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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, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

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

  • 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, p. 519-532Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 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, p. 1993-2000Article in journal (Refereed)
    Abstract [en]

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

  • 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, p. 423-431Article 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.
    Bazzo, M. L.
    et al.
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Golfetto, L.
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Gaspar, P. C.
    Department of Surveillance, Prevention and Control of Sexually Transmitted Infections, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasilia, Brazil.
    Pires, A. F.
    Department of Surveillance, Prevention and Control of Sexually Transmitted Infections, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasilia, Brazil; University of Brasilia Postgraduate Program in Collective Health, Brasilia, Brazil.
    Ramos, M. C.
    Brazilian STD Society, Porto Alegre, Brazil.
    Franchini, M.
    Laboratory Consultant, Brasília, Brazil.
    Ferreira, W. A.
    Alfredo da Mata Foundation, Manaus, Brazil.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Benzaken, A. S.
    Department of Surveillance, Prevention and Control of Sexually Transmitted Infections, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasilia, Brazil.
    First nationwide antimicrobial susceptibility surveillance for Neisseria gonorrhoeae in Brazil, 2015-162018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 7, p. 1854-1861Article in journal (Refereed)
    Abstract [en]

    Objectives: Gonorrhoea and antimicrobial resistance (AMR) in Neisseria gonorrhoeae are major public health concerns globally. Enhanced AMR surveillance for gonococci is essential worldwide; however, recent quality-assured gonococcal AMR surveillance in Latin America, including Brazil, has been limited. Our aims were to (i) establish the first nationwide gonococcal AMR surveillance, quality assured according to WHO standards, in Brazil, and (ii) describe the antimicrobial susceptibility of clinical gonococcal isolates collected from 2015 to 2016 in all five main regions (seven sentinel sites) of Brazil.

    Methods: Gonococcal isolates from 550 men with urethral discharge were examined for susceptibility to ceftriaxone, cefixime, azithromycin, ciprofloxacin, benzylpenicillin and tetracycline using the agar dilution method, according to CLSI recommendations and quality assured according to WHO standards.

    Results: The levels of resistance (intermediate susceptibility) to tetracycline, ciprofloxacin, benzylpenicillin and azithromycin were 61.6%(34.2%), 55.6%(0.5%), 37.1% (60.4%) and 6.9% (8.9%), respectively. All isolates were susceptible to ceftriaxone and cefixime using the US CLSI breakpoints. However, according to the European EUCAST cefixime breakpoints, 0.2% (n= 1) of isolates were cefixime resistant and 6.9% (n = 38) of isolates had a cefixime MIC bordering on resistance.

    Conclusions: This study describes the first national surveillance of gonococcal AMR in Brazil, which was quality assured according to WHO standards. The high resistance to ciprofloxacin (which promptly informed a revision of the Brazilian sexually transmitted infection treatment guideline), emerging resistance to azithromycin and decreasing susceptibility to extended-spectrum cephalosporins necessitate continuous surveillance of gonococcal AMR and ideally treatment failures, and increased awareness when prescribing treatment in Brazil.

  • 6.
    Brikell, I.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ghirardi, L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Chang, Z.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, B. M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Kuja-Halkola, R.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    ADHD medications and the risk of epileptic seizures: a pharmacoepidemiological study using nationwide register data2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, no Suppl. 4, p. S1113-S1114Article in journal (Other academic)
    Abstract [en]

    Background: Attention-deficit/hyperactivity disorder (ADHD) affects 10–30% of children with epilepsy, making it one of the most common comorbidities in epilepsy. Stimulant medications are first line pharmacological treatment of ADHD, yet there areconcerns regarding the safety of stimulant treatment in patients with comorbid ADHD and epilepsy. This is due to the long held view that stimulants may lower the seizure threshold and increase seizure frequency [1]. Evidence for such an effect are however inconsistent and largely based on studies with small sample sizes, highly selected patient populations and observational studies that have not sufficiently addressed issues of confounding [2]. The aim of this pharmacoepidemiological register based study wastherefore to estimate the risk of seizures in relation to ADHD medication use in a population based cohort of individuals with a history of seizures.

    Methods: Using Swedish national registers, we identified a cohort of 62,361 individuals (48% female) born in Sweden between 1960 and 2004, with at least one seizure episode according to ICD codes. Each individual was followed from January 1st 2006, their first seizure or age five, up until December 31st 2013 or death, whichever came first. We identified periods of ADHD medication use (methylphenidate, amphetamine, dexamphetamine, lisdexamfetamine, and atomoxetine) from the Swedish National Prescribed Drug Register. A period was defined as on-medication when two consecutive prescriptions where no more than 183 days apart, and off-medication if more than 183 daysapart. We obtained information on medical visit for unplanned seizures events from the Swedish National Patient register using ICD codes. We estimated the population level association between ADHD medications and the rate of seizures during medicated and non-medication periods using a cox proportional hazards regression model. To adjust for individual-specific confounding that may influence both seizure risk and the likelihood of receiving ADHD medication, we used a stratified Cox regression model to estimate the rate of seizures during medicated and non-medicated periods, within the same individual.

    Preliminary Result: A total of 59,749 seizure events occurred during 361,501 person years of follow-up. ADHD medications were not associated with the rate of seizures at the population level (HR = 1.06, 95%CI 0.91–1.23). In the within-individual analysis, ADHD medication periods were associated with a reduced rate of seizures (HR = 0.70, 95%CI 0.62–0.79), compared to non-medicated periods. Estimates did not differ across sex, nor in age restricted analyses including only ages 5 and 20 years. All analyses were adjusted for age as a time-varying covariate. Population level analyses were additionally adjusted for sex.

    Conclusions: Our findings suggest that ADHD medications are not associated with an increased risk of seizures. Rather, results from the within-individual analysis, which adjusts for factors that are constant within the individual, such as genetic factors and underlying disorder severity, suggest a protective effect of ADHD medication treatment on seizure rates. Next, we will study the effect of concurrent antiepileptic medication use and whether the observed effect differs by stimulant and non-stimulant ADHD medications. We will also further investigate possible mechanisms contributing to the observed protective effect of ADHD medications on seizure rates.

    References

    [1] Williams, A.E., Giust, J.M., Kronenberger, W.G., Dunn, D.W., 2016. Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges. Neuropsychiatr Dis Treat 12, 287–296.

    [2] Ravi, M., Ickowicz, A., 2016. Epilepsy, Attention-Deficit/Hyperactivity Disorder and Methylphenidate: Critical Examination of Guiding Evidence. Journal of the Canadian Academy of Child and Adolescent Psychiatry 25 (1), 50.

  • 7.
    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.
    Pharmacological Treatments Preceding Diagnosis Of Progressive Multifocal Leukencephalopathy2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, p. 496-497Article 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.

  • 8.
    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, Örebro University Hospital, Örebro, Sweden.
    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, p. 92-99Article 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.

  • 9.
    Elvers, Margitta
    et al.
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Grenegård, Magnus
    Faculty of Health Sciences, Department of Medicine and Health, Division of Drug Research/Pharmacology, University of Linköping, Linköping, Sweden.
    Khoshjabinzadeh, Hanieh
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, University of Linköping, Linköping, Sweden.
    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
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, USA.
    Di Paolo, Gilbert
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 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 University, Linköping, Sweden.
    Fälker, Knut
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping University, Linköping, Sweden.
    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, p. 1743-52Article 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.

  • 10.
    Ericsson, Elisabeth
    et al.
    Avd. f omvårdnad, Institutionen för medicin och hälsa, Linköpings universitet, Linköping, Sverige.
    Brattwall, Metha
    Anestesi och intensivvårdskliniken, Sahlgrenska Universitetssjukhuset, Mölndal, Sverige.
    Lundeberg, Stefan
    Smärtbehandlingsenheten, Astrid Lindgrens Barnsjukhus, Stockholm, Sverige.
    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, p. 64-71Chapter 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.

  • 11.
    Eriksson, Carl
    et al.
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Cao, Yang
    Örebro University, School of Medical Sciences. Örebro University Hospital. Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Rundquist, Sara
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Zhulina, Yaroslava
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Henriksson, Ida
    Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    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, p. 897-898Article in journal (Other academic)
  • 12.
    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, p. 1369-1370Article in journal (Refereed)
    Abstract [en]

    No abstract is available for this article.

  • 13.
    Everhov, Å. 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.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, 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 Pediatric Gastroenterology and Nutrition, Sachs’ Children and Youth Hospital, Stockholm, Sweden.
    Letter: phenotype and natural history of elderly onset inflammatory bowel disease2018In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 47, no 10, p. 1420-1421Article in journal (Refereed)
  • 14.
    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 Hospital, 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, p. 1961-1968Article 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.

  • 15.
    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, p. 469-480Article 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.

  • 16.
    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, p. 114-23Article 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.

  • 17.
    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, p. 880-888Article 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.

  • 18.
    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, p. 345-348Article in journal (Refereed)
  • 19.
    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, p. 535-543Article 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.

  • 20.
    Golparian, Daniel
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; 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, Örebro University Hospital, Örebro, Sverige.
    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, p. 2739-2742Article 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.

  • 21.
    Gorreja, Frida
    et al.
    Örebro University Hospital. Hospital Pharmacy, Veneto Institute of Oncology - IRCCS, Padua, Italy.
    Damuzzo, Vera
    Hospital Pharmacy, Veneto Institute of Oncology IRCCS, Padua, Italy; School of Hospital Pharmacy, University of Padua, Padua, Italy.
    Gallo, Umberto
    Pharmaceutical Department, Local Health Unit n. 6 Euganea, Padua, Italy.
    Russi, Alberto
    Hospital Pharmacy, Veneto Institute of Oncology IRCCS, Padua, Italy.
    Lo Re, Francesco
    Hospital Pharmacy, Veneto Institute of Oncology IRCCS, Padua, Italy.
    Ciampalini, Susanna
    Ministry of Health, Rome, Italy.
    Guidotti, Lucia
    Ministry of Health, Rome, Italy.
    Serena, Marta
    School of Hospital Pharmacy, University of Padua, Padua, Italy.
    Palozzo, Claudio
    Hospital Pharmacy, Veneto Institute of Oncology IRCCS, Padua, Italy.
    A survey on patients medication reconciliation process in an oncological hospital2017In: Recenti Progressi in Medicina, ISSN 00341193, Vol. 108, no 3, p. 141-148Article in journal (Other academic)
    Abstract [en]

    Objectives. The purpose of this study was to assess the impact of medication reconciliation in the clinical practice from a hospital pharmacist point of view.

    Methods. A survey of the medication taken by cancer patients was performed on admission and on discharge in an Oncological hospital, and then the subjects were followed up until discharge for 8 weeks. The pharmacist entered the data collected into a computer based tool which, by using Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions (STOPP criteria) and Micromedex™ interactions database, automatically produces a report indicating the possible inconsistencies. The report is to check all potentially inappropriate prescriptions (PIPs) correlated to the drugs assumption by the patient. The appropriateness of the medication was scored using a Medication Appropriateness Index (MAI index) which was used to reconcile the medication list accordingly.

    Results. Patients reconciled at admission were 98, while patients reconciled at discharge were 90, 8 patients dropped out due to death. After the intervention of the hospital pharmacist, the average value of MAI index showed a significant reduction (3,391 to 2,552 p=0.039) and the median number of drugs prescribed per patient was decreased (7 vs 6; p=0.8058).

    Conclusion. Our study demonstrated that the forms used in the reconciliation process, in particular the record card, is a promising method to increase the quality of the information related to drug use in clinical decisions. We think that medication reconciliation softwares should be widely used by health care professionals involved in the recording of drug history or prescription process.

  • 22.
    Goswami, Manish
    et al.
    Molecular Biology Division, Bhabha Atomic Research Centre, Mumbai, India; The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden .
    Subramanian, Mahesh
    Bio-Organic Division, Bhabha Atomic Research Centre, 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, 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, p. 4369-4374Article 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.

  • 23.
    Gouveia, A. C. Damiao
    et al.
    Research Unit for Reproductive Tract Microbiology, Statens Serum Institut, Copenhagen, Denmark.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Öebro University Hospital, Örebro, Sweden.
    Jensen, J. S.
    Research Unit for Reproductive Tract Microbiology, Statens Serum Institut, Copenhagen, Denmark.
    In vitro activity of zoliflodacin (ETX0914) against macrolide-resistan fluoroquinolone-resistant and antimicrobial-susceptible Mycoplasma genitalium strains2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 5, p. 1291-1294Article in journal (Refereed)
    Abstract [en]

    Background: Mycoplasma genitalium is estimated to be the second most common cause of bacterial sexually transmitted infection in Europe. It is of increasing public health concern due to the rapid development of resistance to different antimicrobial classes, including the preferred first- and second-line treatments azithromycin and moxifloxacin. Thus, new antimicrobial agents are urgently needed, especially for the treatment of MDR strains.

    Methods: The in vitro activity of the new spiropyrimidinetrione zoliflodacin against 47 M. genitalium strains was assessed by growing M. genitalium in Vero cell culture and measuring growth by quantitative PCR. The collection included 34 moxifloxacin-susceptible (MIC <1 mg/L) and 13 moxifloxacin-resistant (MIC >= 1 mg/L) strains. Twenty-three of the strains were azithromycin resistant (MIC >= 16 mg/L) and 12 of these strains were MDR.

    Results: Only one (2.1%) strain with substantially increased MIC (4 mg/L) and potential resistance to zoliflodacin was found. Zoliflodacin was overall more potent than moxifloxacin (P = 0.009) and no cross-resistance was observed between the two drug classes of topoisomerase II inhibitors. Differences in the MICs of zoliflodacin and azithromycin were not statistically significant; however, 23 (48.9%) compared with potentially 1 (2.1%) of the strains were resistant to azithromycin and zoliflodacin, respectively.

    Conclusions: Zoliflodacin is a promising candidate for the treatment of M. genitalium and it is important to further develop and evaluate this drug.

  • 24.
    Gustavsson, Anders
    et al.
    Optumlnsight, Stockholm, Sweden.
    Svensson, Mikael
    Örebro University, Örebro University School of Business. Department of Economics and Statistics, Karlstad University, Karlstad, Sweden.
    Jacobi, Frank
    Institute of Clinical Psychology and Psychotherapy, Centre of Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Dresden, Germany.
    Allgulander, Christer
    Department of Clinical Neuroscience, Karolinska University Hospital, Huddinge, Sweden.
    Alonso, Jordi
    Health Services Research Unit, IMIM-Hospital del Mar, Barcelona, Spain.
    Beghi, Ettore
    Laboratorio Malattie Neurologiche, Istituto Mario Negri, Milano, Italy.
    Dodel, Richard
    Department of Neurology Marburg, Philips University, Marburg, Germany.
    Ekman, Mattias
    Optumlnsight, Stockholm, Sweden.
    Faravelli, Carlo
    Department of Psychology, Florence University, Florence, Italy.
    Fratiglioni, Laura
    Aging Research Centre, Karolinska Institute, Stockholm, Sweden.
    Gannon, Brenda
    Academic Unit of Health Economics, Leeds Institute of Health Sciences, Leeds, United Kingdom.
    Jones, David Hilton
    Department of Clinical Neurology, John Radcliffe Hospital, Oxford, United Kingdom.
    Jennum, Pout
    Centre for Sleep Medicine, Glosptup Hospital, Copenhagen, Denmark.
    Jordanova, Albena
    Department of Molecular Genetics, VIB/University of Antwerp, Antwerpen, Belgium; Neurogenetics Laboratory, Institute Born Bunge, University of Antwerp, Antwerpen, Belgium; Department of Chemistry and Biochemistry, Molecular Medicine Centre, Medical University, Sofia, Bulgaria.
    Jonsson, Linus
    Optumlnsight, Stockholm, Sweden.
    Karampampa, Korinna
    Optumlnsight, Stockholm, Sweden.
    Knapp, Martin
    Personal Social Services Research Unit, London School of Economics, London, United Kingdom; Centre for the Economics of Mental Health, Institute of Psychiatry, King's College, London, United Kingdom.
    Kobelt, Gisela
    Lund University, Lund, Sweden; European Health Economics, Mulhouse, France.
    Kurth, Tobias
    Department of Epidemiology, Harvard School of Public Health, Boston, United States.
    Lieb, Roselind
    Department of Psychology, University of Basel, Basel, Switzerland.
    Linde, Mattias
    Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway; Division of Neurology and Neurophysiology, St Olavs Hospital, Trondheim, Norway.
    Ljungcrantz, Christina
    Optumlnsight, Stockholm, Sweden..
    Maercker, Andreas
    Department of Psychology, University of Zürich, Zürich, Switzerland.
    Melin, Beatrice
    Department of Oncology, University of Umeå, Umeå, Sweden.
    Moscarelli, Massimo
    International Centre of Mental Health Policy and Economics, Milan, Italy; Harvard Medical School, Boston, United States.
    Musayev, Amir
    Optumlnsight, Stockholm, Sweden.
    Norwood, Fiona
    Department of Neurology, King's College Hospital, London, United Kingdom.
    Preisig, Martin
    Department of Psychiatry, University Hospital Centre, University of Lausanne, Lausanne, Switzerland.
    Pugliatti, Maura
    Department of Neurosciences, University of Sassari, Sassari, Italy.
    Rehm, Juergen
    Technische Universität Dresden, Dresden, Germany; Centre for Addiction and Mental Health, Toronto, Canada.
    Salvador-Carulla, Luis
    Asociación Científica PSICOST, Jerez de la Frontera, Spain; Psiquiatría, Departamento de Neurociencias, Universidad de Cádiz, Cádiz, Spain.
    Schlehofer, Brigitte
    German Cancer Research Centre, Heidelberg, Germany.
    Simon, Roland
    European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal.
    Steinhausen, Hans-Christoph
    Aalborg Psychiatric Hospital, Aalborg, Denmark; Clinical Psychology and Epidemiology, Institute of Psychology, University of Basel, Basel, Switzerland; Department of Child and Adolescent Psychiatry, University of Zürich, Zürich, Switzerland.
    Stovner, Lars Jacob
    Norwegian National Headache Centre, Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; St. Olavs Hospital, Trondheim, Norway.
    Vallat, Jean-Michel
    Centre national de référence neuropathies périphériques rares, Department of Neurology, University Hospital, Limoges, France.
    Van den Bergh, Peter
    Centre De Référence Neuromusculaire, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
    van Os, Jim
    Department of Psychiatry and Psychology, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, Maastricht, Netherlands; Division of Psychological Medicine, Institute of Psychiatry, King's College London, London, United Kingdom.
    Vos, Pieter E.
    Nijmegen Medical Centre, Radboud University, Nijmegen, The Netherlands.
    Xu, Weili
    Aging Research Centre, Karolinska Institute, Stockholm, Sweden.
    Wittchen, Hans-Ulrich
    Institute of Clinical Psychology and Psychotherapy, Centre of Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Dresden, Germany.
    Jonsson, Bengt
    Stockholm School of Economics, Stockholm, Sweden.
    Olesen, Jes
    Danish Headache Centre at the Department of Neurology, Glostrup University Hospital, Glostrup, Denmark.
    Corrigendum to “Cost of disorders of the brain in Europe 2010” [Eur. Neuropsychopharmacol. 21 (2011) 718–779]2012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no 3, p. 237-238Article in journal (Refereed)
  • 25.
    Hadad, Ronza
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, 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, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    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, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, 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, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    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, p. 750-760Article 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.

  • 26.
    Hall, Diana
    et al.
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Poussin, Carine
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Velagapudi, Vidya R.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Empsen, Christophe
    Vrije Universiteit Brussel, Brussels, Belgium.
    Joffraud, Magali
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Beckmann, Jacques S.
    Service and Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
    Geerts, Albert E.
    Vrije Universiteit Brussel, Brussels, Belgium.
    Ravussin, Yann
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Ibberson, Mark
    Service and Department of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland; Vital-IT, Lausanne, Switzerland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Thorens, Bernard
    Department of Physiology, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
    Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced pro-inflammatory state2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 40, p. 31011-31023Article in journal (Refereed)
    Abstract [en]

    Accumulation of fat in the liver increases the risk to develop fibrosis and cirrhosis and is associated with development of the metabolic syndrome. Here, to identify genes or gene pathways that may underlie the genetic susceptibility to fat accumulation in liver, we studied A/J and C57Bl/6 mice that are resistant and sensitive to diet-induced hepatosteatosis and obesity, respectively. We performed comparative transcriptomic and lipidomic analysis of the livers of both strains of mice fed a high fat diet for 2, 10, and 30 days. We found that resistance to steatosis in A/J mice was associated with the following: (i) a coordinated up-regulation of 10 genes controlling peroxisome biogenesis and β-oxidation; (ii) an increased expression of the elongase Elovl5 and desaturases Fads1 and Fads2. In agreement with these observations, peroxisomal β-oxidation was increased in livers of A/J mice, and lipidomic analysis showed increased concentrations of long chain fatty acid-containing triglycerides, arachidonic acid-containing lysophosphatidylcholine, and 2-arachidonylglycerol, a cannabinoid receptor agonist. We found that the anti-inflammatory CB2 receptor was the main hepatic cannabinoid receptor, which was highly expressed in Kupffer cells. We further found that A/J mice had a lower pro-inflammatory state as determined by lower plasma levels and IL-1β and granulocyte-CSF and reduced hepatic expression of their mRNAs, which were found only in Kupffer cells. This suggests that increased 2-arachidonylglycerol production may limit Kupffer cell activity. Collectively, our data suggest that genetic variations in the expression of peroxisomal β-oxidation genes and of genes controlling the production of an anti-inflammatory lipid may underlie the differential susceptibility to diet-induced hepatic steatosis and pro-inflammatory state.

  • 27.
    Hallberg, Pär
    et al.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Karlsson, Julia
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Kurland, Lisa
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden; AstraZeneca Research & Development, Mölndal, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Malmqvist, Karin
    Division of Internal Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Öhman, K. Peter
    AstraZeneca Research & Development, Mölndal, Sweden; Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Nyström, Fredrik
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden; Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Melhus, Håkan
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    The CYP2C9 genotype predicts the blood pressure response to irbesartan: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial2002In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 20, no 10, p. 2089-2093Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The cytochrome P450 CYP2C9 enzyme (CYP2C9) metabolizes many clinically important drugs, for example, phenytoin, warfarin and the angiotensin II type 1 (AT(1)) receptor antagonists, losartan and irbesartan. Single nucleotide polymorphisms in the CYP2C9 gene result in the expression of three important variants, CYP2C9*1(wild-type), CYP2C9*2 and CYP2C9*3, the last two exhibiting reduced catalytic activity compared with the wild-type. The CYP2C9 genotype is known to determine sensitivity to and dose requirements for both warfarin and phenytoin, and also the rate of metabolism of losartan. However, its influence on clinical response to treatment with the AT(1) receptor antagonist, irbesartan, has not been investigated.

    OBJECTIVE: To determine whether the CYP2C9genotype influences the blood pressure-decreasing response to antihypertensive treatment with irbesartan.

    DESIGN AND METHODS: One hundred and two patients with essential hypertension and left ventricular hypertrophy were allocated randomly to groups to receive double-blind treatment with either irbesartan (n = 49) or the beta(1)-adrenergic receptor blocker, atenolol ( n= 53). Blood pressure was measured before and after 12 weeks of treatment. genotyping was performed using solid-phase minisequencing.

    RESULTS: The diastolic blood pressure (DBP) response differed in relation to the CYP2C9 genotype in patients given irbesartan: the reduction in patients with genotype CYP2C9*1/CYP2C9*1 (n = 33) was 7.5% and that with CYP2C9*1/CYP2C9*2 (n = 12) was 14.4% ( P= 0.036). A similar trend was seen for systolic blood pressure. In contrast, no relation was seen between the CYP2C9 genotype and blood pressure response to atenolol, a drug not metabolized via CYP2C9.

    CONCLUSIONS: The CYP2C9 genotype seems to predict the DBP response to irbesartan, but not to atenolol, in patients with essential hypertension.

  • 28. Hallberg, Pär
    et al.
    Lind, Lars
    Michaëlsson, Karl
    Karlsson, Julia
    Kurland, Lisa
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, K. Peter
    Nyström, Fredrik
    Melhus, Håkan
    B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial2003In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 21, no 3, p. 621-624Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system, including left ventricular (LV) hypertrophy. Studies have demonstrated that bradykinin, through the B2 bradykinin receptor (B2BKR), mediates important cardiovascular effects that may protect against LV hypertrophy. Recently, a +9/-9 exon 1 polymorphism of the B2BKR was shown to be strongly associated with LV growth response among normotensive males undergoing physical training. We aimed to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LV hypertrophy.

    DESIGN AND METHODS: We determined the B2BKR genotype of 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, included in a double-blind study to receive treatment for 48 weeks with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol.

    RESULTS: B2BKR +9/+9 genotypes responded poorly in LV mass regression, independent of blood pressure reduction or treatment, as compared to the other genotypes (adjusted mean change in LV mass index = -10.0 +/- 4.6 versus -21.6 +/- 2.2 g/m2, P = 0.03).

    CONCLUSIONS: Our results suggest an impact of the B2BKR polymorphism on LV mass regression during antihypertensive treatment.

  • 29.
    Hallberg, Pär
    et al.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Lind, Lars
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden; AstraZeneca Research & Development, Mölndal, Sweden.
    Michaëlsson, Karl
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Kurland, Lisa
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Malmqvist, Karin
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Öhman, Karl Peter
    AstraZeneca Research & Development, Mölndal, Sweden; Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Nyström, Fredrik
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden; Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden.
    Liljedahl, Ulrika
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Syvänen, Ann-Christine
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Melhus, Håkan
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy2003In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 3, article id 11Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adipocyte-derived leucine aminopeptidase (ALAP) is a recently identified member of the M1 family of zinc-metallopeptidases and is thought to play a role in blood pressure control through inactivation of angiotensin II and/or generation of bradykinin. The enzyme seems to be particularly abundant in the heart. Recently, the Arg528-encoding allele of the ALAP gene was shown to be associated with essential hypertension.

    METHODS: We evaluated the influence of this polymorphism on the change in left ventricular mass index in 90 patients with essential hypertension and echocardiographically diagnosed left ventricular hypertrophy, randomised in a double-blind study to receive treatment with either the angiotensin II type I receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol for 48 weeks. Genyotyping was performed using minisequencing.

    RESULTS: After adjustment for potential covariates (blood pressure and left ventricular mass index at baseline, blood pressure change, age, sex, dose and added antihypertensive treatment), there was a marked difference between the Arg/Arg and Lys/Arg genotypes in patients treated with irbesartan; those with the Arg/Arg genotype responded on average with an almost two-fold greater regression of left ventricular mass index than patients with the Lys/Arg genotype (-30.1 g/m2 [3.6] vs -16.7 [4.5], p = 0.03).

    CONCLUSIONS: The ALAP genotype seems to determine the degree of regression of left ventricular hypertrophy during antihypertensive treatment with the angiotensin II type I receptor antagonist irbesartan in patients with essential hypertension and left ventricular hypertrophy. This is the first report of a role for ALAP/aminopeptidases in left ventricular mass regulation, and suggests a new potential target for antihypertensive drugs.

  • 30.
    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, p. 293-300Article 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.

  • 31.
    Hedegaard, E. R.
    et al.
    Dept Biomed Pulm & Cardiovasc Pharmacol, Univ Aarhus, Aarhus, Denmark.
    Nielsen, B. D.
    Dept Biomed Pulm & Cardiovasc Pharmacol, Univ Aarhus, Aarhus, Denmark.; Dept Rheumatol, Aarhus Univ Hosp, Aarhus, Denmark.
    Kun, A.
    Dept Biomed Pulm & Cardiovasc Pharmacol, Univ Aarhus, Aarhus, Denmark.
    Hughes, A. D.
    Fac Med, Natl Heart & Lung Inst, Univ London Imperial Coll Sci Technol & Med, London, England.
    Kroigaard, C.
    Dept Biomed Pulm & Cardiovasc Pharmacol, Univ Aarhus, Aarhus, Denmark.
    Mogensen, S.
    Dept Biomed Pulm & Cardiovasc Pharmacol, Univ Aarhus, Aarhus, Denmark.
    Matchkov, V. V.
    Dept Biomed Pulm & Cardiovasc Pharmacol, Univ Aarhus, Aarhus, Denmark.
    Fröbert, Ole
    Örebro University Hospital. Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, University of Aarhus, Aarhus, Denmark; Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Simonsen, U.
    Dept Biomed Pulm & Cardiovasc Pharmacol, Univ Aarhus, 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, p. 69-82Article 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.

  • 32.
    Hedegaard, Elise R.
    et al.
    Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, Aarhus Univ, Aarhus, Denmark.
    Nielsen, Berit D.
    Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, Aarhus Univ, Aarhus, Denmark; Dept Rheumatol, Aarhus Univ Hosp, Aarhus, Denmark.
    Mogensen, Susie
    Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, Aarhus Univ, Aarhus, Denmark.
    Rembold, Christopher M.
    Dept Internal Med, Div Cardiovasc, Univ Virginia Hlth Syst, Charlottesville VA, USA.
    Fröbert, Ole
    Örebro University Hospital. Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, University of Aarhus, Aarhus, Denmark; Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Simonsen, Ulf
    Dept Biomed Pulm & Cardiovasc Pharmacol, MEMBRANES, Aarhus Univ, Aarhus, 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, p. 216-226Article 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.

  • 33.
    Henry, Barbara J.
    et al.
    W.L. Gore & Associates Inc., Elkton MD, USA.
    Carlin, Joseph P.
    W.L. Gore & Associates Inc., Elkton MD, USA.
    Hammerschmidt, Jon A.
    W.L. Gore & Associates Inc., Elkton MD, USA.
    Buck, Robert C.
    The Chemours Company, Wilmington DE, USA.
    Buxton, L. William
    The Chemours Company, Wilmington DE, USA.
    Fiedler, Heidelore
    Örebro University, School of Science and Technology.
    Seed, Jennifer
    Risk Assessment Consultant, Alexandria VA, USA.
    Hernandez, Oscar
    Bergeson & Campbell, Washington DC, USA.
    A critical review of the application of polymer of low concern and regulatory criteria to fluoropolymers2018In: Integrated Environmental Assessment and Management, ISSN 1551-3777, E-ISSN 1551-3793, Vol. 14, no 3, p. 316-334Article, review/survey (Refereed)
    Abstract [en]

    Per- and poly-fluoroalkyl substances (PFAS) are a group of fluorinated substances that are in the focus of researchers and regulators due to widespread presence in the environment and biota, including humans, of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Fluoropolymers, high molecular weight polymers within the PFAS group, have unique properties that constitute a distinct class within the PFAS group. Fluoropolymers have thermal, chemical, photochemical, hydrolytic, oxidative and biological stability. They have negligible residual monomer and oligomer content and low to no leachables. Fluoropolymers are practically insoluble in water and not subject to long-range transport. With a molecular weight well over 100,000 Da, fluoropolymers cannot cross the cell membrane. Fluoropolymers are not bioavailable or bioaccumulative, as evidenced by toxicology studies on PTFE: acute and subchronic systemic toxicity, irritation, sensitization, local toxicity on implantation, cytotoxicity, in vitro and in vivo genotoxicity, hemolysis, complement activation, and thrombogenicity. Clinical studies of patients receiving permanently implanted PTFE cardiovascular medical devices demonstrate no chronic toxicity or carcinogenicity, reproductive or developmental or endocrine toxicity. This paper brings together fluoropolymer toxicity data, human clinical data, and physical-chemical-thermal-biological data for review and assessment to show that fluoropolymers satisfy widely accepted assessment criteria to be considered as "Polymers of Low Concern". This review concludes that fluoropolymers are distinctly different from other polymeric and non-polymeric per- and poly-fluoroalkyl substances and should be separated from them for hazard assessment or regulatory purposes. Grouping fluoropolymers with all classes of PFAS for "read across" or structure activity relationship assessment is not scientifically appropriate.

  • 34.
    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 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, p. 5633-5641Article in journal (Refereed)
  • 35.
    Heymans, Raymond
    et al.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Amsterdam, The Netherlands.
    Bruisten, Sylvia M.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Amsterdam, Netherlands; Department of Experimental Virology, University of Amsterdam, Amsterdam, The 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, Amsterdam, Netherlands; Department of Medical Microbiology, Onze Lieve Vrouwe Gasthuis General Hospital, Amsterdam, The 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, p. 1516-1522Article 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.

  • 36.
    Hukkanen, J.
    et al.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Puurunen, J.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Hyötyläinen, Tuulia
    Steno Diabetes Center, Gentofte, Denmark.
    Savolainen, M. J.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Ruokonen, A.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Morin-Papunen, L.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Oresic, Matej
    Steno Diabetes Center, Gentofte, Denmark.
    Piltonen, T.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
    Tapanainen, J. S.
    University of Oulu, Oulu, Finland; Oulu University Hospital, Oulu, Finland; University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland.
    The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity2015In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 80, no 3, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Aims: Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

    Methods: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20mg day1 (n=15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α- epoxycholesterol ratios were used as negative controls.

    Results: Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference – 0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α- epoxycholesterol to cholesterol did not change.

    Conclusions: The results establish atorvastatin as an inhibitor of CYP3A4 activity.

    Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the

    conditions with altered cholesterol concentrations.

  • 37.
    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. 

  • 38.
    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, p. 99-99Article in journal (Other academic)
  • 39.
    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, p. 693-704Article 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.

  • 40.
    Ito, Teruyo
    et al.
    Dept Bacteriol, Juntendo Univ, Tokyo, Japan .
    Hiramatsu, Keiichi
    Rockefeller University, New York NY, USA .
    Tomasz, Alexander
    Rockefeller University, New York NY, USA .
    de Lencastre, Herminia
    Rockefeller University, New York NY, USA; Inst Tecnol Quim & Biol, University Nova Lisboa, Oeiras, Portugal.
    Perreten, Vincent
    Inst Vet Bacteriol, University Bern, Bern, Switzerland.
    Holden, Matthew T. G.
    Wellcome Trust Sanger Inst, Hinxton, England.
    Coleman, David C.
    Dublin Dent University Hospital, Univ Dublin, Dublin, Ireland; Trinity College, Dublin, Ireland.
    Goering, Richard
    Medical Center, University of Nebraska, Omaha NE, USA.
    Giffard, Philip M.
    Menzies School of Heallth Research, Darwin NT, Australia.
    Skov, Robert L.
    Statens Serum Institut, Copenhagen, Denmark .
    Zhang, Kunyan
    Univ Calgary, Calgary AB, Canada.
    Westh, Henrik
    Faculty of Health, Copenhagen University, Copenhagen, Denmark; Hvidovre Hospital, Copenhagen University, Copenhagen, Denmark.
    O'Brien, Frances
    Curtin Univ Technol, Perth WA, Australia.
    Tenover, Fred C.
    Cepheid, Sunnyvale CA, USA.
    Oliveira, Duarte C.
    Inst Tecnol Quim & Biol, University Nova Lisboa, Oeiras, Portugal; Faculty of Ciencias & Tecnol, Dept Life Sciences, CREM, University Nova Lisboa, Caparica, Portugal .
    Boyle-Vavra, Susan
    Faculty of Ciencias & Tecnol, Dept Life Sciences, CREM, University Nova Lisboa, Caparica, Portugal .
    Laurent, Frederic
    French Natl Reference Ctr Staphylococci, Hosp Civils Lyon, Lyon, France.
    Kearns, Angela M.
    Staphylococcus Reference Unit, Heallth Protecttion Agency, London, England.
    Kreiswirth, Barry
    Pubicl Health Research Institute, New York NY, USA .
    Ko, Kwan Soo
    School of Medicine, Sungkyunkwan University, Seoul, South Korea .
    Grundmann, Hajo
    Nationall Insitute of Public Health & Environment, Utrecht, Netherlands .
    Sollid, Johanna E.
    Tromsø University, Tromsø, Norway .
    John, Joseph F. Jr.
    Ralph H Johnson VA Med Ctr, Charleston SC, USA.
    Daum, Robert
    University of Chicago, Chicago IL, 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, p. 4997-4999Article in journal (Other academic)
  • 41.
    Jacobsson, Susanne
    et al.
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    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, Örebro University Hospital, Örebro, Sweden.
    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, p. 5585-5588Article 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.

  • 42.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Scangarella-Oman, Nicole
    GlaxoSmithKline, Collegeville PA, USA.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 8, p. 2072-2077Article in journal (Refereed)
    Abstract [en]

    Objectives: Increased antimicrobial resistance surveillance and new effective antimicrobials are crucial to maintain treatable gonorrhoea. We examined the in vitro activity of gepotidacin, a novel triazaacenaphthylene, and the effect of efflux pump inactivation on clinical Neisseria gonorrhoeae isolates and international reference strains (n = 252) and compared gepotidacin with antimicrobials currently or previously recommended for gonorrhoea treatment.

    Methods: MICs (mg/L) were determined by agar dilution (gepotidacin) or by Etest (seven other antimicrobials). The gyrA and parC genes were sequenced and the impact of inactivation of the MtrCDE, MacAB and NorM efflux pumps on gepotidacin MICs was examined.

    Results: Gepotidacin showed potent in vitro activity against all gonococcal isolates (n = 252; MIC <= 4 mg/L). The modal MIC, MIC50 , MIC90 and MIC range of gepotidacin were 0.5, 0.5, 1 and 0.032-4 mg/L, respectively. Inactivation of the MtrCDE efflux pump, but not MacAB or NorM, decreased the gepotidacin MICs for most strains. No significant cross-resistance between gepotidacin and any other antimicrobials, including the fluoroquinolone ciprofloxacin, was identified. However, the ParC D86N mutation (possibly together with additional antimicrobial resistance mutation), which is associated with fluoroquinolone resistance, was associated with increased gepotidacin MICs.

    Conclusions: Gepotidacin demonstrated high in vitro activity against gonococcal strains, indicating that gepotidacin could potentially be an effective option for gonorrhoea treatment, particularly in a dual antimicrobialtherapy regimen and for patients with resistance or allergy to extended-spectrum cephalosporins. Nevertheless, elucidating in vitro and in vivo resistance emergence and mechanisms in detail, together with further gonorrhoea clinical studies, ideally also including chlamydia and Mycoplasma genitalium are essential.

  • 43.
    Jeverica, Samo
    et al.
    Fac Med, Inst Microbiol & Immunol, Univ Ljubljana, 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
    Clin Infect Dis & Febrile Illnesses, Univ Med Ctr Ljubljana, 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, Örebro University Hospital, Örebro, Sweden.
    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, p. 1866-1872Article 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.

  • 44.
    Jeverica, Samo
    et al.
    Fac Med, Inst Microbiol & Immunol, Univ Ljubljana, 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
    Clin Infect Dis & Febrile Illnesses, Univ Med Ctr Ljubljana, Ljubljana, Slovenia.
    Potocnik, Marko
    Dept Dermatovenereol, Univ Med Ctr Ljubljana, 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, Örebro University Hospital, Örebro, Sweden.
    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, p. 1517-1525Article 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.

  • 45.
    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, p. 11-18Article 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

  • 46.
    Jonsson, Thomas Björn
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Surgery, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nilsson, T. K.
    Dept Med Biosci Clin Chem, Umeå Univ, Umeå, Sweden.
    Breimer, Lars H.
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Schneede, J.
    Dept Clin Pharmacol, Umeå Univ, 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, Faculty of Health and Medical Sciences, Örebro University, 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, p. 957-963Article 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.

  • 47.
    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, p. 91-101Article 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.

  • 48.
    Kharlyngdoh, Joubert Banjop
    et al.
    Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Centre, Chicago, USA.
    Pradhan, Ajay
    Örebro University, School of Science and Technology.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology.
    Androgen receptor modulation following combination exposure to brominated flame-retardants2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 4843Article in journal (Refereed)
    Abstract [en]

    Endocrine disrupting compounds can interfere with androgen receptor (AR) signaling and disrupt steroidogenesis leading to reproductive failure. The brominated flame-retardant (BFR) 1, 2-dibromo-4-(1, 2-dibromoethyl) cyclohexane (TBECH), is an agonist to human, chicken and zebrafish AR. Recently another group of alternative BFRs, allyl 2, 4, 6-tribromophenyl ether (ATE), and 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether (DPTE) along with its metabolite 2-bromoallyl 2, 4, 6-tribromophenyl ether (BATE) were identified as potent human AR antagonists. These alternative BFRs are present in the environment. The aim of the present study was to determine the effect of mixed exposures to the AR agonist and the AR antagonists at environmentally relevant concentrations. In vitro reporter luciferase assay showed that the AR antagonists, when present at concentration higher than TBECH, were able to inhibit TBECH-mediated AR activity. These AR antagonists also promoted AR nuclear translocation. In vitro gene expression analysis in the non-tumorigenic human prostate epithelial cell RWPE1 showed that TBECH induced AR target genes whereas DPTE repressed these genes. Further analysis of steroidogenic genes showed that TBECH up-regulated most of the genes while DPTE down-regulated the same genes. The results indicate that when TBECH and DPTE are present together they will antagonize each other, thereby reducing their individual effects.

  • 49.
    Kurland, Lisa
    et al.
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Melhus, Håkan
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Karlsson, Julia
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Malmqvist, Karin
    Division of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
    Öhman, K. Peter
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Nyström, Fredrik
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Hägg, Anders
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients2001In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 19, no 10, p. 1783-1787Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol.

    DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction.

    RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment.

    CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.

  • 50.
    Kurland, Lisa
    et al.
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Melhus, Håkan
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Karlsson, Julia
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Kahan, Thomas
    Division of Internal Medicine, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Malmqvist, Karin
    Division of Internal Medicine, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Öhman, Peter
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Nyström, Fredrik
    Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden.
    Hägg, Anders
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Lind, Lars
    Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.
    Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial2002In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 20, no 4, p. 657-663Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Our aim was to determine if gene polymorphisms in the renin-angiotensin-aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment.

    METHODS AND RESULTS: Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (-23 +/- 31SD g/m2 for TM and +0.5 +/- 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (-0.1 +/- 19 g/m2 for AA and -18 +/- 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol.

    DISCUSSION: The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.

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