To Örebro University

oru.seÖrebro University Publications
Change search
Refine search result
12345 1 - 50 of 220
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 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.
    Albrektsson, A.
    et al.
    Anatomy and Cell Biology, Göteborg University, Göteborg, Sweden.
    Bazargani, Farhan
    Anatomy and Cell Biology, Göteborg University, Göteborg, Sweden.
    Wieslander, A.
    Gambro AB, Lund, Sweden.
    Braide, M.
    Anatomy and Cell Biology, Göteborg University, Göteborg, Sweden; Department of Anatomy and Cell Biology, Göteborg University, Göteborg, Sweden.
    Peritoneal dialysis fluid-induced angiogenesis in rat mesentery is increased by lactate in the presence or absence of glucose2006In: ASAIO journal (1992), ISSN 1058-2916, E-ISSN 1538-943X, Vol. 52, no 3, p. 276-281Article in journal (Refereed)
    Abstract [en]

    Angiogenesis may be an important mechanism behind the functional deterioration of the peritoneum leading to ultrafiltration failure in peritoneal dialysis. The present study was designed to compare the angiogenic properties of lactate-, bicarbonate-, and pyruvate-buffered fluids, evaluated separately with and without glucose. Five different fluids (lactate and bicarbonate with and without 2.5% glucose and pyruvate without glucose) were studied for 5 weeks of twice-daily injections in rats. The respective buffers (40 mmol/l) were adjusted to pH 7.2, and sodium, chloride, calcium, and magnesium were present at standard concentrations. The mesenteric window model, based on observation of the translucent peritoneal sections of the small intestine mesentery, was used for immunohistochemical imaging of microvessels (RECA-1 antigen) and macrophages (ED1 and ED2 antigens). All fluids induced angiogenesis as compared with untreated controls. The lactate-buffered fluids induced larger vascularized zones than did their bicarbonate- and pyruvate-buffered counterparts. Angiogenesis was accompanied by a local recruitment of ED1 macrophages from blood. Addition of glucose to the lactate- and bicarbonate-buffered fluids did not seem to alter their pro-angiogenic properties. In conclusion, intraperitoneal exposure to lactate buffer, compared with bicarbonate, stimulates angiogenesis in the presence or absence of glucose.

  • 3.
    Alfalasi, Maryam
    et al.
    College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
    Alzaabi, Sarah
    College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
    Östlundh, Linda
    Örebro University, University Library. National Medical Library, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
    Al-Rifai, Rami H.
    Institute of Public Health, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
    Al-Salam, Suhail
    Department of Pathology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
    Mertes, Paul Michel
    Department of Anesthesia and Intensive Care, University Hospital of Strasbourg, Strasbourg, France; Faculty of Medicine, EA 3072, Federation of Translational Medicine, University of Strasbourg, Strasbourg, France.
    Alper, Seth L.
    Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston MA, USA; Department of Medicine, Harvard Medical School, Boston MA, USA.
    Aburawi, Elhadi H.
    Department of Pediatrics, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
    Bellou, Abdelouahab
    Institute of Sciences in Emergency Medicine, Academy of Medical Sciences of Guangdong, Guangzhou, China; Department of Emergency Medicine, Academy of Medical Sciences of Guangdong, Guangzhou, China; Department of Emergency Medicine, Wayne State University School of Medicine, Detroit MI, USA.
    Effect of Nitric Oxide Pathway Inhibition on the Evolution of Anaphylactic Shock in Animal Models: A Systematic Review2022In: Biology, E-ISSN 2079-7737, Vol. 11, no 6, article id 919Article, review/survey (Refereed)
    Abstract [en]

    Simple Summary: Anaphylactic shock (AS) is the most serious consequence of anaphylaxis, with life-threatening sequelae including hypovolemia, shock, and arrhythmias. The literature lacks evidence for the effectiveness of interventions other than epinephrine in the acute phase of anaphylaxis. Our objective was to assess, through a systematic review, how inhibition of nitric oxide (NO) pathways affects blood pressure, and whether such blockade improves survival in AS animal models. AS was induced in all included studies after or before drug administration that targeted blockade of the NO pathway. In all animal species studied, the induction of AS caused a reduction in arterial blood pressure. However, the results show different responses to the inhibition of nitric oxide pathways. Overall, seven of fourteen studies using inhibition of nitric oxide pathways as pre-treatment before induction of AS showed improvement of survival and/or blood pressure. Four post-treatment studies from eight also showed positive outcomes. This review did not find strong evidence to propose modulation of blockade of the NO/cGMP pathway as a definitive treatment for AS in humans. Well-designed in vivo AS animal pharmacological models are needed to explore the other pathways involved, supporting the concept of pharmacological modulation.

    Abstract: Nitric oxide (NO) induces vasodilation in various types of shock. The effect of pharmacological modulation of the NO pathway in anaphylactic shock (AS) remains poorly understood. Our objective was to assess, through a systematic review, whether inhibition of NO pathways (INOP) was beneficial for the prevention and/or treatment of AS. A predesigned protocol for this systematic review was published in PROSPERO (CRD42019132273). A systematic literature search was conducted till March 2022 in the electronic databases PubMed, EMBASE, Scopus, Cochrane and Web of Science. Heterogeneity of the studies did not allow meta-analysis. Nine hundred ninety unique studies were identified. Of 135 studies screened in full text, 17 were included in the review. Among six inhibitors of NO pathways identified, four blocked NO synthase activity and two blocked guanylate cyclase downstream activity. Pre-treatment was used in nine studies and post-treatment in three studies. Five studies included both pre-treatment and post-treatment models. Overall, seven pre-treatment studies from fourteen showed improvement of survival and/or arterial blood pressure. Four post-treatment studies from eight showed positive outcomes. Overall, there was no strong evidence to conclude that isolated blockade of the NO/cGMP pathway is sufficient to prevent or restore anaphylactic hypotension. Further studies are needed to analyze the effect of drug combinations in the treatment of AS.

  • 4.
    Alfaro-Moreno, Ernesto
    et al.
    Örebro University, School of Science and Technology.
    Quintana-Belmares, R.
    Instituto Nacional de Cancerologia, Investigacion Basica, Mexico City, Mexico.
    Montiel-Davalos, A.
    Instituto Nacional de Cancerologia, Investigacion Basica, Mexico City, Mexico.
    Gustafsson, A.
    Örebro University, Man-Technology-Environment Research Center, Örebro, Sweden.
    Miranda, J.
    Universidad Nacional Autonoma de Mexico, Instituto de Fisica, Mexico City, Mexico.
    Lopez-Marure, R.
    Instituto Nacional de Cardiologia, Investigacion, Mexico City, Mexico.
    Rosas-Perez, I.
    Universidad Nacional Autonoma de Mexico, Centro de Ciencias de la Atmosfera, Mexico City, Mexico.
    Expression of receptors for adhesion molecules in monocytes exposed to urban particulate matter is independent of size and composition of the particles2019In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 314, no Suppl., p. S232-S233Article in journal (Other academic)
  • 5.
    Andersson, Sören
    et al.
    Örebro University, School of Medical Sciences. Folkhälsomyndigheten, Public Health Agency of Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    CHIMERIC MOMP ANTIGEN2015Patent (Other (popular science, discussion, etc.))
    Download full text (pdf)
    Patent
  • 6.
    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.

  • 7.
    Arnone, Danilo
    et al.
    United Arab Emirates University, College of Medicine and Health Sciences, Al Ain, United Arab Emirates; Centre for Affective Disorders, Psychological Medicine, Institute of Psychiatry, Psychology and Neurosciences, King’s College London, London, UK.
    Galadari, Hassan
    United Arab Emirates University, College of Medicine and Health Sciences, Al Ain, United Arab Emirates.
    Rodgers, Carl J.
    Centre for Affective Disorders, Psychological Medicine, Institute of Psychiatry, Psychology and Neurosciences, King’s College London, London, UK.
    Östlundh, Linda
    United Arab Emirates University, College of Medicine and Health Sciences, Al Ain, United Arab Emirates.
    Aziz, Karim Abdel
    United Arab Emirates University, College of Medicine and Health Sciences, Al Ain, United Arab Emirates.
    Stip, Emmanuel
    United Arab Emirates University, College of Medicine and Health Sciences, Al Ain, United Arab Emirates; Centre Hospitalier Universitaire de Montreal (CHUM), Institute Universitaire en Santé Mentale de Montréal, Université de Montreal, Montreal, Canada.
    Young, Allan H.
    Centre for Affective Disorders, Psychological Medicine, Institute of Psychiatry, Psychology and Neurosciences, King’s College London, London, UK.
    Efficacy of onabotulinumtoxinA in the treatment of unipolar major depression: Systematic review, meta-analysis and meta-regression analyses of double-blind randomised controlled trials2021In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 35, no 8, p. 910-918, article id 0269881121991827Article, review/survey (Refereed)
    Abstract [en]

    Background: OnabotulinumtoxinA is a novel therapeutic intervention whose mechanism of action is believed to modify the negative facial feedback, thus abating symptoms of depression. This putative new antidepressant agent offers minimal systemic side effects and negligible risk of pharmacological interactions. We set out to examine the evidence for the use of onabotulinumtoxinA in major depression.

    Methods: A systematic search of the literature identified double-blind randomised controlled trials (RCTs) investigating the use of onabotulinumtoxinA in the treatment of major depression versus placebo. Data, reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), was combined in meta-analyses (PROSPERO registration ID: CRD42020183538).

    Results: The search identified five RCTs (four double-blind) comparing onabotulinumtoxinA to placebo. OnabotulinumtoxinA was more effective than placebo when administered within the 20-40 IU dose range in double-blind RCTs. The analysis was free of publication bias and significantly heterogeneous. Meta-regression analyses indicated that onabotulinumtoxinA was more efficacious in women and in higher doses in female patients and less effective with polypharmacy, especially when an increasing number of antidepressants were prescribed. The effectiveness of onabotulinumtoxinA was higher in more recently published double-blind RCTs.

    Conclusion: The meta-analysis supports the efficacy of the intervention with the results being highly heterogeneous across studies. In view of the heterogeneity of the findings and the significant moderators of benefit (sex, year of study completion and the interaction between sex and dose), more research is required to better understand the role of onabotulinumtoxinA in the treatment of depression.

  • 8.
    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.

  • 9.
    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.

  • 10.
    Bazargani, Farhan
    et al.
    Department of Anatomy and Cell Biology, University of Göteborg, Göteborg, Sweden.
    Albrektsson, A.
    Department of Anatomy and Cell Biology, University of Göteborg, Göteborg, Sweden.
    Yahyapour, N.
    Department of Anatomy and Cell Biology, University of Göteborg, Göteborg, Sweden.
    Braide, M.
    Department of Anatomy and Cell Biology, University of Göteborg, Göteborg, Sweden.
    Low molecular weight heparin improves peritoneal ultrafiltration and blocks complement and coagulation2005In: Peritoneal Dialysis International, ISSN 0896-8608, E-ISSN 1718-4304, Vol. 25, no 4, p. 394-404Article in journal (Refereed)
    Abstract [en]

    Objectives: Clinical studies have demonstrated that the intraperitoneal (IP) complement and coagulation systems are activated in peritoneal dialysis (PD) patients. In animal models, low molecular weight heparin (LMWH) was seen to inhibit peritoneal angiogenesis, and related compounds have increased ultrafiltration volumes after repeated administration to PD patients. The present study evaluated the effects of LMWH on ultrafiltration, coagulation, and complement activation during a single PD dwell.

    Design: Rats were exposed to a single dose of 20 mL 2.5% glucose-based, filter-sterilized PD fluid, with or without supplementation with LMWH. The PD fluid was administered either as an IP injection or as an infusion through an indwelling catheter. The dwell fluid was analyzed 2 hours later concerning activation of the complement and coagulation cascades, chemotactic activity, neutrophil recruitment, ultrafiltration volume, and glucose and urea concentrations.

    Results: Exposure to PD fluid induced activation of IP complement [formation of C3a(desArg) and increase of C5a-dependent chemotactic activity] and coagulation (formation of thrombin-antithrombin complex) and recruitment of neutrophils. In the case of IP injection, neutrophil recruitment and complement activation were inhibited by LMWH. In both models, LMWH inhibited thrombin formation, reduced complement-dependent chemotactic activity, and increased the IP fluid volume, indicating an improved ultrafiltration.

    Conclusions: The acute inflammatory reaction to PD fluid involves the complement and coagulation cascades. Addition of LMWH to the PD fluid improves ultrafiltration, inhibits formation of thrombin, and potentially blocks C5a activity. The present results motivate further investigations of the IP cascade systems in PD. 

  • 11.
    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.

  • 12.
    Benfenati, Emilio
    et al.
    Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Milano, Italy.
    Golbamaki, Azadi
    Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Milano, Italy.
    Raitano, Giuseppa
    Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Milano, Italy.
    Roncaglioni, Alessandra
    Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Milano, Italy.
    Manganelli, Serena
    Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Milano, Italy; Nestlé Research Center, Lausanne, Switzerland.
    Lemke, Fabian
    KnowledgeMiner, Berlin, Germany.
    Norinder, Ulf
    Swetox, Södertälje, Sweden; Dept of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
    Lo Piparo, Elena
    Nestlé Research Center, Lausanne, Switzerland.
    Honma, Masamitsu
    National Institute of Health Sciences, Kawasaki, Japan.
    Manganaro, Alberto
    KODE, Pisa, Italy.
    Gini, Giuseppina
    Politecnico di Milano, Milano, Italy.
    A large comparison of integrated SAR/QSAR models of the Ames test for mutagenicity($)2018In: SAR and QSAR in environmental research (Print), ISSN 1062-936X, E-ISSN 1029-046X, Vol. 29, no 8, p. 591-611Article in journal (Refereed)
    Abstract [en]

    Results from the Ames test are the first outcome considered to assess the possible mutagenicity of substances. Many QSAR models and structural alerts are available to predict this endpoint. From a regulatory point of view, the recommendation from international authorities is to consider the predictions of more than one model and to combine results in order to develop conclusions about the mutagenicity risk posed by chemicals. However, the results of those models are often conflicting, and the existing inconsistency in the predictions requires intelligent strategies to integrate them. In our study, we evaluated different strategies for combining results of models for Ames mutagenicity, starting from a set of 10 diverse individual models, each built on a dataset of around 6000 compounds. The novelty of our study is that we collected a much larger set of about 18,000 compounds and used the new data to build a family of integrated models. These integrations used probabilistic approaches, decision theory, machine learning, and voting strategies in the integration scheme. Results are discussed considering balanced or conservative perspectives, regarding the possible uses for different purposes, including screening of large collection of substances for prioritization.

  • 13.
    Bergman, David
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Brommaplans Primary Health Care Center, Stockholm, Sweden.
    Clemente, Mark S.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Khalili, Flamed
    Division of Gastroenterology, Massachusetts General Hospital, Boston Massachusetts, USA; Harvard Medical School, Boston Massachusetts, USA.
    Agréus, Lars
    Division for Family Medicine and Primary Care, Karolinska Institutet, Huddinge, Sweden.
    Hultcrantz, Rolf
    Unit of Hepatology, Centre for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    A nationwide cohort study of the incidence of microscopic colitis in Sweden2019In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 49, no 11, p. 1395-1400Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiological studies of microscopic colitis have shown varying but increasing incidence rates. Aim To assess the incidence of microscopic colitis in Sweden.

    Methods: Nationwide cohort study performed in 1995-2015 based on biopsy reports. Age-specific and age-standardised incidence rates were calculated.

    Results: We identified 13 844 patients with an incident diagnosis of microscopic colitis. Lymphocytic colitis (n = 9238) constituted 67% and collagenous colitis (n = 4606) 33% of microscopic colitis. The mean age at time of diagnosis of microscopic colitis was 60.2 years (58.6 for lymphocytic colitis, 63.3 for collagenous colitis). The lifetime risk of developing microscopic colitis was 0.87% in women (95% confidence interval, CI: 0.85-0.88) and 0.35% in men (95% CI: 0.34-0.36). From 2006, the overall incidence of microscopic colitis was approximately 10.5 cases per 100 000 person-years (95% CI: 9.8-11.3) with higher rates in women (72% of cases, incidence rate ratio = 2.4 (95% CI: 2.3-2.5) and the elderly with increasing rates up to 75-79 years. From 2006-2015, there was a significant increase of 1% per year (P = 0.02) in the overall microscopic colitis incidence rate in women; the estimated annual percent change was similar, although not statistically significant, in men (P = 0.15).

    Conclusions: In Sweden, the incidence of microscopic colitis is still increasing in women, although the rate appears to be stabilising. The incidence is particularly high in women and the elderly up to age 75-79 years. Finally, across a lifetime, 1 in 115 females and 1 in 286 males are expected to be diagnosed with microscopic colitis and thus posing a considerable disease burden.

  • 14.
    Bergman, Åke
    et al.
    Swedish Toxicology Sciences Research Center (Swetox), Södertälje, Sweden.
    Becher, Georg
    Norwegian Institute of Public Health, Oslo, Norway.
    Blumberg, Bruce
    University of California, Irvine, USA.
    Bjerregaard, Poul
    University of Southern Denmark, Odense, Denmark.
    Bornman, Riana
    School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa.
    Brandt, Ingvar
    Uppsala University, Uppsala, Sweden.
    Casey, Stephanie C.
    University of California, Irvine, USA.
    Frouin, Heloise
    Vancouver Aquarium Marine Science Center, Vancouver, Canada.
    Giudice, Linda C.
    University of California, San Francisco, USA.
    Heindel, Jerrold J.
    National Institute of Environmental Health Sciences, USA.
    Iguchi, Taisen
    National Institute for Basic Biology, Okazaki, Japan.
    Jobling, Susan
    Brunel University London, Uxbridge, England.
    Kidd, Karen A.
    University of New Brunswick, Saint John, Canada.
    Kortenkamp, Andreas
    Brunel University London, Uxbridge, England.
    Lind, P. Monica
    Uppsala University, Uppsala, Sweden.
    Muir, Derek
    Environment Canada, Burlington, Canada.
    Ochieng, Roseline
    Aga Khan University Hospital, Nairobi, Kenya.
    Ropstad, Erik
    Norwegian University of Life Sciences, Oslo, Norway.
    Ross, Peter S.
    Vancouver Aquarium Marine Science Center, Vancouver, Canada.
    Skakkebaek, Niels E.
    Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
    Toppari, Jorma
    University of Turku, Turku, Finland.
    Vandenberg, Laura N.
    University of Massachusetts Amherst, Amherst, USA.
    Woodruff, Tracey J.
    University of California, San Francisco, USA.
    Zoeller, R. Thomas
    University of Massachusetts Amherst, Amherst, USA.
    Manufacturing doubt about endocrine disrupter science: A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"2015In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 73, no 3, p. 1007-1017Article in journal (Refereed)
    Abstract [en]

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.

  • 15.
    Björn, Niclas
    et al.
    Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Jakobsen Falk, Ingrid
    Örebro University, School of Medical Sciences. Örebro University Hospital. Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Udagawa, Chihiro
    Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Lewensohn, Rolf
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    De Petris, Luigi
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Zembutsu, Hitoshi
    Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
    Gréen, Henrik
    Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    The association of four genetic variants with myelosuppression in gemcitabine-treated Japanese is not evident in gemcitabine/carboplatin-treated Swedes2022In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 130, no 4, p. 513-521Article in journal (Refereed)
    Abstract [en]

    Gemcitabine/carboplatin-induced myelosuppressive adverse drug reactions (ADRs) are clinical problems leading to patient suffering and dose alterations. There is a need for personalised medicine to improve treatment effects and patients' well-being. We tested four genetic variants, rs11141915, rs1901440, rs12046844 and rs11719165, previously suggested as potential biomarkers for gemcitabine-induced leukopenia/neutropenia in Japanese patients, in 213 Swedish gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients. DNA was genotyped using TaqMan probes and real-time PCR. The relationships between the risk alleles and low toxicity (non-ADR: Common Terminology Criteria for Adverse Events [CTCAE] grades 0) or high toxicity (ADR: CTCAE grades 3-4) of platelets, leukocytes and neutrophils were evaluated using Fisher's exact test. The risk alleles did not correlate with myelosuppression, and the strongest borderline significance (not withstanding adjustment for multiple testing) was for rs1901440 (neutropenia, p = 0.043) and rs11719165 (leukopenia, p = 0.049) where the risk alleles trended towards lower toxicity, contrasting with previous study findings. Risk alleles and higher risk scores were more common among our patients. We conclude that the genetic variants do not apply to Swedish patients treated with gemcitabine/carboplatin. However, they can still be important in other populations and cohorts, especially in a gemcitabine monotherapy setting, where the causal genetic variation might influence myelosuppressive ADRs.

  • 16.
    Breimer, Lars H.
    et al.
    Centre for Assessment of Medical Technology in Örebro, School of Health and Medical Sciences, Örebro University, Örebro University Hospital, Örebro, Sweden; Department of Laboratory Medicine, Clinical Chemistry Division, Örebro University Hospital, Örebro, Sweden.
    Nousios, Petros
    Centre for Assessment of Medical Technology in Örebro, School of Health and Medical Sciences, Örebro University, Örebro University Hospital, Örebro, Sweden.
    Olsson, Louise
    Örebro University, School of Medical Sciences. Örebro University Hospital. Centre for Assessment of Medical Technology in Örebro.
    Brunnström, Hans
    Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
    Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer: promise, controversies and ambiguities in the novel treatment paradigm2020In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 80, no 5, p. 360-369Article, review/survey (Refereed)
    Abstract [en]

    Immune checkpoint inhibitors (ICIs) have received much attention not least for melanoma since the award of the Nobel prize in 2018. Here, we review the current state of knowledge about the use of these monoclonal antibodies (mAbs) in non-small cell lung cancer (NSCLC). These drugs have generally been conditionally approved on limited early data and there are few long-term follow-up data from randomized clinical trials. The effect observed for NSCLC thus far is, on average, moderately better than that obtained with chemotherapy. Severe side-effects are more common than might have been expected. The drugs themselves are expensive and are associated with time-consuming histopathologic testing even though the predictive value of these tests can be discussed. In addition, monitoring for side-effects involves increased workload and budgetary expense for clinical chemistry laboratories. Here, we review and summarize the current knowledge, controversies and ambiguities of ICIs for the treatment of NSCLC.

  • 17.
    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.

  • 18.
    Brink, B.
    et al.
    Södersjukhuset, Stockholm, Sweden.
    Kimland, E.
    Läkemedelsinformationscentralen, Sweden.
    von Euler, Mia
    Huddinge Universitetssjukhus, Stockholm, Sweden; Dept. of Clinical Pharmacology, Huddinge Universitetssjukhus, Stockholm, Sweden.
    Ovanligt fall av läkemedelsbiverkan: Cefotaximutlöst konfusion hos patient med njursvikt [Unusual side effect of cefotaxime: Confusion in a patient with renal failure]2003In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 100, no 28-29, p. 2370-2371Article in journal (Other academic)
    Abstract [sv]

    Third-generation cephalosporins in general have few adverse effects and cefotaxime (Claforan) particularly is considered to be a good choice because of the favourable side effect profile. In patients with severe renal failure there have been reports of confusion and psychosis. The manufacturer therefore recommends that half the ordinary dose should be given to patients with severe renal failure. Half the ordinary dose can still be too much. We describe a patient in hemodialysis who reacted with a reversible encephalopathy with psychosis in spite of reduced doses of cefotaxime. The plasma concentration of cefotaxime was high and the reaction was diagnosed as a dose dependent side effect.

  • 19.
    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.

  • 20.
    Burkill, Sarah
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Vattulainen, Pia
    EPID research, Helsinki, Finland.
    Geissbuehler, Yvonne
    Novartis Pharma AG, Basel, Switzerland.
    Sabido, Meritxell
    Merck Group, Darmstadt, Germany.
    Popescu, Catrinel
    Biogen, Maidenhead, UK.
    Suzart-Woischnik, Kiliana
    Bayer AG, Berlin, Germany.
    Hillert, Jan
    Karolinska Institute, Stockholm, Sweden.
    Cnattingus, Sven
    Karolinska Institute, Stockholm, Sweden.
    Artama, Miia
    National Institute for Health and Welfare Finland, Helsinki, Finland.
    Verkkoiemi-Ahola, Auli
    University of Helsinki, Helsinki, Finland.
    Myhr, Kjell-Morten
    University of Bergen,Bergen, Norway.
    Korhonen, Pasi
    EPID research, Helsinki, Finland.
    Montgomery, Scott
    Örebro University, School of Medical Sciences.
    Bahmanyar, Shahram
    Karolinska Institute, Stockholm, Sweden.
    The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis2019In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 28, no Suppl. 2, p. 371-372Article in journal (Other academic)
  • 21.
    Cao, Yang
    et al.
    Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
    Chen, Aimin
    Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE, USA.
    Jones, Robert L.
    Organic Analytical Toxicology Branch, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
    Radcliffe, Jerilynn
    The Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
    Caldwell, Kathleen L.
    Organic Analytical Toxicology Branch, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
    Dietrich, Kim N.
    Department of Environmental Health, Division of Epidemiology and Biostatistics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
    Rogan, Walter J.
    Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
    Does background postnatal methyl mercury exposure in toddlers affect cognition and behavior?2010In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 31, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Because the toxicological effects of mercury (Hg) are more serious in the developing central nervous system of children than adults, there are growing concerns about prenatal and early childhood Hg exposure. This study examined postnatal methylmercury (MeHg) exposure and cognition and behavior in 780 children enrolled in the Treatment of Lead (Pb)-exposed Children clinical trial (TLC) with 396 children allocated to the succimer and 384 to the placebo groups. Mercury exposure was determined from analyses of blood drawn 1 week before randomization and 1 week after treatment began when succimer had its maximal effect on blood Pb (PbB). The baseline MeHg concentrations were 0.54 microg/L and 0.52 microg/L and post-treatment concentrations were 0.51 microg/L and 0.48 microg/L for placebo and succimer groups, respectively. Because the baseline characteristics in the two groups were balanced and because succimer had little effect on MeHg concentration and no effect on the cognitive or behavioral test scores, the groups were combined in the analysis of MeHg and neurodevelopment. The children's IQ and neurobehavioral performance were tested at age 2, 5 and 7 years. We saw weak, non-significant but consistently positive associations between blood MeHg and IQ test scores in stratified, spline regression and generalized linear model data analyses. The behavioral problem scores were constant or decreased slightly with increasing MeHg concentration. Additional adjustment for PbB levels in multivariable models did not alter the conclusion for MeHg and IQ scores, but did confirm that concurrent PbB was strongly associated with IQ and behavior in TLC children. The effects of MeHg on neurodevelopmental indices did not substantially differ by PbB strata. We conclude that at the present background postnatal MeHg exposure levels of US children, adverse effects on children's IQ and behavior are not detectable.

  • 22.
    Cao, Yang
    et al.
    Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; Department of Health Statistics, Faculty of Health Services, Second Military Medical University, Shanghai, China.
    Chen, Aimin
    Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska, USA.
    Radcliffe, Jerilynn
    Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
    Dietrich, Kim N.
    Department of Environmental Health, Division of Epidemiology and Biostatistics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
    Jones, Robert L.
    Inorganic and Radiation Analytical Toxicology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
    Caldwell, Kathleen
    Inorganic and Radiation Analytical Toxicology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
    Rogan, Walter J.
    Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Postnatal cadmium exposure, neurodevelopment, and blood pressure in children at 2, 5, and 7 years of age2009In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 117, no 10, p. 1580-1586Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adverse health effects of cadmium in adults are well documented, but little is known about the neuropsychological effects of cadmium in children, and no studies of cadmium and blood pressure in children have been conducted.

    OBJECTIVE: We examined the potential effects of low-level cadmium exposure on intelligence quotient, neuropsychological functions, behavior, and blood pressure among children, using blood cadmium as a measure of exposure.

    METHODS: We used the data from a multicenter randomized clinical trial of lead-exposed children and analyzed blood cadmium concentrations using the whole blood samples collected when children were 2 years of age. We compared neuropsychological and behavioral scores at 2, 5, and 7 years of age by cadmium level and analyzed the relationship between blood cadmium levels at 2 years of age and systolic and diastolic blood pressure at 2, 5, and 7 years of age.

    RESULTS: The average cadmium concentration of these children was 0.21 microg/L, lower than for adults in the National Health and Nutrition Examination Survey (NHANES), but comparable to concentrations in children < 3 years of age in NHANES. Except for the California Verbal Learning Test for Children, there were no differences in test scores among children in different cadmium categories. For children with detectable pretreatment blood cadmium, after adjusting for a variety of covariates, general linear model analyses showed that at none of the three age points was the coefficient of cadmium on Mental Development Index or IQ statistically significant. Spline regression analysis suggested that behavioral problem scores at 5 and 7 years of age tended to increase with increasing blood cadmium, but the trend was not significant. We found no significant associations between blood cadmium levels and blood pressure.

    CONCLUSION: We found no significant associations between background blood cadmium levels at 2 years of age and neurodevelopmental end points and blood pressure at 2, 5, and 7 years of age. The neuropsychological or hypertensive effects from longer background exposures to cadmium need further study.

  • 23.
    Caspillo, Nasim Reyhanian
    et al.
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden; Örebro Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Volkova, Kristina
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden; Örebro Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Hallgren, Stefan
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology. Örebro Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Porsch-Hällström, Inger
    School of Natural Sciences, Technology and Environmental Studies, Södertörn University, Huddinge, Sweden.
    Short-term treatment of adult male zebrafish (Danio Rerio) with 17α-ethinyl estradiol affects the transcription of genes involved in development and male sex differentiation.2014In: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 164, p. 35-42Article in journal (Refereed)
    Abstract [en]

    The synthetic estrogen 17α-ethinyl estradiol (EE2) disturbs reproduction and causes gonadal malformation in fish. Effects on the transcription of genes involved in gonad development and function that could serve as sensitive biomarkers of reproductive effects in the field is, however, not well known. We have studied mRNA expression in testes and liver of adult zebrafish (Danio rerio) males treated with 0, 5 or 25ng/L EE2for 14days. qPCR analysis showed that the mRNA expression of four genes linked to zebrafish male sex determination and differentiation, Anti-Mullerian Hormone, Double sex and mab-related protein, Sry-related HMG box-9a and Nuclear receptor subfamily 5 group number 1b were significantly decreased by 25ng/L, but not 5ng/L EE2 compared with the levels in untreated fish. The decreased transcription was correlated with a previously shown spawning failure in these males (Reyhanian et al., 2011. Aquat Toxicol 105, 41-48), suggesting that decreased mRNA expression of genes regulating male sexual function could be involved in the functional sterility. The mRNA level of Cytochrome P-45019a, involved in female reproductive development, was unaffected by hormone treatment. The transcription of the female-specific Vitellogenin was significantly induced in testes. While testicular Androgen Receptor and the Estrogen Receptor-alpha mRNA levels were unchanged, Estrogen receptor-beta was significantly decreased by 25ng/L EE2. Hepatic Estrogen Receptor-alpha mRNA was significantly increased by both exposure concentrations, while Estrogen Receptor-beta transcription was unaltered. The decreased transcription of male-predominant genes supports a demasculinization of testes by EE2 and might reflect reproductive disturbances in the environment.

  • 24.
    Chavan, Swapnil
    et al.
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Scherbak, Nikolai
    Örebro University, School of Science and Technology.
    Engwall, Magnus
    Örebro University, School of Science and Technology.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Predicting Chemical-Induced Liver Toxicity Using High-Content Imaging Phenotypes and Chemical Descriptors: A Random Forest Approach2020In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 33, no 9, p. 2261-2275Article in journal (Refereed)
    Abstract [en]

    Hepatotoxicity is a major reason for the withdrawal or discontinuation of drugs from clinical trials. Thus, better tools are needed to filter potential hepatotoxic drugs early in drug discovery. Our study demonstrates utilization of HCI phenotypes, chemical descriptors, and both combined (hybrid) descriptors to construct random forest classifiers (RFCs) for the prediction of hepatotoxicity. HCI data published by Broad Institute provided HCI phenotypes for about 30 000 samples in multiple replicates. Phenotypes belonging to 346 chemicals, which were tested in up to eight replicates, were chosen as a basis for our analysis. We then constructed individual RFC models for HCI phenotypes, chemical descriptors, and hybrid (chemical and HCI) descriptors. The model that was constructed using selective hybrid descriptors showed high predictive performance with 5-fold cross validation (CV) balanced accuracy (BA) at 0.71, whereas within the given applicability domain (AD), independent test set and external test set prediction BAs were equal to 0.61 and 0.60, respectively. The model constructed using chemical descriptors showed a similar predictive performance with a 5-fold CV BA equal to 0.66, a test set prediction BA within the AD equal to 0.56, and an external test set prediction BA within the AD equal to 0.50. In conclusion, the hybrid and chemical descriptor-based models presented here should be considered as a new tool for filtering hepatotoxic molecules during compound prioritization in drug discovery.

  • 25.
    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.

  • 26.
    Chester, Lucy A.
    et al.
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Englund, Amir
    National Addiction Centre (NAC), Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Chesney, Edward
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Oliver, Dominic
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Wilson, Jack
    The Matilda Centre for Research in Mental Health and Substance Use, The University of Sydney, New South Wales, Australia.
    Sovi, Simina
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Dickens, Alex M.
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Linderman, Tuomas
    Turku Bioscience Center, University of Turku and Åbo Akademi University, Turku, Finland.
    Hodsoll, John
    Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Minichino, Amedeo
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Strang, John
    National Addiction Centre (NAC), Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Murray, Robin M
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
    Freeman, Tom P.
    Department of Psychology, University of Bath, Bath, United Kingdom.
    McGuire, Philip
    Department of Psychosis Studies and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
    Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study2022In: Cannabis and cannabinoid research, ISSN 2378-8763Article in journal (Refereed)
    Abstract [en]

    Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers.

    Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry.

    Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively.

    Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).

  • 27.
    Connolly, Eamonn
    et al.
    The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden.
    Nånberg, Eewa
    The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden.
    Nedergaard, Jan
    The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden.
    Norepinephrine-induced Na+ influx in brown adipocytes is cyclic AMP-mediated1986In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 261, no 31, p. 14377-14385Article in journal (Refereed)
    Abstract [en]

    To examine the involvement of Na+ ions in adrenergic responses in brown adipose tissue, a method is described for measuring Na+ influx into isolated brown adipocytes, using short (30 s) incubations with 22Na+, followed by a two-step centrifugation recovery procedure. Using this method, a clear norepinephrine-stimulated accumulation of intracellular 22Na+ was observed, which was enhanced by the addition of ouabain, was insensitive to amiloride (a Na+/H+ exchange blocker), and could not be mimicked by the total removal of oxygen from the incubation medium. The norepinephrine-stimulated Na+ influx was dose-dependent for the hormone with an EC50 of 250 nM, was blocked by the beta-antagonist propranolol but not by the alpha 1-antagonist prazosin, and could be induced by adrenergic agonists with the order of potency: isoproterenol greater than norepinephrine greater than phenylephrine, indicating a beta-receptor-mediated process. The Na+ influx was found to be cAMP-dependent since it could be induced by both theophylline (a phosphodiesterase inhibitor) and forskolin (an adenylate cyclase activator), but it was independent of other known cellular cAMP-dependent responses since neither addition of fatty acid substrates (octanoate or palmitate), nor of the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone could induce the phenomenon, despite having significant stimulatory effects on cellular respiration. Furthermore, total respiratory inhibition with rotenone, or total oxygen depletion of the medium with dithionite, did not prevent the normal norepinephrine-induced Na+ influx. The possibility that this beta-mediated norepinephrine-stimulated Na+ influx plays an important physiological role in brown adipose tissue activity is discussed, perhaps as one of the, as yet undefined, signals initiating tissue growth in the chronically beta-stimulated tissue of animals facing long-term increases in thermogenic demands.

  • 28.
    Dharpure, Rupal
    et al.
    Jyoti and Bhupat Mehta School of Health Science and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
    Pramanik, Subrata
    Jyoti and Bhupat Mehta School of Health Science and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
    Pradhan, Ajay
    Örebro University, School of Science and Technology. Biology, The Life Science Center.
    In silico analysis decodes transthyretin (TTR) binding and thyroid disrupting effects of per- and polyfluoroalkyl substances (PFAS)2023In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 97, no 3, p. 755-768Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) is a homo-tetramer protein involved in the transport of thyroid hormone (thyroxine; T4) in the plasma and cerebrospinal fluid. Many pollutants have been shown to bind to TTR, which could be alarming as disruption in the thyroid hormone system can lead to several physiological problems. It is also indicated that the monomerization of tetramer and destabilization of monomer can lead to amyloidogenesis. Many compounds are identified that can bind to tetramer and stabilize the tetramer leading to the inhibition of amyloid fibril formation. Other compounds are known to bind tetramer and induce amyloid fibril formation. Among the pollutants, per- and polyfluoroalkyl substances (PFAS) are known to disrupt the thyroid hormone system. The molecular mechanisms of thyroid hormone disruption could be diverse, as some are known to bind with thyroid hormone receptors, and others can bind to membrane transporters. Binding to TTR could also be one of the important pathways to alter thyroid signaling. However, the molecular interactions that drive thyroid-disrupting effects of long-chain and short-chain PFASs are not comprehensively understood at the molecular level. In this study, using a computational approach, we show that carbon chain length and functional group in PFASs are structural determinants, in which longer carbon chains of PFASs and sulfur-containing PFASs favor stronger interactions with TTR than their shorter-chained counterparts. Interestingly, short-chain PFAS also showed strong binding capacity, and the interaction energy for some was as close to the longer-chain PFAS. This suggests that short-chain PFASs are not completely safe, and their use and build-up in the environment should be carefully regulated. Of note, TTR homologs analysis suggests that thyroid-disrupting effects of PFASs could be most likely translated to TTR-like proteins and other species.

  • 29.
    Dong, Junze
    et al.
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Shandong, PR China.
    Zhang, Jingya
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Shandong, PR China.
    Li, Zilu
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Shandong, PR China.
    Asnake, Solomon
    Örebro University, School of Science and Technology. Biology, The Life Science Center.
    Zhang, Daoguang
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Shandong, PR China.
    Olsson, Per-Erik
    Örebro University, School of Science and Technology. Biology, The Life Science Center.
    Zhao, Guisen
    Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Shandong, PR China.
    Design, synthesis, and biological evaluation of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives as androgen receptor antagonists2019In: Medicinal Chemistry Research, ISSN 1054-2523, E-ISSN 1554-8120, Vol. 28, no 3, p. 380-386Article in journal (Refereed)
    Abstract [en]

    Androgen receptor (AR) signaling is often activated in prostate cancer (PCa) cells, and blockage of this signaling by AR antagonists is an important strategy in PCa therapy. In this study, we designed and synthesized a series of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives, and evaluated their biological activities. AR luciferase reporter assay revealed compound 6f (59.7%) as a potent AR antagonist. Some compounds in this series showed higher anti-proliferative activity against LNCaP cells than Bicalutamide (IC50=35.0M), especially 6g with IC50 value of 13.6 mu M.

  • 30.
    Eklund, Martin
    et al.
    Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; AstraZeneca Research and Development, Mölndal, Sweden.
    Norinder, Ulf
    Lundbeck Corporation, Valby, Denmark.
    Boyer, Scott
    AstraZeneca Research and Development, Mölndal, Sweden.
    Carlsson, Lars
    AstraZeneca Research and Development, Mölndal, Sweden.
    The application of conformal prediction to the drug discovery process2015In: Annals of Mathematics and Artificial Intelligence, ISSN 1012-2443, E-ISSN 1573-7470, Vol. 74, no 1-2, p. 117-132Article in journal (Refereed)
    Abstract [en]

    QSAR modeling is a method for predicting properties, e.g. the solubility or toxicity, of chemical compounds using machine learning techniques. QSAR is in widespread use within the pharmaceutical industry to prioritize compounds for experimental testing or to alert for potential toxicity during the drug discovery process. However, the confidence or reliability of predictions from a QSAR model are difficult to accurately assess. We frame the application of QSAR to preclinical drug development in an off-line inductive conformal prediction framework and apply it prospectively to historical data collected from four different assays within AstraZeneca over a time course of about five years. The results indicate weakened validity of the conformal predictor due to violations of the randomness assumption. The validity can be strengthen by adopting semi-off-line conformal prediction. The non-randomness of the data prevents exactly valid predictions but comparisons to the results of a traditional QSAR procedure applied to the same data indicate that conformal predictions are highly useful in the drug discovery process.

  • 31.
    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.

  • 32.
    Emilsson, Louise
    et al.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston Massachusetts, USA; Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; Centre for Clinical Research, Vårdcentralen Värmlands Nysäter, Värmlands Nysäter, Sweden.
    Ludvigsson, Jonas F.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Letter: anxiety after coeliac disease diagnosis predicts mucosal healing-a population-based study. Authors' reply2019In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 49, no 5, p. 620-620Article in journal (Refereed)
  • 33.
    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.

    Download full text (pdf)
    fulltext
  • 34.
    Eriksen, Jaran
    et al.
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Gustafsson, Lars L
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Ateva, Kristina
    Stockholm Drug and Therapeutics Committee, Public Healthcare Services Committee, Stockholm, Sweden.
    Bastholm-Rahmner, Pia
    Medical Management Centre, Department of Learning, Informatics, Management and Ethics (LIME), Karolinska Institutet, Stockholm, Sweden.
    Ovesjö, Marie-Louise
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Quality and Development, Södersjukhuset, Stockholm, Sweden.
    Jirlow, Malena
    Public Healthcare Services Committee, Stockholm, Sweden.
    Juhasz-Haverinen, Maria
    Public Healthcare Services Committee, Stockholm, Sweden.
    Lärfars, Gerd
    Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
    Malmström, Rickard E.
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Wettermark, Björn
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Andersén-Karlsson, Eva
    Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
    DTC, Stockholm
    High adherence to the 'Wise List' treatment recommendations in Stockholm: a 15-year retrospective review of a multifaceted approach promoting rational use of medicines2017In: BMJ Open, E-ISSN 2044-6055, Vol. 7, no 4, article id e014345Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To present the 'Wise List' (a formulary of essential medicines for primary and specialised care in Stockholm Healthcare Region) and assess adherence to the recommendations over a 15-year period.

    DESIGN: Retrospective analysis of all prescription data in the Stockholm Healthcare Region between 2000 and 2015 in relation to the Wise List recommendations during the same time period.

    SETTING: All outpatient care in the Stockholm Healthcare Region.

    PARTICIPANTS: All prescribers in the Stockholm Healthcare Region.

    MAIN OUTCOME MEASURES: The number of core and complementary substances included in the Wise List, the adherence to recommendations by Anatomic Therapeutic Chemical (ATC) 1st level using defined daily doses (DDDs) adjusted to the DDD for 2015, adherence to recommendations over time measured by dispensed prescriptions yearly between 2002 and 2015.

    RESULTS: The number of recommended core substances was stable (175-212). Overall adherence to the recommendations for core medicines for all prescribers increased from 75% to 84% (2000 to 2015). The adherence to recommendations in primary care for core medicines increased from 80% to 90% (2005 to 2015) with decreasing range in practice variation (32% to 13%). Hospital prescriber adherence to core medicine recommendations was stable but increased for the combination core and complementary medicines from 77% to 88% (2007 to 2015). Adherence varied between the 4 therapeutic areas studied.

    CONCLUSIONS: High and increasing adherence to the Wise List recommendations was seen for all prescriber categories. The transparent process for developing recommendations involving respected experts and clinicians using strict criteria for handling potential conflicts of interests, feedback to prescribers, continuous medical education and financial incentives are possible contributing factors. High-quality evidence-based recommendations to prescribers, such as the Wise List, disseminated through a multifaceted approach, will become increasingly important and should be developed further to include recommendations and introduction protocols for new expensive medicines.

  • 35. Eriksen, Jaran
    et al.
    von Euler, Mia
    arolinska universitetssjukhuset, Stockholm, Sweden.
    Vetenskapligt stöd saknas för effekt av naltrexon i låg dos2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 49, p. 2224-2224, article id DPU3Article in journal (Other (popular science, discussion, etc.))
  • 36.
    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)
  • 37.
    Eriksson, Irene
    et al.
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden.
    Cars, Thomas
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
    Malmström, Rickard E.
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Wettermark, Björn
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden .
    von Euler, Mia
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden .
    Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 2, p. 219-226Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To describe patients initiating dimethyl fumarate (DMF) and measure persistence with DMF, discontinuation, and switching in treatment-naïve DMF patients and patients switching to DMF from other multiple sclerosis disease-modifying treatments (DMTs).

    METHODS: A population-based cohort study of all Stockholm County residents initiating DMF from 9 May 2014 until 31 May 2017. All data were derived from a regional database that collects individual-level data on healthcare and drug utilization of all residents. The study outcomes were persistence with DMF and DMF discontinuation and switching to other DMTs. Persistence was measured as the number of days until either DMF discontinuation (treatment gap ≥ 60 days) or switching to another DMT.

    RESULTS: The study included 400 patients (median follow-up = 2.5 years). The majority had previously been treated with other DMTs (61%). Throughout the follow-up period, 124 patients (31%) discontinued DMF and 114 patients (29%) switched treatment. Overall, 34% of patients initiating DMF stopped treatment within 1 year and only 43% of patients remained on DMF at 2 years from treatment initiation.

    CONCLUSIONS: DMF had a rapid market uptake likely due to high expectations held by both patients and clinicians. However, persistence with DMF in routine clinical practice was found to be low.

  • 38.
    Eriksson, Irene
    et al.
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden.
    Komen, Joris
    Department of Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
    Piehl, Fredrik
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.
    Malmström, Rickard E.
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Wettermark, Björn
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden .
    von Euler, Mia
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden .
    The changing multiple sclerosis treatment landscape: impact of new drugs and treatment recommendations2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 5, p. 663-670Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of this study is to describe the utilization of disease-modifying treatments (DMTs) in relapsing-remitting multiple sclerosis (MS) and assess the impact of both the introduction of new drugs and treatment recommendations (local recommendation on rituximab use issued at the largest MS clinic in Stockholm and regional Drug and Therapeutics Committee (DTC) recommendation on how dimethyl fumarate should be used).

    METHODS: Interrupted time series analyses using monthly data on all MS patients treated with DMTs in the Stockholm County, Sweden, from January 2011 to December 2017.

    RESULTS: There were 4765 individuals diagnosed with MS residing in the Stockholm County from 2011 to 2017. Of these, 2934 (62%) were treated with an MS DMT. Since 2011, fingolimod, alemtuzumab, teriflunomide, dimethyl fumarate, peginterferon beta-1a, and daclizumab were introduced. Only fingolimod and dimethyl fumarate significantly impacted MS DMT utilization. In parallel, the use of rituximab off-label increased steadily, reaching 58% of all DMT-treated MS patients by the end of the study period. The local recommendation on rituximab was associated with an increase in rituximab use. The regional DTC recommendation on dimethyl fumarate was associated with a decrease in dimethyl fumarate use.

    CONCLUSIONS: Three MS DMTs-fingolimod, dimethyl fumarate, and rituximab off-label-impacted MS DMT utilization in the Stockholm County. The associations between the treatment recommendations and the subsequent changes in MS DMT utilization indicate that such interventions can influence the uptake and utilization of new drugs used in the specialized care setting.

  • 39.
    Eriksson, Irene
    et al.
    Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Solna, Sweden.
    Wettermark, Björn
    Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Solna, Sweden.
    Persson, Marie
    Healthcare Administration, Stockholm County Council, Stockholm, Sweden.
    Edström, Morgan
    Department of Clinical Pharmacology, County Council of Östergötland, Linköping University Hospital, Linköping, Sweden.
    Godman, Brian
    Health Economics Unit, University of Liverpool Management School, Liverpool, United Kingdom; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, United Kingdom.
    Lindhé, Anna
    Department of Healthcare, Regional Head Office, Region Västra Götaland, Gothenburg, Sweden.
    Malmström, Rickard E.
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Ramström, Helena
    Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden.
    von Euler, Mia
    Department of Medicine Solna, Karolinska Institutet, Solna, Sweden; Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Solna, Sweden.
    Bergkvist Christensen, Anna
    Department of Medicines Management and Informatics, Regional Head Office, Region Skåne, Malmö, Sweden.
    The Early Awareness and Alert System in Sweden: History and Current Status2017In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 8, article id 674Article, review/survey (Refereed)
    Abstract [en]

    The Swedish EAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the system today is its complete integration into the national process for managed introduction and follow-up of new medicines. The system will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international level.

  • 40.
    Escher, Sylvia E.
    et al.
    Fraunhofer Institute for Toxicology and Experimental Medicine, Chemical Safety and Toxicology, Germany.
    Aguayo-Orozco, Alejandro
    Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark.
    Benfenati, Emilio
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
    Bitsch, Annette
    Fraunhofer Institute for Toxicology and Experimental Medicine, Chemical Safety and Toxicology, Germany.
    Braunbeck, Thomas
    Aquatic Ecology and Toxicology Group, Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Brotzmann, Katharina
    Aquatic Ecology and Toxicology Group, Center for Organismal Studies, University of Heidelberg, Heidelberg, Germany.
    Bois, Frederic
    Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom.
    van der Burg, Bart
    BioDetection Systems, Amsterdam, the Netherlands.
    Castel, Jose
    Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
    Exner, Thomas
    Edelweiss Connect GmbH, Basel, Switzerland.
    Gadaleta, Domenico
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
    Gardner, Iain
    Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom.
    Goldmann, Daria
    University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria.
    Hatley, Oliver
    Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom.
    Golbamaki, Nazanin
    Lhasa Limited, Leeds, United Kingdom.
    Graepel, Rabea
    Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
    Jennings, Paul
    Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
    Limonciel, Alice
    Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
    Long, Anthony
    Lhasa Limited, Leeds, United Kingdom.
    Maclennan, Richard
    Cyprotex, Cheshire, United Kingdom.
    Mombelli, Enrico
    Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
    Norinder, Ulf
    Örebro University, School of Science and Technology.
    Jain, Sankalp
    University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria.
    Capinha, Liliana Santos
    Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
    Taboureau, Olivier T.
    Université de Paris, France.
    Tolosa, Laia
    Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
    Vrijenhoek, Nanette G.
    Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
    van Vugt-Lussenburg, Barbara M. A.
    BioDetection Systems, Amsterdam, the Netherlands.
    Walker, Paul
    Cyprotex, Cheshire, United Kingdom.
    van de Water, Bob
    Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
    Wehr, Matthias
    Fraunhofer Institute for Toxicology and Experimental Medicine, Chemical Safety and Toxicology, Germany.
    White, Andrew
    Unilever Safety and Environmental Assurance Centre, Sharnbrook, Bedfordshire, United Kingdom.
    Zdrazil, Barbara
    University of Vienna, Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Vienna, Austria.
    Fisher, Ciarán
    Certara UK Ltd, Simcyp Division, Sheffield, United Kingdom.
    Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action2022In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 79, article id 105269Article in journal (Refereed)
    Abstract [en]

    Read-across approaches often remain inconclusive as they do not provide sufficient evidence on a common mode of action across the category members. This read-across case study on thirteen, structurally similar, branched aliphatic carboxylic acids investigates the concept of using human-based new approach methods, such as in vitro and in silico models, to demonstrate biological similarity.

    Five out of the thirteen analogues have preclinical in vivo studies. Three out of them induced lipid accumulation or hypertrophy in preclinical studies with repeated exposure, which leads to the read-across hypothesis that the analogues can potentially induce hepatic steatosis.

    To confirm the selection of analogues, the expression patterns of the induced differentially expressed genes (DEGs) were analysed in a human liver model. With increasing dose, the expression pattern within the tested analogues got more similar, which serves as a first indication of a common mode of action and suggests differences in the potency of the analogues.

    Hepatic steatosis is a well-known adverse outcome, for which over 55 adverse outcome pathways have been identified. The resulting adverse outcome pathway (AOP) network, comprised a total 43 MIEs/KEs and enabled the design of an in vitro testing battery. From the AOP network, ten MIEs, early and late KEs were tested to systematically investigate a common mode of action among the grouped compounds.

    The targeted testing of AOP specific MIE/KEs shows that biological activity in the category decreases with side chain length. A similar trend was evident in measuring liver alterations in zebra fish embryos. However, activation of single MIEs or early KEs at in vivo relevant doses did not necessarily progress to the late KE “lipid accumulation”. KEs not related to the read-across hypothesis, testing for example general mitochondrial stress responses in liver cells, showed no trend or biological similarity.

    Testing scope is a key issue in the design of in vitro test batteries. The Dempster-Shafer decision theory predicted those analogues with in vivo reference data correctly using one human liver model or the CALUX reporter assays.

    The case study shows that the read-across hypothesis is the key element to designing the testing strategy. In the case of a good mechanistic understanding, an AOP facilitates the selection of reliable human in vitro models to demonstrate a common mode of action. Testing DEGs, MIEs and early KEs served to show biological similarity, whereas the late KEs become important for confirmation, as progression from MIEs to AO is not always guaranteed.

  • 41.
    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.

  • 42.
    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)
  • 43.
    Fjæraa Alfredsson, Christina
    et al.
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Ding, Menglei
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Liang, Qiu-Li
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Sundström, Birgitta
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Nånberg, Eewa
    Department of Health Sciences, Karlstad University, Karlstad, Sweden.
    Ellagic acid induces a dose- and time-dependent depolarization of mitochondria and activation of caspase-9 and -3 in human neuroblastoma cells2014In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 68, no 1, p. 129-135Article in journal (Refereed)
    Abstract [en]

    The polyphenol ellagic acid is found in many natural food sources and has been proposed as a candidate compound for clinical applications due to its anti-oxidative capacity and as a potential anti-tumorigenic compound. The objective of the present study was to evaluate the sensitivity to and possible apoptosis mechanism induced by ellagic acid in neuronal tumor cells. As a model the human neuroblastoma SH-SY5Y cell line was used. The methods applied were bright field and phase contrast microscopy, XTT- and LDH-assays, western blot, and flow cytometric analysis of DNA degradation and mitochondrial membrane potential. Ellagic acid treatment was found to induce a reduction in cell number preceded by alterations of the mitochondrial membrane potential and activation of caspase-9 and -3, DNA-fragmentation and cell death by apoptosis. The apoptotic cell death studied was not due to anoikis since it was significant in the adherent fraction of the cells. We conclude that ellagic acid induces dose- and time-dependent apoptosis, at least partly by the mitochondrial pathway, in an embryonal neuronal tumor cell system. This finding is in agreement with previously reported data on adult carcinoma cells thus suggesting a more general effect of ellagic acid on tumor cells.

  • 44.
    Flodström, Emelie
    et al.
    Karolinska universitetssjukhuset, Stockholm, Sweden.
    von Euler, Mia
    Karolinska universitetssjukhuset, Stockholm, Sweden.
    Valproat under graviditet ska undvikas2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 32-33, article id DCT9Article in journal (Other (popular science, discussion, etc.))
  • 45.
    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.

  • 46.
    Forreryd, Andy
    et al.
    Department of Immunotechnology, Lund University, Lund, Sweden.
    Norinder, Ulf
    Swetox, Karolinska Institute, Unit of Toxicology Sciences, Södertälje, Sweden; Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
    Lindberg, Tim
    Department of Immunotechnology, Lund University, Lund, Sweden.
    Lindstedt, Malin
    Department of Immunotechnology, Lund University, Lund, Sweden.
    Predicting skin sensitizers with confidence: Using conformal prediction to determine applicability domain of GARD2018In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 48, p. 179-187Article in journal (Refereed)
    Abstract [en]

    GARD - Genomic Allergen Rapid Detection is a cell based alternative to animal testing for identification of skin sensitizers. The assay is based on a biomarker signature comprising 200 genes measured in an in vitro model of dendritic cells following chemical stimulations, and consistently reports predictive performances similar to 90% for classification of external test sets. Within the field of in vitro skin sensitization testing, definition of applicability domain is often neglected by test developers, and assays are often considered applicable across the entire chemical space. This study complements previous assessments of model performance with an estimate of confidence in individual classifications, as well as a statistically valid determination of the applicability domain for the GARD assay. Conformal prediction was implemented into current GARD protocols, and a large external test dataset (n = 70) was classified at a confidence level of 85%, to generate a valid model with a balanced accuracy of 88%, with none of the tested chemical reactivity domains identified as outside the applicability domain of the assay. In conclusion, results presented in this study complement previously reported predictive performances of GARD with a statistically valid assessment of uncertainty in each individual prediction, thus allowing for classification of skin sensitizers with confidence.

  • 47.
    Forsgård, Richard A.
    et al.
    Pharmacology, University of Helsinki, Helsinki, Finland.
    Korpela, Riitta
    Pharmacology, University of Helsinki, Helsinki, Finland.
    Holma, Reetta
    Pharmacology, University of Helsinki, Helsinki, Finland.
    Lindén, Jere
    Department ofVeterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, FinlandHelsinki, Dept Vet Biosci, Fac Vet Med, Helsinki, Finland..
    Frias, Rafael
    Central Animal Laboratory, University of Turku, Turku, Finland; Comparative Medicine, Karolinska Institutet, Stockholm, Sweden.
    Spillmann, Thomas
    Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
    Österlund, Pia
    Department of Oncology, University of Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland.
    Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague-Dawley rats2016In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 78, no 4, p. 863-874Article in journal (Refereed)
    Abstract [en]

    Purpose: Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity.

    Methods: Male Sprague-Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg) or irinotecan (200 mg/kg). Clinical signs of gastrointestinal toxicity were assessed daily by weighing the animals and by checking for diarrhea. After 48 h, intestinal permeability to iohexol was measured in vivo by giving the animals 1 ml of 647 mg/ml iohexol solution by oral gavage and collecting all the excreted urine for 24 h. All of the animals were euthanized 72 h after drug administration and tissue samples were harvested from the jejunum and colon.

    Results: All chemotherapeutics caused significant body weight loss and diarrhea. Intestinal permeability to iohexol was also increased in all treatment groups and histological analysis revealed significant intestinal damage in both jejunum and colon. Iohexol permeability correlated with the severity of clinical signs of gastrointestinal toxicity and with acute colonic injury.

    Conclusions: Chemotherapeutic drugs, such as 5-fluorouracil, oxaliplatin, and irinotecan, increase intestinal permeability to iohexol. Measuring intestinal permeability to iohexol could provide a simple marker for assessing chemotherapy-induced gastrointestinal toxicity.

  • 48.
    Forsgård, Richard A.
    et al.
    Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Marrachelli, Vannina G.
    Metabolomics and Molecular Imaging Lab, Health Research Institute INCLIVA, Valencia, Spain.
    Korpela, Katri
    Immunobiology Research Program, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
    Frias, Rafael
    Central Animal Laboratory, University of Turku, Turku, Finland; Comparative Medicine, Karolinska Institutet, Stockholm, Sweden.
    Carmen Collado, Maria
    Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain.
    Korpela, Riitta
    Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Monleon, Daniel
    Metabolomics and Molecular Imaging Lab, Health Research Institute INCLIVA, Valencia, Spain.
    Spillmann, Thomas
    Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
    Österlund, Pia
    Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Oncology, Tampere University Hospital, Tampere, Finland.
    Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats2017In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 80, no 2, p. 317-332Article in journal (Refereed)
    Abstract [en]

    Purpose: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a complex process that involves multiple pathophysiological mechanisms. We have previously shown that commonly used chemotherapeutics 5-fluorouracil, oxaliplatin, and irinotecan damage the intestinal mucosa and increase intestinal permeability to iohexol. We hypothesized that CIGT is associated with alterations in fecal microbiota and metabolome. Our aim was to characterize these changes and examine how they relate to the severity of CIGT.

    Methods: A total of 48 male Sprague-Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg), or irinotecan (200 mg/kg). Body weight change was measured daily after drug administration and the animals were euthanized after 72 h. Blood, urine, and fecal samples were collected at baseline and at the end of the experiment. The changes in the composition of fecal microbiota were analyzed with 16S rRNA gene sequencing. Metabolic changes in serum and urine metabolome were measured with 1 mm proton nuclear magnetic resonance (1H-NMR).

    Results: Irinotecan increased the relative abundance of Fusobacteria and Proteobacteria, while 5-FU and oxaliplatin caused only minor changes in the composition of fecal microbiota. All chemotherapeutics increased the levels of serum fatty acids and N(CH3)(3) moieties and decreased the levels of Krebs cycle metabolites and free amino acids.

    Conclusions: Chemotherapeutic drugs, 5-fluorouracil, oxaliplatin, and irinotecan, induce several microbial and metabolic changes which may play a role in the pathophysiology of CIGT. The observed changes in intestinal permeability, fecal microbiota, and metabolome suggest the activation of inflammatory processes.

  • 49.
    Forslund, Tomas
    et al.
    Gröndals vårdcentral, Stockholm, Sweden.
    von Euler, Mia
    Södersjukhuset, Stockholm, Sweden.
    Jonsson, Hans
    Holmström, Margareta
    Karolinska universitetssjukhuset, Stockholm, Sweden.
    Wettermark, Björn
    Stockholms läns landsting, Stockholm, Sweden.
    Hjemdal, Paul
    Karolinska universitetssjukhuset, Stockholm, Sweden.
    More with atrial fibrillation, anticoagulants since the coming of NOAK [Fler med förmaksflimmer får antikoagulantia sedan NOAK kom]2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, article id CZYSArticle, review/survey (Other academic)
    Abstract [sv]

    Sedan introduktionen av NOAK (non-vitamin K antagonist oral anticoagulants) som trombosprofylax vid förmaksflimmer har det skett en markant ökning av antalet diagnostiserade patienter med förmaksflimmer i Stockholms läns landsting. Andelen som är behandlade med antikoagulantia har samtidigt ökat från 47 till 58 procent. Vid nyinsättning är NOAK lika vanliga som warfarin i nuläget. Förskrivningen av ASA sjunker kraftigt. NOAK-förskrivningen har varit avvaktande avseende de äldsta patienterna med hög risk för stroke, blödning och nedsatt njurfunktion.

  • 50.
    Forslund, Tomas
    et al.
    Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wettermark, Björn
    Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wändell, Per
    Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    von Euler, Mia
    Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Hasselström, Jan
    Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Hjemdahl, Paul
    Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Risks for stroke and bleeding with warfarin or aspirin treatment in patients with atrial fibrillation at different CHA(2)DS(2)VASc scores: experience from the Stockholm region2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 12, p. 1477-1485Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study evaluated the benefits of and possible contraindications to warfarin treatment in patients with atrial fibrillation (AF) prior to the introduction of new oral anticoagulants using health registry data from inpatient care, specialist ambulatory care, and primary care.

    METHODS: This is a cohort study including all patients in the region of Stockholm, Sweden (2.1 million inhabitants) with a diagnosis of non-valvular AF (n = 41 810) recorded during 2005-2009. The risks of suffering ischemic stroke, bleeding, or death with warfarin, aspirin, or no antithrombotic treatment during 2010 were related to CHA2DS2VASc scores, age, and complicating co-morbidities.

    RESULTS: One-year risks for ischemic stroke were 1.0-1.2 % with aspirin, 0-0.3 % with warfarin, and 0.1-0.2 % without treatment at CHA2DS2VASc scores 0-1. Among the aspirin-treated patients with CHA2DS2VASc scores ≥2, half had possible contraindications and high risks for ischemic stroke (5.2 %), bleeding (5.0 %), and death (19.3 %). The other half of the patients with no identified contraindications had a high risk for ischemic stroke (4.0 %) but a low bleeding risk (1.8 %) and a moderate mortality rate (8.4 %).

    CONCLUSIONS: The present observations confirm earlier findings of undertreatment with warfarin and half of the high-risk patients treated with aspirin were obvious candidates for anticoagulant treatment. However, the other half of the patients had complicating co-morbidities, high bleeding risk, and poor prognosis. This and possible overtreatment of low-risk patients should be taken into account when considering more aggressive use of anticoagulant treatment.

12345 1 - 50 of 220
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf