA..
    Fowlie, Andrew J.
    Vertex Pharmaceut Inc, Boston, MA USA..
    Maticic, Mojca
    Univ Med Ctr Ljubljana, Clin Infect Dis & Febrile Illnesses, Ljubljana, Slovenia..
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Lab. Medicine, Microbiology.
    High in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (VT12-008911) against Neisseria gonorrhoeae isolates with various high-level antimicrobial resistance and multidrug resistance2014In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 7, 1866-1872 p.Article in journal (Refereed)
    Abstract [en]

    Clinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining options for empirical antimicrobial monotherapy of gonorrhoea globally, has been reported. New antimicrobials are essential to avoid the emergence of untreatable gonorrhoea. We have investigated the in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (Vertex aminobenzimidazole VT12-008911), compared with antimicrobials currently or previously recommended for gonorrhoea treatment.

    MICs were determined using agar dilution (VT12-008911) or Etest (seven antimicrobials) for international reference strains (naEuroS=aEuroS28) and clinical Neisseria gonorrhoeae isolates (naEuroS=aEuroS220). The latter included three extensively drug-resistant isolates with high-level ceftriaxone resistance, additional isolates with clinical ESC resistance and a high number of isolates with ciprofloxacin resistance and multidrug resistance.

    The MIC50, MIC90 and MIC range of VT12-008911 were 0.064, 0.125 and a parts per thousand currency sign0.002-0.25 mg/L, respectively. One-hundred and seventy (69%) isolates were ciprofloxacin resistant; however, only 54 of those isolates had a VT12-008911 MIC > 0.064 mg/L (47 and 7 with MICaEuroS=aEuroS0.125 mg/L and MICaEuroS=aEuroS0.25 mg/L, respectively). The in vitro activity of VT12-008911 was superior to that of ciprofloxacin and all additional antimicrobials investigated. Time-kill curve analysis showed that VT12-008911 exhibited potent time-dependent bactericidal activity, at or very close to the MIC, against N. gonorrhoeae.

    In vitro results suggest that VT12-008911 might be an effective treatment option for gonorrhoea. However, it will be important to detail the pharmacokinetics/pharmacodynamics, toxicity, selection and mechanisms of VT12-008911 resistance in N. gonorrhoeae and, finally, to perform well-designed in vivo randomized clinical trials.

  • 31.
    Jeverica, Samo
    et al.
    Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia..
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Maticic, Mojca
    Univ Med Ctr Ljubljana, Clin Infect Dis & Febrile Illnesses, Ljubljana, Slovenia..
    Potocnik, Marko
    Univ Med Ctr Ljubljana, Dept Dermatovenereol, Ljubljana, Slovenia..
    Mlakar, Bostjan
    Surg Ctr Zdrav Splet, Ljubljana, Slovenia..
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology.
    Phenotypic and molecular characterization of Neisseria gonorrhoeae isolates from Slovenia, 2006-12: rise and fall of the multidrug-resistant NG-MAST genogroup 1407 clone?2014In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 6, 1517-1525 p.Article in journal (Refereed)
    Abstract [en]

    To determine the phenotypic and molecular characteristics of Neisseria gonorrhoeae isolates obtained between 2006 and 2012 in Slovenia.

    Gonococcal isolates obtained between 2006 and 2012 in Slovenia (naEuroS=aEuroS194) were investigated with Etest for susceptibility to cefixime, ceftriaxone, penicillin, ciprofloxacin, azithromycin, tetracycline, gentamicin and spectinomycin. All isolates were examined with N. gonorrhoeae multiantigen sequence typing for molecular epidemiology and sequencing of the major extended-spectrum cephalosporin (ESC) resistance determinants (penA, mtrR and penB) was performed.

    The overall prevalence of decreased susceptibility or resistance to cefixime and ceftriaxone (MIC a parts per thousand yen0.125 mg/L) was 11% and 5%, respectively. The decreased susceptibility or resistance showed an epidemic peak in 2011 (33% for cefixime and 11% for ceftriaxone), decreasing to 6% and 4%, respectively, in 2012. ST1407 (9% of isolates), ST21 (6%) and ST225 (6%) were the most common sequence types (STs) during 2006-12. Genogroup G1407 (ST1407 most prevalent ST), an internationally spread clone with decreased susceptibility or resistance to ESCs, was most prevalent (48%) in 2009. However, the G1407 prevalence then declined: in 2010, 30%; in 2011, 28%; and in 2012, 8%. Instead, in 2012 the ESC- and ciprofloxacin-susceptible G21 was the predominant genogroup (26%).

    The prevalence of gonococcal resistance to ESCs in Slovenia has been high, but fluctuating. Fortunately, in 2012 some ESC- and ciprofloxacin-susceptible clones, such as genogroups G21, G1195 and G2992, appeared to have mainly replaced the multidrug-resistant G1407 clone, a replacement also seen in several European countries.

  • 32.
    Joensuu, Heikki
    et al.
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Kellokumpu-Lehtinen, Pirkko-Liisa
    Tampere University Hospital, Tampere, Finland.
    Huovinen, Riikka
    Turku University Central Hospital, Turku, Finland.
    Jukkola-Vuorinen, Arja
    Oulu University Hospital, Oulu, Finland.
    Tanner, Minna
    Tampere University Hospital, Tampere, Finland.
    Kokko, Riitta
    Kanta-Häme Central Hospital, Hämeenlinna, Finland.
    Ahlgren, Johan
    Gävle Hospital, Gävle, Sweden.
    Auvinen, Paivi
    Cancer Center, Kuopio University Hospital, Kuopio, Finland.
    Paija, Outi
    Turku University Central Hospital, Turku, Finland.
    Helle, Leena
    Kotka Central Hospital, Kotka, Finland.
    Villman, Kenneth
    Örebro University Hospital.
    Nyandoto, Paul
    Päijät-Häme Central Hospital, Lahti, Finland.
    Nilsson, Greger
    Uppsala University Hospital, Uppsala, Sweden.
    Pajunen, Marjo
    Jyväskylä Central Hospital, Jyväskylä, Finland.
    Asola, Raija
    Satakunta Central Hospital, Pori, Finland.
    Poikonen, Paula
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Leinonen, Mika
    4Pharma, Turku, Finland.
    Kataja, Vesa
    Cancer Center, Kuopio University Hospital, Kuopio, Finland; Vaasa Central Hospital, Vaasa, Finland.
    Bono, Petri
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Lindman, Henrik
    Uppsala University Hospital, Uppsala, Sweden.
    Adjuvant Capecitabine, Docetaxel, Cyclophosphamide, and Epirubicin for Early Breast Cancer: Final Analysis of the Randomized FinXX Trial2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 1, 11-18 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Capecitabine is an active agent in the treatment of breast cancer. It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane, an anthracycline, and cyclophosphamide improves outcome in early breast cancer.

    Patients and Methods: Women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive either three cycles of docetaxel and capecitabine (TX) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX; n = 753) or three cycles of docetaxel (T) followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF; n = 747). The primary end point was recurrence-free survival (RFS).

    Results: During a median follow-up time of 59 months, 214 RFS events occurred (local or distant recurrences or deaths; TX/CEX, n = 96; T/CEF, n = 118). RFS was not significantly different between the groups (hazard ratio [HR], 0.79; 95% CI, 0.60 to 1.04; P = .087; 5-year RFS, 86.6% for TX/CEX v 84.1% for T/CEF). Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF (HR, 0.73; 95% CI, 0.52 to 1.04; P = .080). In exploratory analyses, TX/CEX improved breast cancer-specific survival (HR, 0.64; 95% CI, 0.44 to 0.95; P = .027) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis. We detected little severe late toxicity.

    Conclusion: Integration of capecitabine into a regimen that contains docetaxel, epirubicin, and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine. J Clin Oncol 30:11-18. (c) 2011 by American Society of Clinical Oncology

  • 33.
    Jonsson, Thomas Björn
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Surgery, Örebro University Hospital, Örebro, Sweden; .
    Nilsson, T. K.
    Umeå Univ, Dept Med Biosci Clin Chem, Umeå, Sweden.
    Breimer, Lars H.
    Örebro University Hospital. Department of Laboratory Medicine.
    Schneede, J.
    Umeå Univ, Dept Clin Pharmacol, Umeå, Sweden.
    Arfvidsson, B.
    Department of Surgery, Örebro University Hospital, Örebro, Sweden.
    Norgren, Lars
    Örebro University, School of Health and Medical Sciences. Department of Surgery, Örebro University Hospital, Örebro, Sweden.
    Cloxacillin concentrations in serum, subcutaneous fat, and muscle in patients with chronic critical limb ischemia2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 8, 957-963 p.Article in journal (Refereed)
    Abstract [en]

    Patients suffering from critical limb ischemia (CLI) have poor wound healing in the ankle and foot areas. Secondary wound infections are frequent and often treated with prolonged courses of antibiotics.

    This study set out to investigate to what extent the unbound fraction of 4 g of cloxacillin i.v. reaches its target organ in poorly vascularized tissues, i.e., the calf and foot of patients suffering from CLI.

    Cloxacillin concentrations were measured by HPLC in serum and in microdialysis samples from skin and muscle of the lower part of the calf and as reference subcutaneously at the pectoral level in eight patients suffering from CLI (four males, four females, mean age 78 years, range 66-85 years) and in three healthy controls (two females, one male, mean age 67, range 66-68 years).

    In patients suffering from CLI, the tissue penetration of cloxacillin after a single 4 g dose was comparable to that of healthy controls, despite impaired blood circulation.

    The reduced blood flow in the peripheral vessels of the CLI patients presented here apparently is not the rate-limiting factor for delivery or tissue penetration of cloxacillin.

  • 34.
    Kharlyngdoh, Joubert Banjop
    et al.
    Örebro University, School of Science and Technology.
    Asnake, Solomon
    Örebro University, School of Science and Technology.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer2016In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 307, 91-101 p.Article in journal (Refereed)
    Abstract [en]

    Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the ART877A mutation, which is frequently detected mutation in PCa tumors and the ARW741C that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (ARW741C and ART877A) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The ART877A mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (ART877A) compared to T-47D cells (ARWT) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of ART877A and ARW741C to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters.

  • 35.
    Kälvegren, Hanna
    et al.
    Division of Pharmacology, Department of Medicine and Care, Cardiovascular Inflammation Research Centre, Linköping, Sweden.
    Andersson, Johanna
    Division of Pharmacology, Department of Medicine and Care, Cardiovascular Inflammation Research Centre, Linköping, Sweden.
    Grenegård, Magnus
    Division of Pharmacology, Department of Medicine and Care, Cardiovascular Inflammation Research Centre, Linköping, Sweden.
    Bengtsson, Torbjörn
    Division of Pharmacology, Department of Medicine and Care, Cardiovascular Inflammation Research Centre, Linköping, Sweden.
    Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors2007In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 566, no 1-3, 20-27 p.Article in journal (Refereed)
    Abstract [en]

    Chlamydia pneumoniae is a respiratory pathogen that has been linked to cardiovascular disease. We have recently shown that C. pneumoniae activates platelets, leading to oxidation of low-density lipoproteins. The aim of the present study was to evaluate the inhibitory effects of different pharmacological agents on platelet aggregation and secretion induced by C. pneumoniae. Platelet interaction with C. pneumoniae was studied by analyzing platelet aggregation and ATP-secretion with Lumi-aggregometry. Platelet aggregation and ATP-secretion induced by C. pneumoniae was markedly inhibited by the NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), an effect that was counteracted by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Pre-treatment of platelets with the 12-lipoxygenase (12-LOX) inhibitors cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC) and 5,6,7-trikydroxyflavone (baicalein) completely blocked the activation, whereas the cyclooxygenase (COX) inhibitors 2-acetyloxybenzoic acid (aspirin) and (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9-methyl-10,10-dioxo-10$l;(6)thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one (piroxicam) had no inhibitory effects. Opposite to C. pneumoniae-induced activation, platelets stimulated by collagen were inhibited by the COX-inhibitors but were unaffected by the 12-LOX-inhibitors. The platelet activating factor (PAF) antagonist Ginkgolide B blocked the C. pneumoniae-induced platelet activation, whereas the responses to collagen were unaffected. Furthermore, the P2Y1 and P2Y12 purinergic receptor antagonists 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179) and N(6)-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (cangrelor) inhibited the aggregation and secretion caused by C. pneumoniae. It is well-known that the efficacy of COX inhibitors in the prevention and treatment of cardiovascular disease varies between different patients, and that patients with low responses to aspirin have a higher risk to encounter cardiovascular events. The findings in this study showing that platelets stimulated by C. pneumoniae are unaffected by COX inhibitors but sensitive to 12-LOX inhibitors, may thus be of importance in future management of atherosclerosis and thrombosis.

  • 36.
    König, Julia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brummer, Robert-Jan
    Örebro University, School of Medicine, Örebro University, Sweden.
    Modulation of the gut ecosystem in irritable bowel syndrome2014In: Pharma-Nutrition: an overview / [ed] Gert Folkerts, Johan Garssen, Springer International Publishing , 2014, 55-73 p.Chapter in book (Refereed)
  • 37.
    König, Julia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brummer, Robert Jan
    Örebro University, School of Medicine, Örebro University, Sweden.
    The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS)2013In: Food and Nutrition Sciences, ISSN 2157-944X, E-ISSN 2157-9458, Vol. 4, no 11, 27-39 p.Article in journal (Refereed)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a multifactorial chronic disorder characterized by various abdominal complaints and a worldwide prevalence of 10% - 20%. Although its etiology and pathophysiology are complex and still not completely understood, aberrations along the microbe-gut-brain axis are known to play a central role. IBS is characterized by inter-related alterations in intestinal barrier function, gut microbe composition, immune activation, afferent sensory signaling and brain activity. Pharmaceutical treatment is generally ineffective and, hence, most therapeutic strategies are based on non-drug approaches. A promising option is the administration of probiotics, in which lactic acid bacteria strains are considered specifically beneficial. This review aims to provide a concise, although comprehensive, overview of the role of lactic acid bacteria in the pathophysiology and treatment of IBS.

  • 38.
    König, Julia
    et al.
    Örebro University, School of Medical Sciences.
    Siebenhaar, A.
    Hamburg, Germany.
    Högenauer, C.
    Graz, Austria.
    Arkkila, P.
    Helsinki, Finland.
    Nieuwdorp, M.
    Amsterdam, The Netherlands; Gothenburg, Sweden.
    Norén, Torbjörn
    Örebro University, School of Medical Sciences.
    Ponsioen, C. Y.
    Amsterdam, The Netherlands.
    Rosien, U.
    Hamburg, Germany.
    Rossen, N. G.
    Amsterdam, The Netherlands.
    Satokari, R.
    Helsinki, Finland.
    Stallmach, A.
    Jena, Germany.
    de Vos, W.
    Helsinki, Finland; Wageningen, The Netherlands.
    Keller, J.
    Hamburg, Germany.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Consensus report: Faecal microbiota transfer - clinical applications and procedures2017In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 45, no 2, 222-239 p.Article in journal (Refereed)
    Abstract [en]

    Background: Faecal microbiota transplantation or transfer (FMT) aims at replacing or reinforcing the gut microbiota of a patient with the microbiota from a healthy donor. Not many controlled or randomised studies have been published evaluating the use of FMT for other diseases than Clostridium difficile infection, making it difficult for clinicians to decide on a suitable indication.

    Aim: To provide an expert consensus on current clinical indications, applications and methodological aspects of FMT.

    Methods: Well-acknowledged experts from various countries in Europe have contributed to this article. After literature review, consensus has been achieved by repetitive circulation of the statements and the full manuscript among all authors with intermittent adaptation to comments (using a modified Delphi process). Levels of evidence and agreement were rated according to the GRADE system. Consensus was defined a priori as agreement by at least 75% of the authors.

    Results: Key recommendations include the use of FMT in recurrent C. difficile infection characterised by at least two previous standard treatments without persistent cure, as well as its consideration in severe and severe-complicated C. difficile infection as an alternative to total colectomy in case of early failure of antimicrobial therapy. FMT in inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and metabolic syndrome should only be performed in research settings.

    Conclusions: Faecal microbiota transplantation or transfer is a promising treatment for a variety of diseases in which the intestinal microbiota is disturbed. For indications other than C. difficile infection, more evidence is needed before more concrete recommendations can be made.

  • 39.
    Lebwohl, B.
    et al.
    Coeliac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Editorial: 'brain fog' and coeliac disease - evidence for its existence2014In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 40, no 5, 565-565 p.Article in journal (Other academic)
  • 40.
    Lebwohl, B.
    et al.
    Department of Medicine, Columbia University, New York, NY, United States; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Editorial: mucosal healing and adherence to the gluten-free diet in coeliac disease2014In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 40, no 10, 1241-1242 p.Article in journal (Refereed)
  • 41.
    Lebwohl, B.
    et al.
    Department of Medicine, Columbia University, New York, NY, United States; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Editorial: sprue-like enteropathy due to olmesartan and other angiotensin receptor blockers - the plot thickens2014In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 40, no 10, 1245-1246 p.Article in journal (Refereed)
  • 42.
    Lebwohl, B.
    et al.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY 10032 USA.;Karolinska Univ Hosp, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Murray, J. A.
    Mayo Clin, Coll Med, Dept Med, Div Gastroenterol & Hepatol, Rochester, MN USA..
    Rubio-Tapia, A.
    Mayo Clin, Coll Med, Dept Med, Div Gastroenterol & Hepatol, Rochester, MN USA..
    Green, P. H. R.
    Columbia Univ Coll Phys & Surg, Dept Med, Celiac Dis Ctr, New York, NY 10032 USA..
    Ludvigsson, Jonas F.
    Örebro University Hospital. Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Predictors of persistent villous atrophy in coeliac disease: a population-based study2014In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 39, no 5, 488-495 p.Article in journal (Refereed)
    Abstract [en]

    Background: Villous atrophy (VA) with intraepithelial lymphocytosis is the histological hallmark of coeliac disease (CD), but reported rates of mucosal recovery are variable.

    Aim: To determine the impact of age and other demographic variables on the probability of persistent VA on follow-up biopsy.

    Methods: We identified patients with VA on duodenal histology at all 28 Swedish pathology departments during the years spanning 1969-2008. We examined age, gender, calendar period, duration of disease and educational attainment to determine predictors of persistent VA.

    Results: Of 7648 patients with CD who underwent follow-up biopsy, persistent VA was present in 3317 (43%; 95% CI 42-44%). The effect of age on persistent VA varied according to time period; among those biopsied in the years spanning 2000-2008, the prevalence of persistent VA was 31%, and increasing age was associated with increasing rates of persistent VA (17% among those younger than 2years compared to 56% among those 70years). In contrast, persistent VA did not vary widely by age in earlier years. On multivariate analysis (restricted to the calendar period 2000-2008, 2-5years after CD diagnosis), persistent VA was more common among males (OR 1.43; 95% CI 1.07-1.90) and less common among patients with higher educational attainment (OR for college degree vs. <2years of high school 0.52, 95% CI 0.35-0.78).

    Conclusions: The prevalence of persistent villous atrophy has changed over time, with greater rates of healing in recent years. Social differences in persistent villous atrophy suggest that access and/or education regarding the gluten-free diet impact mucosal healing.

  • 43.
    Lee, Hyukmin
    et al.
    Department of Laboratory Medicine, International St Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Clinical Microbiology, Örebro, Sweden.
    Kim, Hyo Jin
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Seo, Younghee
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Lee, Kyungwon
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Chong, Yunsop
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Emergence of decreased susceptibility and resistance to extended-spectrum cephalosporins in Neisseria gonorrhoeae in Korea2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 9, 2536-2542 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major concern globally; however, no comprehensive AMR data for gonococcal isolates cultured after 2006 in Korea have been published internationally. We determined the susceptibility of N. gonorrhoeae isolates cultured in 2011-13, the mechanism of extended-spectrum cephalosporin (ESC) resistance and the molecular epidemiology of gonococcal strains in Korea.

    Methods: In 2011-13, 210 gonococcal isolates were collected in Korea and their AMR profiles were examined by the agar dilution method. The penA, mtrR, penB, ponA and pilQ genes were sequenced in 25 isolates that were resistant to ESCs and 70 randomly selected isolates stratified by year. For molecular epidemiology, N. gonorrhoeae multiantigen sequence typing and MLST were performed.

    Results: None of the N. gonorrhoeae isolates was susceptible to penicillin G and most were resistant to tetracycline (50%) and ciprofloxacin (97%). The rates of resistance to ceftriaxone, azithromycin, cefpodoxime and cefixime were 3%, 5%, 8% and 9%, respectively. However, all isolates were susceptible to spectinomycin. Twenty-one (84%) of the 25 ESC-resistant isolates contained the non-mosaic PBP2 XIII allele; however, the remaining 4 (16%) possessed the mosaic PBP2 X allele, which has been previously associated with ESC resistance including treatment failures.

    Conclusions: In Korea, susceptibility to spectinomycin remains high. However, the recent emergence of ESC-resistant N. gonorrhoeae strains, including strains possessing the PBP2 mosaic X and non-mosaic XIII alleles, is a major concern and enhanced AMR surveillance is necessary to prevent transmission of these strains.

  • 44.
    Leong, Su-Iin
    et al.
    Department of Microbiology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Schnürer, Johan
    Department of Microbiology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Broberg, Anders
    Department of Chemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Verrucine F, a quinazoline from Penicillium verrucosum2008In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 71, no 8, 1455-1457 p.Article in journal (Refereed)
    Abstract [en]

    Verrucine F (3), a quinazoline similar to verrucines A (1) and B (2), contains one anthranilic acid residue, one L-glutamine residue, and one alpha,beta-unsaturated phenylalanine residue, as determined by NMR, MS, and chemical methods. Compounds I and 3, but not 2, were produced by Penicillium verrucosum J255 and eight additional P. verrucosum strains. Verrucines were typically more concentrated in the inner (older) parts of the colony, and 3 peaked 4-8 days after 1, but at 10-fold lower concentrations (similar to 200 mu g/g). Verrucine F (3) formed spontaneously from 1 in buffered water solutions. probably by oxidation at C-1 followed by water elimination.

  • 45.
    Lewis, David A.
    et al.
    Natl Inst Communicable Dis, Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, ZA-2192 Johannesburg, South Africa.;Univ Witwatersrand, Dept Internal Med, Fac Hlth Sci, ZA-2193 Pk Town, South Africa.;Univ Cape Town, Sch Med, Div Med Microbiol, ZA-7925 Observatory, South Africa..
    Sriruttan, Charlotte
    Ampath Natl Lab Serv, Dept Clin Microbiol, ZA-0157 Centurion, South Africa..
    Mueller, Etienne E.
    Natl Inst Communicable Dis, Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, ZA-2192 Johannesburg, South Africa..
    Golparian, Daniel
    Orebro Univ Hosp, Dept Lab Med, Swedish Reference Lab Pathogen Neisseria, WHO Collaborating Ctr Gonorrhoea & Other STIs, SE-70185 Orebro, Sweden..
    Gumede, Lindy
    Natl Inst Communicable Dis, Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, ZA-2192 Johannesburg, South Africa..
    Fick, Donald
    Meldene Medicross Clin, ZA-2109 Melville, South Africa..
    de Wet, Johan
    Springs Medicross Clin, ZA-2213 Springs, South Africa..
    Maseko, Venessa
    Natl Inst Communicable Dis, Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, ZA-2192 Johannesburg, South Africa..
    Coetzee, Jennifer
    Ampath Natl Lab Serv, Dept Clin Microbiol, ZA-0157 Centurion, South Africa..
    Unemo, Magnus
    Örebro University Hospital. Orebro Univ Hosp, Dept Lab Med, Swedish Reference Lab Pathogen Neisseria, WHO Collaborating Ctr Gonorrhoea & Other STIs, SE-70185 Orebro, Sweden.
    Phenotypic and genetic characterization of the first two cases of extended-spectrum-cephalosporin-resistant Neisseria gonorrhoeae infection in South Africa and association with cefixime treatment failure2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 6, 1267-1270 p.Article in journal (Refereed)
    Abstract [en]

    To describe the phenotypic and genetic characteristics of the first two cases of extended-spectrum cephalosporin (ESC)-resistant Neisseria gonorrhoeae in South Africa, one of which was associated with verified cefixime treatment failure. Two ESC-resistant N. gonorrhoeae isolates were cultured from the urethral discharge of two men who have sex with men (MSM). One man reported a persistent urethral discharge that had failed to respond to previous therapy with oral cefixime. Agar dilution MICs were determined for eight antibiotics. -Lactam-associated resistance mutations were identified through PCR-based amplification and sequencing for several key genes: penA, mtrR and its promoter, porB1b (penB), ponA and pilQ. For molecular epidemiological characterization, full-length porB gene sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST) and multilocus sequence typing (MLST) were performed. Both isolates were resistant to cefixime, ciprofloxacin, penicillin and tetracycline and intermediate/resistant to azithromycin, but susceptible to ceftriaxone, gentamicin and spectinomycin. Both isolates had the type XXXIV penA mosaic allele in addition to previously described resistance mutations in the mtrR promoter (A deletion), porB1b (penB) (G101K and A102N) and ponA1 (L421P). Both isolates had an identical NG-MAST sequence type (ST4822) and MLST sequence type (ST1901). Both isolates were resistant to cefixime and possessed a number of identical mutations in key genes contributing to ESC resistance in N. gonorrhoeae. The two isolates contained the type XXXIV penA mosaic allele and belonged to a successful international MSM-linked multidrug-resistant gonococcal clone (MLST ST1901) associated with several cefixime treatment failures in Europe and North America.

  • 46.
    Lind, L.
    et al.
    Uppsala University, Uppsala, Sweden.
    Salihovic, Samira
    Örebro University, School of Science and Technology. Uppsala University, Uppsala, Sweden.
    Van Bavel, Bert
    Örebro University, School of Science and Technology.
    Lind, M.
    Uppsala University, Uppsala, Sweden.
    Circulating levels of perfluorinated compounds and left ventricular geometry2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, S93-S93 p.Article in journal (Other academic)
  • 47.
    Lind, M.
    et al.
    Uppsala University, Occupational and Environmental Medicine, Uppsala, Sweden.
    Salihovic, Samira
    Örebro University, School of Science and Technology. Uppsala University, Department of Medicine, Uppsala, Sweden.
    Larsson, A.
    Uppsala University, Department of Clinical Chemistry, Uppsala, Sweden.
    van Bavel, Bert
    Örebro University, School of Science and Technology.
    Lind, L.
    Uppsala University, Department of Medicine, Uppsala, Sweden.
    Circulating levels of perfluoroalkyl substances and biomarkers of liver function in a large population based sample of elderly men and women from Sweden2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, S91-S91 p.Article in journal (Other academic)
    Abstract [en]

    Objective: Since perfluoroalkyl substances (PFAS), also called perfluorinated compounds (PFCs), have been shown to accumulate in the liver in experimental studies, we investigated the relationships between PFAS and biomarkers of liver function in the general population.

    Methods: 1016 subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFAS were detected in almost all participants era by liquid chromatograph/tandem mass spectrometry. Several biomarkers of liver function were measured in parallel.

    Results: Bilirubin levels were significantly related to several of the PFAS, like perfluoroheptanoic acid (PFHpA), perfluorooctanoicacid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA). Of those, PFHpA, PFOA, PFDA, and PFNA were also related to Alanine Aminotransferase (ALT) levels. PFNA and PFUnDA were inversely related to alkaline phosphatases, while only PFHpA levels were significantly related to gamma-glutamyl transferase (GGT) levels. All associations were adjusted for life-style factors, like smoking, education, exercise habits, energy and alcohol intake.

    Conclusion: Circulating level of PFAS were related to biomarkers of liver function in this population-based sample, suggesting that PFAS could have a negative effect on liver function also in humans.

  • 48.
    Ljungberg, Liza U.
    et al.
    Faculty of Health Sciences, Linköping University, Linköping.
    Persson, Karin
    Faculty of Health Sciences, Linköping University, Linköping.
    Eriksson, Andreas C
    Faculty of Health Sciences, Linköping University, Linköping.
    Green, Henrik
    Faculty of Health Sciences, Linköping University, Linköping; Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna,.
    Whiss, Per A
    Faculty of Health Sciences, Linköping University, Linköping.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, 932-8 p.Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent. The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets. None of the metabolites cotinine, cotinine-N-oxide, nicotine-1'-N-oxide or trans-3'-hydroxycotinine (0.1-10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3'-hydroxycotinine (0.1 μM) and nicotine-1'-N-oxide (1-10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor. Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 49.
    Ludvigsson, Jonas F.
    Örebro University Hospital. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Orebro Univ Hosp, Dept Pediat, Orebro, Sweden..
    Commentary: coeliac disease and atherosclerosis - hand in hand?2013In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 38, no 5, 549-550 p.Article in journal (Refereed)
  • 50.
    Ludvigsson, Jonas F.
    Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden; Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester MN, United States.
    Commentary: coeliac disease, mortality and malignancy2012In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 35, no 7, 839-840 p.Article in journal (Refereed)
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