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  • 301.
    Jones, Michael P.
    et al.
    Macquarie Univ, Australia.
    Walter, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Olsen Faresjö, Åshild
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care. Division of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Sweden.
    Kjellstrom, Lars
    Department of Clinical Neuroscience, Sweden.
    Viktorsson, Lisa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Talley, Nicholas J.
    Univ Newcastle, Australia.
    Agreus, Lars
    Karolinska Institutet, Sweden.
    Andreasson, Anna
    Karolinska Institutet, Sweden; Stockholm Univ, Sweden.
    Gastrointestinal recall questionnaires compare poorly with prospective patient diaries for gastrointestinal symptoms: data from population and primary health centre samples2019In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 31, no 2, p. 163-169Article in journal (Refereed)
    Abstract [en]

    Background Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome.

    Patients and methods Data are reported from a randomly selected general population sample (n=238) and also a primary healthcare centre (PHC) sample (n=503, 10 PHCs). All the patients completed the questionnaires, which included Rome III-qualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated.

    Results Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample.

    Conclusion Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments.

  • 302.
    Jones, Rachel B.
    et al.
    Addenbrookes Hospital, England.
    Furuta, Shunsuke
    Addenbrookes Hospital, England.
    Cohen Tervaert, Jan Willem
    Maastricht University, Netherlands.
    Hauser, Thomas
    IZZ Immunol Zentrum, Switzerland.
    Luqmani, Raashid
    Nuffield Orthopaed Centre, England.
    Morgan, Matthew D.
    University of Birmingham, England.
    Au Peh, Chen
    Royal Adelaide Hospital, Australia; University of Adelaide, Australia.
    Savage, Caroline O.
    University of Birmingham, England.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Tesar, Vladimir
    Charles University of Prague, Czech Republic.
    van Paassen, Pieter
    Maastricht University, Netherlands.
    Walsh, Michael
    McMaster University, Canada; McMaster University, Canada.
    Westman, Kerstin
    University Hospital Skåne, Sweden; Lund University, Sweden.
    Jayne, David R. W.
    Addenbrookes Hospital, England.
    Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial2015In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 74, no 6, p. 1178-1182Article in journal (Refereed)
    Abstract [en]

    Objectives The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. Methods Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375mg/m(2)/weekx4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6months followed by azathioprine (n=11, control group). Results The primary end point at 24months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. Conclusions At 24months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. Trial registration number ISRCTN28528813.

  • 303.
    Jones, Rachel B.
    et al.
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Tervaer, Jan Willem Cohen
    Division of Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands .
    Hauser, Thomas
    ImmunologieZentrum Zürich and University Hospital, Zurich, Switzerland .
    Luqmani, Raashid
    Department of Rheumatology, Nuffield Orthopaedic Centre, Oxford , UK.
    Morgan, Matthew D.
    Department of Renal Immunobiolo - gy, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
    Peh, Chen Au
    Renal Unit, Royal Adelaide Hospital, Adelaide, Australia .
    Savage, Caroline O.
    Department of Renal Immunobiolo - gy, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Department of Nephrology in Lund, University Hospital of Skane and Lund University, Lund, Sweden.
    Tesar, Vladimir
    First Faculty of Medicine, Charles University, Prague, Czech Republic.
    Paassen, Pieter van
    Division of Clinical and Experimental Immunology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
    Wals, Dorothy
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Walsh, Michael
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Westman, Kerstin
    Department of Nephrology and Transplantation in Malmö, University Hospital of Skane and Lund University, Malmö, Sweden.
    Jayne, David R.W.
    Vasculitis and Lupus Clinic, Renal Unit, Addenbrooke’s Hospital, Cambridge, UK.
    Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 363, no 3, p. 211-220Article in journal (Refereed)
    Abstract [en]

    Background

    Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens.

    Methods

    We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events.

    Results

    The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m2 of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14).

    Conclusions

    A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events.

  • 304.
    Jones, Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Letter: Evidential breath alcohol analysis and the venous blood-to-breath ratio in FORENSIC SCIENCE INTERNATIONAL, vol 262, issue , pp E37-E392016In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 262, p. E37-E39Article in journal (Other academic)
    Abstract [en]

    n/a

  • 305.
    Jones, Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H-1 and H-2 Antagonists2016In: Clinical Pharmacology in Drug Development, ISSN 2160-7648, Vol. 5, no 1Article, review/survey (Refereed)
    Abstract [en]

    Knowledge about the history and development of therapeutic agents holds a central position in the education and training of pharmacists and pharmacologists. Students enjoy learning about the discovery of drugs, including details about the pioneer workers involved (apothecaries, organic chemists, pharmacologists, and physiologists) and the role played by serendipity. The treatment of people suffering from allergies and the development of drugs that block the actions of histamine at H-1 and H-2 receptors are the subject of this review. Pharmaceutical products that block H-1 receptors are widely used as prophylactic treatment for seasonal allergies that plague millions of people worldwide. The development of H-2 receptor antagonists revolutionized treatment of gastric hyperacidity, the principal cause of peptic ulcers. Antihistamine research has changed focus toward the development of drugs that block the action of histamine at H-3 and H-4 receptors and the therapeutic potential is gradually being appreciated.

  • 306.
    Jones, Wayne A
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Profiles in drug metabolism and toxicology: Richard Tecwyn Williams (1909-1979)2015In: Drug metabolism reviews (Softcover ed.), ISSN 0360-2532, E-ISSN 1097-9883, Vol. 47, no 4, p. 401-405Article, review/survey (Refereed)
    Abstract [en]

    This article pays homage to the life and work of a veritable pioneer in toxicology and drug metabolism, namely a Welshman, Richard Tecwyn Williams, FRS. Professor Williams, or RT as he was known, made major contributions to knowledge about the metabolism and toxicology of drugs and xenobiotics during a scientific career spanning nearly 50 years. Author or coauthor of close to 400 research articles and reviews, including a classic book, entitled Detoxication Mechanisms, Williams and his research school investigated virtually all aspects of drug metabolism, especially conjugations. In particular, the concepts of phase 1 and phase II metabolic pathways were introduced by Williams; the biliary excretion of drugs was extensively studied as were species differences in drug metabolism and detoxication. Besides investigating the metabolism of many pharmaceutical drugs, such as sulfonamides and thalidomide, Williams and his group investigated the disposition and fate in the body of organic pesticides and recreational drugs of abuse, such as amphetamine, methamphetamine and lysergic acid diethylamide (LSD).

  • 307.
    Jones, Wayne A.
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Holmgren, Anita
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden .
    Concentrations of alprazolam in blood from impaired drivers and forensic autopsies were not much different but showed a high prevalence of co-ingested illicit drugs2013In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 27, no 3, p. 276-281Article in journal (Refereed)
    Abstract [en]

    Alprazolam is a benzodiazepine anxiolytic widely prescribed for treatment of panic-disorder and social phobias, although this medication is also subject to abuse. In this paper, the concentrations of alprazolam in venous blood samples from impaired drivers were compared with femoral blood samples from forensic autopsies classified as intoxication or other causes of death (e.g. natural, trauma). After liquid-liquid extraction (n-butyl acetate) alprazolam was determined in blood by capillary gas chromatography with a nitrogen-phosphorous detector. The mean (median) and range of alprazolam concentrations in blood from impaired drivers (n = 773) were 0.08 mg/L (0.05 mg/L) and 0.02-3.9 mg/L, respectively. Many traffic offenders had co-ingested ethanol (13%), amphetamine (46%), cannabis (32%), or heroin (14%), as well as other drugs. In deaths attributed to drug intoxication, the mean (median) and range of alprazolam concentrations in blood (n = 438) were 0.10 mg/L (0.06 mg/L) and 0.02-1.6 mg/L, respectively, which were not much different from other causes of death (n = 278); 0.08 mg/L (0.05 mg/L) and 0.02-0.9 mg/L. Median concentrations of alprazolam in blood from living and deceased persons did not seem to depend on the number of co-ingested substances. The result of this pharmacoepidemiological study suggests that alprazolam is a fairly innocent drug when used as monotherapy, but toxicity problems arise when co-ingested with illicit drugs and/or psychoactive medication.

  • 308.
    Jones, Wayne A.
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National.
    Holmgren, Anita
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden .
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Toxicology findings in suicides: Concentrations of ethanol and other drugs in femoral blood in victims of hanging and poisoning in relation to age and gender of the deceased2013In: Journal of Forensic and Legal Medicine, ISSN 1752-928X, E-ISSN 1878-7487, Vol. 20, no 7, p. 842-847Article in journal (Refereed)
    Abstract [en]

    Over-consumption of alcohol and/or abuse of other drugs are closely linked to attempted or completed suicides. In this retrospective 10-year study (2001-2010), we compared the toxicology findings in hanging suicides (n = 4551) with drug poisoning (intoxication) suicides (n = 2468). The mean age of hanging deaths was 49 +/- 19 y (+/- SD) and 80% were male, compared with a mean age of 52 +/- 17 y and 47% males for the intoxication deaths. Poly-drug use was more common in poisoning suicides with an average of 3.6 drugs/case compared with 1.8 drugs/case in hangings. Moreover, 31% of hangings were negative for alcohol and/or drugs. Alcohol was detected (andgt;0.20 g/L) in femoral blood in 30% of hanging suicides (mean 1.39 g/L) and 36% of drug poisonings (mean 1.39 g/L). The median BACs did not depend on the persons age or gender (p andgt; 0.05). Ethanol, paracetamol, citalopram, diazepam, propiomazine, alimemazine and zopiclone were amongst the top-ten drugs detected in both methods of suicide. With the exception of ethanol, the concentrations of drugs in blood were considerably higher in the poisoning deaths, as might be expected. Regardless of the method of suicide, antidepressants and/or antipsychotics were common findings, which could implicate mental health as a significant suicide risk factor.

  • 309.
    Jonsson, Anna K.
    et al.
    National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Lövborg, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Lohr, Wolfgang
    Umeå University, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Rocklov, Joacim
    Umeå University, Sweden; Heidelberg University, Germany.
    Increased Risk of Drug-Induced Hyponatremia during High Temperatures2017In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 14, no 7, article id 827Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the relationship between outdoor temperature in Sweden and the reporting of drug-induced hyponatremia to the Medical Products Agency (MPA). Methods: All individual adverse drug reactions (ADR) reported to MPA from 1 January 2010 to 31 October 2013 of suspected drug-induced hyponatremia and random controls were identified. Reports where the ADR had been assessed as having at least a possible relation to the suspected drug were included. Information on administered drugs, onset date, causality assessment, sodium levels, and the geographical origin of the reports was extracted. A case-crossover design was used to ascertain the association between heat exposure and drug-induced hyponatremia at the individual level, while linear regression was used to study its relationship to sodium concentration in blood. Temperature exposure data were obtained from the nearest observation station to the reported cases. Results: During the study period, 280 reports of hyponatremia were identified. More cases of drug-induced hyponatremia were reported in the warmer season, with a peak in June, while other ADRs showed an opposite annual pattern. The distributed lag non-linear model indicated an increasing odds ratio (OR) with increasing temperature in the warm season with a highest odds ratio, with delays of 1-5 days after heat exposure. A cumulative OR for a lag time of 1 to 3 days was estimated at 2.21 at an average daily temperature of 20 degrees C. The change in sodium per 1 degrees C increase in temperature was estimated to be -0.37 mmol/L (95% CI: -0.02, -0.72). Conclusions: Warm weather appears to increase the risk of drug-induced hyponatremia.

  • 310.
    Jonsson, Anna K.
    et al.
    Natl Board Forens Med, Dept Forens Chem and Genet, Linkoping, Sweden.
    Spigset, Olav
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Sickle Univ Hosp, Sweden.
    A Compilation of Serum Concentrations of 12 Antipsychotic Drugs in a Therapeutic Drug Monitoring Setting2019In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 41, no 3, p. 348-356Article in journal (Refereed)
    Abstract [en]

    Background: No comprehensive collection of routine therapeutic drug monitoring data for antipsychotic drugs has been published. Methods: In this compilation, data on 12 antipsychotics are presented. The drugs included are amisulpride (n = 506), aripiprazole (n = 1610), clozapine (n = 1189), flupentixol (n = 215), haloperidol (n = 390), olanzapine (n = 10,268), perphenazine (n = 1065), quetiapine (n = 5853), risperidone (n = 3255), sertindole (n = 111), ziprasidone (n = 1235), and zuclopenthixol (n = 691). Because only one sample per patient is included, the number of patients equals the number of samples. For each drug, median serum concentrations as well as that of the 10th and 90th percentiles are given for a range of daily doses. Comparisons are made between males and females, between patients younger than 65 years and 65 years and older, and between those treated with a low and a high dose of each drug. The concentration-to-dose (C/D) ratio is the primary variable used in these comparisons. Coefficients of variation (CVs) for the serum concentrations of each drug within and between subjects are presented. Results: In general, the C/D ratios were higher in females than in males, higher in those 65 years and older than in younger subjects, and lower in those treated with higher doses than in those treated with lower doses. CVs between individuals were larger than within subjects, and the CVs were highest for the drugs with short elimination half-lives. Conclusions: For each antipsychotic drug, the results presented can serve as a reference tool for pharmacokinetic interpretation of the individual patients serum drug level. The compiled serum concentrations and the C/D ratios can support the physicians decision when individualizing dosing and determining treatment strategies for a specific patient.

  • 311.
    Junker, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lönnqvist, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Rakar, Jonathan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Karlsson, Lisa K.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Differentiation of human dermal fibroblasts towards endothelial cells2013In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 85, no 3, p. 67-77Article in journal (Refereed)
    Abstract [en]

    The ultimate goal of vascular tissue engineering is the production of functional grafts for clinical use. Difficulties acquiring autologous endothelial cells have motivated the search for alternative cell sources. Differentiation of dermal fibroblasts towards several mesenchymal lineages as well as endothelial cells has been proposed. The aim of the present study was to investigate the endothelial differentiation capacity of human dermal fibroblasts on a gene expression, protein expression and functional physiological level. Endothelial differentiation of fibroblasts was induced by culturing cells in 30% human serum, but not in fetal calf serum. Expression of proteins and genes relevant for endothelial function and differentiation was increased after induction. Furthermore, fibroblasts exposed to 30% human serum displayed increased uptake of low-density lipoprotein and formation of capillary-like networks. The results of this study may have an impact on cell sourcing for vascular tissue engineering, and the development of methods for vascularization of autologous tissue engineered constructs.

  • 312.
    Jönsson, Anna K
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Natl Board Forens Med, Dept Forens Genet and Forens Chem, Linkoping, Sweden.
    Schill, Johan
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Jönköping, Sweden.
    Olsson, Hans
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Region Jönköping, Sweden.
    Spigset, Olav
    St Olavs Univ Hosp, Norway; Norwegian Univ Sci and Technol, Norway.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence2018In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 32, no 1, p. 47-64Article, review/survey (Refereed)
    Abstract [en]

    This article summarises the current evidence on the risk of venous thromboembolism (VTE) with the use of antipsychotics. An increasing number of observational studies indicate an elevated risk of VTE in antipsychotic drug users. Although the use of certain antipsychotics has been associated with VTE, current data can neither conclusively verify differences in occurrence rates of VTE between first- and second-generation antipsychotics or between individual compounds, nor identify which antipsychotic drugs have the lowest risk of VTE. The biological mechanisms involved in the pathogenesis of this adverse drug reaction are still to be clarified but hypotheses such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia have been suggested. Risk factors associated with the underlying psychiatric disorder may at least partly explain the increased risk. Physicians should be aware of this potentially serious and even sometimes fatal adverse drug reaction and should consider discontinuing or switching the antipsychotic treatment in patients experiencing a VTE. Even though supporting evidence is limited, prophylactic antithrombotic treatment should be considered in risk situations for VTE.

  • 313.
    Jönsson, Anna K
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Schioler, L.
    University of Gothenburg, Sweden .
    Lesen, E.
    Nordic Health Econ AB, Sweden .
    Andersson Sundell, K.
    University of Gothenburg, Sweden Nordic School Public Heatlh, Sweden .
    Mardby, A-C
    University of Gothenburg, Sweden Sahlgrens University Hospital, Sweden .
    Influence of refill adherence method when comparing level of adherence for different dosing regimens2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 5, p. 589-597Article in journal (Refereed)
    Abstract [en]

    To examine the impact of two methods when estimating refill adherence in patients using bisphosphonates with different dosing regimens. In the Swedish Prescribed Drug Register, 18,203 new users of bisphosphonates aged 18-85 years were identified between 1 July 2006 and 30 June 2007 and followed for a maximum of 2 years. The patients were categorised based on dosing regimen: one tablet daily, one tablet weekly, switching between these regimens, and other regimens. Refill adherence was estimated with Continuous measure of Medication Acquisition (CMA, adherent if CMA a parts per thousand yenaEuro parts per thousand 80 %) and the maximum gap method (adherent if gaps less than 45 days). Differences in adherence between patients in the groups were assessed with logistic regression models controlling for confounding factors. The proportion of patients classified as adherent was higher using CMA compared with patients classified as adherent using the maximum gap method. Patients on one tablet weekly had significantly lower adherence compared with patients on one tablet daily in the main analyses of both methods (the maximum gap method: 73 % vs. 80 %; adjusted OR = 0.71; 95 % CI 0.57-0.89 and CMA: 84 % vs. 88 %, adjusted OR = 0.75; 95 % CI 0.57-0.99). Patients using the other two dosing regimens had significantly lower adherence compared with patients on one tablet daily using both methods. Choice of method has an impact on the estimates of refill adherence to bisphosphonates. Patients on one tablet weekly dosing had lower adherence compared with patients on one tablet daily dosing using both methods.

  • 314.
    Jönsson, Anna K
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Soderberg, Carl
    Karolinska Institute, Sweden .
    Arne Espnes, Ketil
    St Olavs University Hospital, Norway .
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Eriksson, Anders
    Umeå University, Sweden .
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Druid, Henrik
    Karolinska Institute, Sweden .
    Sedative and hypnotic drugs-Fatal and non-fatal reference blood concentrations2014In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 236, p. 138-145Article in journal (Refereed)
    Abstract [en]

    In postmortem investigations of fatal intoxications it is often challenging to determine which drug/s caused the death. To improve the interpretation of postmortem blood concentrations of sedative and hypnotic drugs and/or clonazepam, all medico-legal autopsies in Sweden - where these drugs had been detected in femoral vein blood during 1992-2006 - were identified in the databases of the National Board of Forensic Medicine. For each drug, concentrations in postmortem control cases - where the cause of death was not intoxication and where incapacitation by drugs could be excluded - were compiled as well as the levels found in living subjects; drugged driving cases and therapeutic drug monitoring cases. Subsequently, fatal intoxications were assessed with regards to the primary substances contributing to death, and blood levels were compiled for single and multiple drug intoxications. The postmortem femoral blood levels are reported for 16 sedative and hypnotic drugs, based on findings in 3560 autopsy cases. The cases were classified as single substance intoxications (N = 498), multiple substance intoxications (N = 1555) and postmortem controls (N = 1507). Each autopsy case could be represented more than once in the group of multiple intoxications and among the postmortem controls if more than one of the included substances were detected. The concentration ranges for all groups are provided. Overlap in concentrations between fatal intoxications and reference groups was seen for most substances. However, the concentrations found in single and multiple intoxications were significantly higher than concentrations found in postmortem controls for all substances except alprazolam and triazolam. Concentrations observed among drugged drivers were similar to the concentrations observed among the therapeutic drug monitoring cases. Flunitrazepam was the substance with the highest number of single intoxications, when related to sales. In summary, this study provides reference drug concentrations primarily to be used for improving interpretation of postmortem drug levels in obscure cases, but which also may assist in drug safety work and in pharmacovigilance efforts.

  • 315.
    Kahn, Robin
    et al.
    Lund University, Sweden.
    Mossberg, Maria
    Lund University, Sweden.
    Stahl, Anne-lie
    Lund University, Sweden.
    Johansson, Karl
    Lund University, Sweden.
    Lopatko Lindman, Ingrid
    Lund University, Sweden.
    Heijl, Caroline
    Lund University, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Morgelin, Matthias
    Lund University, Sweden.
    Fredrik Leeb-Lundberg, L. M.
    Lund University, Sweden.
    Karpman, Diana
    Lund University, Sweden.
    Microvesicle transfer of kinin B1-receptors is a novel inflammatory mechanism in vasculitis2017In: KIDNEY INTERNATIONAL, ISSN 0085-2538, Vol. 91, no 1, p. 96-105Article in journal (Refereed)
    Abstract [en]

    During vasculitis, activation of the kinin system induces inflammation, whereby the kinin B1-receptor is expressed and activated after ligand binding. Additionally, activated blood cells release microvesicles into the circulation. Here we determined whether leukocyte-derived microvesicles bear B1-kinin receptors during vasculitis, and if microvesicles transfer functional B1-receptors to recipient cells, thus promoting inflammation. By flow cytometry, plasma from patients with vasculitis were found to contain high levels of leukocyte-derived microvesicles bearing B1-receptors. Importantly, renal biopsies from two patients with vasculitis showed leukocyte-derived microvesicles bearing B1-receptors docking on glomerular endothelial cells providing in vivo relevance. Microvesicles derived from B1-receptor-transfected human embryonic kidney cells transferred B1-receptors to wild-type human embryonic kidney cells, lacking the receptor, and to glomerular endothelial cells. The transferred B1-receptors induced calcium influx after B1-receptor agonist stimulation: a response abrogated by a specific B1-receptor antagonist. Microvesicles derived from neutrophils also transferred B1-receptors to wild-type human embryonic kidney cells and induced calcium influx after stimulation. Thus, we found a novel mechanism by which microvesicles transfer functional receptors and promote kinin-associated inflammation.

  • 316.
    Kalaiarasi, Arunachalam
    et al.
    Bharathidasan Univ, India.
    Sankar, Renu
    Bharathidasan Univ, India; Ohio State Univ, OH 44691 USA.
    Anusha, Chidambaram
    Bharathidasan Univ, India.
    Saravanan, Kandasamy
    Bharathidasan Univ, India.
    Aarthy, Kalyanasundaram
    Bharathidasan Univ, India.
    Karthic, Selvaraj
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Mathuram, Theodore Lemuel
    Univ Madras, India.
    Ravikumar, Vilwanathan
    Bharathidasan Univ, India.
    Copper oxide nanoparticles induce anticancer activity in A549 lung cancer cells by inhibition of histone deacetylase2018In: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 40, no 2, p. 249-256Article in journal (Refereed)
    Abstract [en]

    Copper oxide nanoparticles (CuO NPs) promoting anticancer activity may be due to the regulation of various classes of histone deacetylases (HDACs). Green-synthesized CuO NPs significantly arrested total HDAC level and also suppressed class I, II and IV HDACs mRNA expression in A549 cells. A549 cells treated with CuO NPs downregulated oncogenes and upregulated tumor suppressor protein expression. CuO NPs positively regulated both mitochondrial and death receptor-mediated apoptosis caspase cascade pathway in A549 cells. Green-synthesized CuO NPs inhibited HDAC and therefore shown apoptosis mediated anticancer activity in A549 lung cancer cell line.

  • 317.
    Kallen, Bengt
    et al.
    Lund University, Sweden .
    Reis, Margareta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Neonatal Complications After Maternal Concomitant Use of SSRI and Other Central Nervous System Active Drugs During the Second or Third Trimester of Pregnancy2012In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 32, no 5, p. 608-614Article in journal (Refereed)
    Abstract [en]

    Drugs acting on the central nervous system(CNS) and given to a pregnant woman during the latter part of pregnancy may affect neonatal morbidity of the infant. Little is known on the combined effects of different categories of such drugs. The redeeming of prescriptions for CNS-active drugs during the second or third trimester of pregnancy was studied by linkage between a register of prescribed drugs and the Swedish Medical Birth Register for the deliveries during 2006-2008 (n - 15,045 live-born infants). Neonatal morbidity was defined as the presence of neonatal diagnoses of respiratory problems, hypoglycemia, convulsions, or other CNS pathologic abnormalities including intraventricular hemorrhage, or low 5-minute Apgar score. The risk of such neonatal morbidity after maternal use of selective serotonin reuptake inhibitors (SSRIs) with or without other CNS-active drugs were evaluated as odds ratios or risk ratios, comparing with unexposed infants or infants only exposed to SSRI drugs. An increased risk for neonatal morbidity was seen for most studied groups of CNS-active drugs when used alone. Benzodiazepines seemed to have a stronger effect than other sedatives/hypnotics. The combination of SSRIs with 1 or more other CNS-active drug groups increased the risk for neonatal morbidity. This was seen for all types of sedatives/hypnotics, which may suggest a confounding by indication. Polypharmacy with CNS-active drugs during the later part of the pregnancy seems to increase the occurrence of neonatal morbidity but difference in nature or strength of underlying psychiatric pathology may confound the findings.

  • 318.
    Kallen, Bengt
    et al.
    Lund University, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Skåne University Hospital, Sweden.
    Ongoing Pharmacological Management of Chronic Pain in Pregnancy2016In: Drugs, ISSN 0012-6667, E-ISSN 1179-1950, Vol. 76, no 9, p. 915-924Article, review/survey (Refereed)
    Abstract [en]

    The article discusses possible effects of the use of analgesics during pregnancy. It summarizes the pertinent literature and reports some previously unpublished data from the Swedish Medical Birth Register. Most likely the use of analgesics does not cause spontaneous abortion. Only small malformation risk increases are seen after the use of opioids and perhaps non-steroid anti-inflammatory drug (NSAID) use. If possible, the latter should be avoided during the first trimester. If exposure has occurred there is no reason to consider an interruption of the pregnancy. Continued use of analgesics may increase the risk of preeclampsia and of preterm birth, especially valid for opioids. Use of acetylsalicylic acid (ASA) in late pregnancy should be avoided because of the risk of bleeding and (valid also for NSAIDs) premature closure of the ductus arteriosus. A small risk for neonatal abstinence syndrome may exist after the use of opioids for chronic pain, notably during the third trimester and long-lasting effects on child development can possibly occur. For a woman with chronic pain, adequate use of pain killers during pregnancy is needed. It is prudent to avoid ASA and NSAIDs towards the end of the pregnancy, while acetaminophen is an acceptable option all through pregnancy. If continued use of opioids is necessary, the associated risks are low. Triptans can be used for migraine during pregnancy. If possible sumatriptan is preferable to other triptans as data for the latter are largely lacking. Ergots are preferably avoided as not enough data are available.

  • 319.
    Kallen, Bengt
    et al.
    Lund University, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Skåne University Hospital, Sweden.
    Use of tramadol in early pregnancy and congenital malformation risk2015In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 58, p. 246-251Article in journal (Refereed)
    Abstract [en]

    Only few studies exist regarding the risk of a teratogenic effect of tramadol when used in early pregnancy. Using the Swedish Medical Birth Register, women (deliveries in 1997-2013) who had reported the use of tramadol in early pregnancy were identified. Maternal characteristics and concomitant drug use were analyzed. Among 1,682,846 women (1,797,678 infants), 1751 (1776 infants) had used tramadol, 96 of the infants had a congenital malformation and 70 of them were relatively severe. The adjusted odds ratio for a relatively severe malformation was 1.33 (95% CI 1.05-1.70). The odds ratios for cardiovascular defects (1.56, 95% CI 1.04-2.29) and for pes equinovarus (3.63, 95% CI 1.61-6.89) were significantly increased. The study suggests a teratogenic effect of tramadol but the risk increase is moderate. (C) 2015 Elsevier Inc. All rights reserved.

  • 320.
    Kalman, L. V.
    et al.
    Centre Disease Control and Prevent, GA USA.
    Agundez, J. A. G.
    University of Extremadura, Spain.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Black, J. L.
    Mayo Clin, MN USA.
    Bell, G. C.
    University of S Florida, FL 33682 USA.
    Boukouvala, S.
    Democritus University of Thrace, Greece.
    Bruckner, C.
    Affymetrix, CA USA.
    Bruford, E.
    European Molecular Biol Lab, England.
    Caudle, K.
    St Jude Childrens Research Hospital, TN 38105 USA.
    Coulthard, S. A.
    Newcastle University, England.
    Daly, A. K.
    Newcastle University, England.
    Del Tredici, A. L.
    Millennium Health LLC, CA USA.
    den Dunnen, J. T.
    Leiden University, Netherlands.
    Drozda, K.
    US FDA, MD USA.
    Everts, R. E.
    Agena Bioscience, CA USA.
    Flockhart, D.
    Indiana University of School Med, IN 46202 USA.
    Freimuth, R. R.
    Mayo Clin, MN USA.
    Gaedigk, A.
    University of Missouri, MO 64110 USA; University of Missouri, MO 64108 USA.
    Hachad, H.
    Translat Software, WA USA.
    Hartshorne, T.
    Thermo Fisher Science, CA USA.
    Ingelman-Sundberg, M.
    Karolinska Institute, Sweden.
    Klein, T. E.
    Stanford University, CA 94305 USA.
    Lauschke, V. M.
    Karolinska Institute, Sweden.
    Maglott, D. R.
    National Lib Med, MD USA.
    McLeod, H. L.
    University of S Florida, FL 33682 USA.
    McMillin, G. A.
    University of Utah, UT USA; ARUP Labs, UT USA.
    Meyer, U. A.
    University of Basel, Switzerland.
    Mueller, D. J.
    University of Toronto, Canada.
    Nickerson, D. A.
    University of Washington, WA 98195 USA.
    Oetting, W. S.
    University of Minnesota, MN USA.
    Pacanowski, M.
    US FDA, MD USA.
    Pratt, V. M.
    Indiana University of School Med, IN 46202 USA.
    Relling, M. V.
    St Jude Childrens Research Hospital, TN 38105 USA.
    Roberts, A.
    Aegis Science Corp, TN USA.
    Rubinstein, W. S.
    National Lib Med, MD USA.
    Sangkuhl, K.
    Stanford University, CA 94305 USA.
    Schwab, M.
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University Hospital, Germany.
    Scott, S. A.
    Icahn School Medical Mt Sinai, NY 10029 USA.
    Sim, S. C.
    Karolinska Institute, Sweden.
    Thirumaran, R. K.
    Genelex Corp, WA USA.
    Toji, L. H.
    Coriell Institute Medical Research, NJ USA.
    Tyndale, R. F.
    University of Toronto, Canada.
    van Schaik, R. H. N.
    Erasmus MC, Netherlands.
    Whirl-Carrillo, M.
    Stanford University, CA 94305 USA.
    Yeo, K. T. J.
    University of Chicago, IL 60637 USA.
    Zanger, U. M.
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University Hospital, Germany.
    Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting2016In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 99, no 2, p. 172-185Article in journal (Refereed)
    Abstract [en]

    This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

  • 321.
    Kareliusson, Frida
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    de Geer, Lina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Oscarsson Tibblin, Anna
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Risk prediction of ICU readmission in a mixed surgical and medical population2015In: Journal of Intensive Care, ISSN 2052-0492, Vol. 3, no 30Article in journal (Refereed)
    Abstract [en]

    Background

    Readmission to intensive care units (ICU) is accompanied with longer ICU stay as well as higher ICU, in-hospital and 30-day mortality. Different scoring systems have been used in order to predict and reduce readmission rates.

    Methods

    The purpose of this study was to evaluate the Stability and Workload Index for Transfer (SWIFT) score as a predictor of readmission. Further, we wanted to study steps and measures taken at the ward prior to readmission.

    Results

    This was a retrospective study conducted at the mixed surgical and medical ICU at Linköping University Hospital. One thousand sixty-seven patients >18 years were admitted to the ICU during 2 years and were included in the study. During the study period, 27 patients were readmitted to the ICU. Readmitted patients had a higher SWIFT score than the non-readmitted (16.1 ± 6.8 vs. 13.0 ± 7.5, p = 0.03) at discharge. The total ICU length of stay was longer (7.5 ± 7.5 vs. 2.9 ± 5.1, p = 0.004), and the 30-day mortality was higher (26 vs. 7 %, p < 0.001) for readmitted patients. Fifty-six percent of readmitted patients were assessed by the critical care outreach service (CCOS) at the ward prior to ICU readmission. A SWIFT score of 15 or more was associated with a significantly higher readmission rate (p = 0.03) as well as 30-day mortality (p < 0.001) compared to a score of ≤14.

    Conclusions

    A SWIFT score of 15 or more is associated with higher readmission rate and 30-day mortality. The SWIFT score could therefore be used for risk prediction for readmission and mortality at ICU discharge.

  • 322.
    Karim, Hazhar
    et al.
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Lindqvist Appell, Malin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Fotoohi, Alan
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Comparison of three methods for measuring thiopurine methyltransferase activity in red blood cells and human leukemia cells2013In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 939, p. 80-85Article in journal (Refereed)
    Abstract [en]

    Thiopurine efficacy is partly reflected by the genetic polymorphism of the thiopurine methyltransferase (TPMT) enzyme, which is responsible for variation in the metabolism, toxicity and therapeutic efficacy of the thiopurines azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). Determination of TPMT activity before administration of thiopurines is thus crucial for individualized dosing in order to prevent toxicity in TPMT deficient individuals. These individuals must be treated with markedly lower (eg, 5-10% of the standard) doses of the prescribed medications. This paper describes a comparison of three different methods for the quantification of TPMT activity in red blood cells (RBC) and cultured human cell lines. We succeeded to perform the measurement of TPMT activity in a minimum amount of 1×10(6) cultured cells with an HPLC-UV system modified and optimized in our laboratory. The TPMT activity was linearly correlated with the cell concentration of the cultured cell line in a range of 1-10×10(6) cells. A significant correlation of determination of TPMT activity in RBC between radiometric detection by HPLC, classic radiochemical detection and UV detection by HPLC, was observed, correlation coefficient (r) were 0.72 and 0.73, respectively. The within-day and day-to-day coefficients of variation of the HPLC-UV-based method were 8% and 16%, respectively. The evaluation of the methods was demonstrated by studying the TPMT activity in RBC isolated from 198 patients, as well as in MOLT4 leukemic cell line and its sub-cell lines with acquired resistance to 6-MP and 6-TG.

  • 323.
    Karimi, Ghazaleh
    et al.
    WHO Collaborating Centre Int Drug Monitoring, Sweden.
    Star, Kristina
    WHO Collaborating Centre Int Drug Monitoring, Sweden.
    Noren, Niklas G.
    WHO Collaborating Centre Int Drug Monitoring, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    The Impact of Duration of Treatment on Reported Time-to-Onset in Spontaneous Reporting Systems for Pharmacovigilance2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7Article in journal (Refereed)
    Abstract [en]

    Within pharmacovigilance, knowledge of time-to-onset (time from start of drug administration to onset of reaction) is important in causality assessment of drugs and suspected adverse drug reactions (ADRs) and may indicate pharmacological mechanisms involved. It has been suggested that time-to-onset from individual case reports can be used for detection of safety signals. However, some ADRs only occur during treatment, while those that do occur later are less likely to be reported. The aim of this study was to investigate the impact of treatment duration on the reported time-to-onset. Case reports from the WHO Global ICSR database, VigiBase, up until February 5th 2010 were the basis of this study. To examine the effect of duration of treatment on reported time-to-onset, angioedema and hepatitis were selected to represent short and long latency ADRs, respectively. The reported time-to-onset for each of these ADRs was contrasted for a set of drugs expected to be used short- or long-term, respectively. The study included 2,980 unique reports for angioedema and 1,159 for hepatitis. Median reported time-to-onset for angioedema in short-term treatments ranged 0-1 days (median 0.5), for angioedema in long-term treatments 0-26 days (median 8), for hepatitis in short-term treatments 4-12 days (median 7.5) and for hepatitis in long term treatments 19-73 days (median 28). Short-term treatments presented significantly shorter reported time-to-onset than long-term treatments. Of note is that reported time-to-onset for angioedema for long-term treatments (median value of medians being 8 days) was very similar to that of hepatitis for short-term treatments (median value of medians equal 7.5 days). The expected duration of treatment needs to be considered in the interpretation of reported time-to-onset and should be accounted for in signal detection method development and case evaluation.

  • 324.
    Karlsson, Henning
    et al.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Senkowski, Wojciech
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Fryknäs, Mårten
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Mansoori, Sharmineh
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Linder, Stig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gullbo, Joachim
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Larsson, Rolf
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Nygren, Peter
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation2019In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 10, no 51, p. 5372-5382Article in journal (Refereed)
    Abstract [en]

    There is a need for preclinical models that can enable identification of novel radiosensitizing drugs in clinically relevant high-throughput experiments. We used a new high-throughput compatible total cell kill spheroid assay to study the interaction between drugs and radiation in order to identify compounds with radiosensitizing activity. Experimental drugs were compared to known radiosensitizers and cytotoxic drugs clinically used in combination with radiotherapy. VLX600, a novel iron-chelating inhibitor of oxidative phosphorylation, potentiated the effect of radiation in tumor spheroids in a synergistic manner. This effect was specific to spheroids and not observed in monolayer cell cultures. In conclusion, the total cell kill spheroid assay is a feasible high-throughput method in the search for novel radiosensitizers. VLX600 shows encouraging characteristics for development as a novel radiosensitizer.

  • 325.
    Karlsson, Jan Olof
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Adolfsson, Karin
    County Hospital Ryhov, Sweden .
    Thelin, Bo
    County Hospital Ryhov, Sweden .
    Jynge, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Falkmer, Ursula G
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    First Clinical Experience with the Magnetic Resonance Imaging Contrast Agent and Superoxide Dismutase Mimetic Mangafodipir as an Adjunct in Cancer Chemotherapy-A Translational Study2012In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 5, no 1, p. 32-38Article in journal (Refereed)
    Abstract [en]

    Preclinical research suggests that the clinically approved magnetic resonance imaging contrast agent mangafodipir may protect against adverse events (AEs) caused by chemotherapy, without interfering negatively with the anticancer efficacy. The present translational study tested if pretreatment with mangafodipir lowers AEs during curative (adjuvant) FOLFOX6 chemotherapy in stage III colon cancer (Dukes C). The study was originally scheduled to include 20 patients, but because of the unforeseen withdrawal of mangafodipir from the market, the study had to be closed after 14 patients had been included. The withdrawal of mangafodipir was purely based on commercial considerations from the producer and not on any safety concerns. The patients were treated throughout the first 3 of 12 scheduled cycles. Patients were randomized to a 5-minute infusion of either mangafodipir or placebo (7 in each group). AEs were evaluated according to the National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events and the Sanofi-NCI criteria. The primary end points were neutropenia and neurosensory toxicity. There were four AEs of grade 3 (severe) and one AE of grade 4 (life threatening) in four patients in the placebo group, whereas there were none in the mangafodipir group (P andlt; .05). Of the grade 3 and 4 events, two were neutropenia and one was neurosensory toxicity. Furthermore, white blood cell count was statistically, significantly higher in the mangafodipir group than in the placebo group (P andlt; .01) after treatment with FOLFOX. This small feasibility study seems to confirm what has been demonstrated preclinically, namely, that pretreatment with mangafodipir lowers AEs during adjuvant 5-fluorouracil plus oxaliplatin-based chemotherapy in colon cancer patients.

  • 326.
    Karlsson, Jan Olof
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jynge, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Mangafodipir a Selective Cytoprotectant - with Special Reference to Oxaliplatin and Its Association to Chemotherapy-Induced Peripheral Neuropathy (CIPN)2017In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, no 4, p. 641-649Article, review/survey (Refereed)
    Abstract [en]

    Oxaliplatin, in combination with 5-fluorouracil plus folinate (or capecitabine), has increased survival substantially in stage III colorectal cancer and prolonged life in stage IV patients, but its use is compromised because of severe toxicity. Chemotherapy-induced peripheral neuropathy (CIPN) is the most problematic dose-limiting toxicity of oxaliplatin. Oncologists included for years calciumand magnesium infusion as part of clinical practice for preventing CIPN. Results from a phase III prospective study published in 2014, however, overturned this practice. No other treatments have been clinically proven to prevent this toxicity. There is a body of evidence that CIPN is caused by cellular oxidative stress. Clinical and preclinical data suggest that the manganese chelate and superoxide dismutase mimetic mangafodipir (MnDPDP) is an efficacious inhibitor of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy. MnPLED, the metabolite of MnDPDP, attacks cellular oxidative stress at several critical levels. Firstly, MnPLED catalyzes dismutation of superoxide (O-2(center dot-) ), and secondly, having a tremendous high affinity for iron (and copper), PLED binds and disarms redox active iron/copper, which is involved in several detrimental oxidative steps. A case report from 2009 and a recent feasibility study suggest that MnDPDP may prevent or even cure oxaliplatin-induced CIPN. Preliminary results from a phase II study (PLIANT) suggest efficacy also of calmangafodipir, but these results are according to available data obscured by a surprisingly low number of adverse events and a seemingly lower than expected efficacy of FOLFOX.

  • 327.
    Karlsson, Jan Olof G
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Ignarro, Louis J
    Department of Molecular and Medical Pharmacology, University of California, USA.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Jynge, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Almén, Torsten
    Department of Diagnostic Radiology, Lund University.
    Calmangafodipir [Ca4Mn(DPDP)5], mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and therapeutic properties2015In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 20, no 4, p. 411-421Article, review/survey (Refereed)
    Abstract [en]

    Reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in pathological tissue damage. Mitochondrial manganese superoxide dismutase (MnSOD) normally keeps ROS and RNS in check. During development of mangafodipir (MnDPDP) as a magnetic resonance imaging (MRI) contrast agent, it was discovered that MnDPDP and its metabolite manganese pyridoxyl ethyldiamine (MnPLED) possessed SOD mimetic activity. MnDPDP has been tested as a chemotherapy adjunct in cancer patients and as an adjunct to percutaneous coronary intervention in patients with myocardial infarctions, with promising results. Whereas MRI contrast depends on release of Mn2+, the SOD mimetic activity depends on Mn2+ that remains bound to DPDP or PLED. Calmangafodipir [Ca4Mn(DPDP)5] is stabilized with respect to Mn2+ and has superior therapeutic activity. Ca4Mn(DPDP)5 is presently being explored as a chemotherapy adjunct in a clinical multicenter Phase II study in patients with metastatic colorectal cancer.

  • 328.
    Karlsson, Jan Olof
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Jynge, Per
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Is it possible to draw firm conclusions from the PLIANT trial?2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 6, p. 862-864Article in journal (Other academic)
    Abstract [en]

    n/a

  • 329.
    Karlsson, Jan Olof
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Jynge, Per
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Sensor and Actuator Systems. Linköping University, Faculty of Science & Engineering.
    Ignarro, Louis J.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Letter in response to: "Randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with the 12-h regimen of N acetylcysteine for paracetamol overdosethe PP100-01 for Overdose of Paracetamol (POP) trial: study protocol for a randomised controlled trial"2019In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 20, article id 380Article in journal (Other academic)
    Abstract [en]

    n/a

  • 330.
    Karlsson, Jan-Erik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden.
    El-Saadi, Walid
    Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden.
    Ali, Mustafa
    Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden; Department of Radiology, County Council of Jönköping, Jönköping, Sweden.
    Puskar, Werner
    Department of Radiology, County Council of Jönköping, Jönköping, Sweden.
    Skogvard, Patrik
    Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden.
    Engvall, Jan E
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Maret, Eva
    Department of Radiology, County Council of Jönköping, Jönköping, Sweden; Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
    Jynge, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. PledPharma AB, Stockholm, Sweden.
    Mangafodipir as a cardioprotective adjunct to reperfusion therapy: a feasibility study in patients with ST-segment elevation myocardial infarction2015In: European Heart Journal - Cardiovascular Pharmacotherapy, ISSN 2055-6837, Vol. 1, no 1, p. 39-45Article in journal (Refereed)
    Abstract [en]

    Aims The aim of the present study was to examine the feasibility of applying the catalytic antioxidant mangafodipir [MnDPDP, manganese (Mn) dipyridoxyl diphosphate] as a cardioprotective adjunct to primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation (STE) myocardial infarction (STEMI). Both MnDPDP and a metabolite (Mn dipyridoxyl ethyldiamine) possess properties as mitochondrial superoxide dismutase mimetics and iron chelators, and combat oxidative stress in various tissues and conditions.

    Methods and results

    The study tested MnDPDP (n ¼ 10) vs. saline placebo (n ¼ 10), given as a brief intravenous (i.v.) infusion prior to balloon inflation during pPCI in patients with STEMI. Mangafodipir waswell tolerated and did not affect heart rate or blood pressure. Despite longer ischaemic time (205 vs. 144 min, P ¼ 0.019) in theMnDPDPgroup, plasma biomarker releaseswere identical for the two groups. With placebo vs.MnDPDP, mean STE resolutions were 69.8 vs. 81.9% (P ¼ 0.224) at 6 h and 73.1 vs. 84.3% (P ¼ 0.077) at 48 h. Cardiac magnetic resonance revealed mean infarct sizes of 32.5 vs. 26.2% (P ¼ 0.406) andmeanleft ventricular (LV) ejection fractions of 41.8 vs. 47.7% (P ¼ 0.617) with placebovs.MnDPDP.More LVthrombi were detected in placebo hearts (5 of 8) than MnDPDP-treated hearts (1 of 10; P ¼ 0.011).

    Conclusions Mangafodipir is a safe drug for use as an adjunct to reperfusion therapy. A tendency to benefit of MnDPDP needs confirmation in a larger population. The study revealed important information for the design of a Phase II trial.

     

  • 331.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Andersson, Mikael
    National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Mephedrone, Methylone and 3,4-Methylenedioxypyrovalerone (MDPV) Induce Conditioned Place Preference in Mice2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 5, p. 411-416Article in journal (Refereed)
    Abstract [en]

    During the last decade, there has been a worldwide increase in popularity and abuse of synthetic cathinones. Common ingredients of the so-called bath salts include mephedrone, methylone and 3,4-methylenedioxypyrovalerone (MDPV). Relatively little information about the pharmacology and addiction potential of these drugs is available. We used the conditioned place preference (CPP) paradigm to explore the reinforcing effects of three different synthetic cathinones. The primary aim of this study was to investigate whether mephedrone, methylone and MDPV induce CPP in mice. The secondary aims were to investigate a possible dose-response CPP and whether the synthetic cathinones induce higher CPP than amphetamine at equal dose. C57BL/6 mice were conditioned to mephedrone, methylone, MDPV and amphetamine at doses of 0.5, 2, 5, 10 or 20mg/kg (i.p.). During the conditioning, the mice received two training sessions per day for 4days. All four tested drugs showed a significant place preference compared with controls. Mice conditioned with MDPV (5 and 10mg/kg) displayed a greater preference score compared to mice conditioned with amphetamine (5 and 10mg/kg). Our findings show that mephedrone, methylone and MDPV produce CPP equal or higher than amphetamine strongly suggesting addictive properties. Given the public health concern of abuse, future pharmacological studies are necessary to fully understand the effects of these drugs.

  • 332.
    Karlsson, Louise
    et al.
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Josefsson, M
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden; 3Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
    Carlsson, Björn
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics andForensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Kugelberg, Fredrik C
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.2015In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, no 2, p. 165-71Article in journal (Refereed)
    Abstract [en]

    We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases. In all, 94 postmortem cases found positive for VEN during toxicological screening were included. The CYP2D6 genotype was shown to significantly influence the ODV/VEN (P=0.003), DDV/NDV (P=0.010) and DDV/ODV (P=0.034) ratios. The DDV/ODV (P=0.013) and DDV/VEN (P=0.021) ratios were significantly influenced by the CYP2C19 genotype. The S/R ratios of VEN were significantly influenced by both CYP2D6 and CYP2C19 genotypes. CYP2D6 poor metabolizers (PMs) had lower S/R VEN ratios and CYP2C19 PMs had high S/R ratios of VEN in comparison. Our results show that the CYP2D6 genotype influences the O-demethylation whereas CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favours the R-enantiomer whereas CYP2C19 favours the S-enantiomer.

  • 333.
    Karlsson, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Frennesson, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Gustafsson, Therese
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Erik Nilsson, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Autophagy of iron-binding proteins may contribute to the oxidative stress resistance of ARPE-19 cells2013In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 116, p. 359-365Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to elucidate possible reasons for the remarkable resistance of human retinal pigment epithelial (RPE) cells to oxidative stress. Much oxidative damage is due to hydrogen peroxide meeting redox-active iron in the acidic and reducing lysosomal environment, resulting in the production of toxic hydroxyl radicals that may oxidize intralysosomal content, leading to lipofuscin (LF) formation or, if more extensive, to permeabilization of lysosomal membranes. Formation of LF is a risk factor for age-related macular degeneration (AMD) and known to jeopardize normal autophagic rejuvenation of vital cellular biomolecules. Lysosomal membrane permeabilization causes release of lysosomal content (redox-active iron, lytic enzymes), which may then cause cell death. Total cellular and lysosomal low-mass iron of cultured, immortalized human RPE (ARPE-19) cells was compared to that of another professional scavenger cell line, J774, using atomic absorption spectroscopy and the cytochemical sulfide-silver method (SSM). It was found that both cell lines contained comparable levels of total as well as intralysosomal iron, suggesting that the latter is mainly kept in a non-redox-active state in ARPE-19 cells. Basal levels and capacity for upregulation of the iron-binding proteins ferritin, metallothionein and heat shock protein 70 were tested in both cell lines using immunoblotting. Compared to J774 cells, ARPE-19 cells were found to contain very high basal levels of all these proteins, which could be even further upregulated following appropriate stimulation. These findings suggest that a high basal expression of iron-binding stress proteins, which during their normal autophagic turnover in lysosomes may temporarily bind iron prior to their degradation, could contribute to the unusual oxidative stress-resistance of ARPE-19 cells. A high steady state influx of such proteins into lysosomes would keep the level of lysosomal redox-active iron permanently low. This, in turn, should delay intralysosomal accumulation of LF in RPE cells, which is known to reduce autophagic turnover as well as uptake and degradation of worn out photoreceptor tips. This may explain why severe LF accumulation and AMD normally do not develop until fairly late in life, in spite of RPE cells being continuously exposed to high levels of oxygen and light, as well as large amounts of lipid-rich material.

  • 334.
    Karlsson, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Attenuation of iron-binding proteins in ARPE-19 cells reduces their resistance to oxidative stress2016In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 94, no 6, p. 556-565Article in journal (Refereed)
    Abstract [en]

    Purpose

    Oxidative stress-related damage to retinal pigment epithelial (RPE) cells is an important feature in the development of age-related macular degeneration. Iron-catalysed intralysosomal production of hydroxyl radicals is considered a major pathogenic factor, leading to lipofuscin formation with ensuing depressed cellular autophagic capacity, lysosomal membrane permeabilization and apoptosis. Previously, we have shown that cultured immortalized human RPE (ARPE-19) cells are extremely resistant to exposure to bolus doses of hydrogen peroxide and contain considerable amounts of the iron-binding proteins metallothionein (MT), heat-shock protein 70 (HSP70) and ferritin (FT). According to previous findings, autophagy of these proteins depresses lysosomal redox-active iron. The aim of this study was to investigate whether up- or downregulation of these proteins would affect the resistance of ARPE-19 cells to oxidative stress.

    Methods

    The sensitivity of ARPE-19 cells to H2O2 exposure was tested following upregulation of MT, HSP70 and/or FT by pretreatment with ZnSO4, heat shock or FeCl3, as well as siRNA-mediated downregulation of the same proteins.

    Results

    Upregulation of MT, HSP70 and FT did not improve survival following exposure to H2O2. This was interpreted as existence of an already maximal protection. Combined siRNA-mediated attenuation of both FT chains (H and L), or simultaneous downregulation of all three proteins, made the cells significantly more susceptible to oxidative stress confirming the importance of iron-binding proteins.

    Conclusion

    The findings support our hypothesis that the oxidative stress resistance exhibited by RPE cells may be explained by a high autophagic influx of iron-binding proteins that would keep levels of redox-active lysosomal iron low.

  • 335.
    Karlsson, Sofia A.
    et al.
    University of Gothenburg, Sweden.
    Jacobsson, Ingela
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Danell Boman, Marit
    University of Umeå Hospital, Sweden.
    Hakkarainen, Katja M.
    Nordic School Public Health NHV, Sweden; Jonköping County Council, Sweden.
    Lövborg, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Jönköping County Council, Jönköping, Sweden.
    Jönsson, Anna K
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    The impact of a changed legislation on reporting of adverse drug reactions in Sweden, with focus on nurses reporting2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 5, p. 631-636Article in journal (Refereed)
    Abstract [en]

    In March 2007, a legislative amendment was issued in Sweden compelling nurses to report all suspected adverse drug reactions (ADRs) to the national pharmacovigilance system. The aims of this study were to describe the status of ADR reporting, before and after the implementation of the legislative changes, and to describe the general characteristics of suspected ADRs reported by nurses. The Swedish pharmacovigilance system during the study period constituted six regional centres responsible for the handling of all spontaneous ADR reports within their region. In this study, we identified all individual ADR reports from 2005 and 2010, analysed in depth the ADR reports from two regional centres and collated information about the reporter and the nature of the reported ADR. From the two regional centres, a total of 898 and 1074 reports were submitted in 2005 and 2010 respectively. Nurses submitted 31 % (275 reports) of the reports in 2005 and 24 % (260 reports) in 2010. Nurses reporting of serious ADRs was 3 % (seven reports) in 2005 and 7 % (17 reports) in 2010 with reporting of unlabelled ADRs at 4 % (11 reports) in 2005 and 17 % (45 reports) in 2010. Most of the serious and/or unlabelled reactions were related to vaccine administration (14 reports in 2005 and 36 reports in 2010). The overall ADR reporting by nurses did not appear to increase after the change in reporting legislation. The proportion of serious and/or unlabelled ADRs reported by nurses did however appear to increase during the same period. Taken together, our data suggests that further pro-active measures should be considered in order to involve nurses in the reporting of suspected ADRs.

  • 336.
    Karras, Alexandre
    et al.
    Hop Europeen Georges Pompidou, France; University of Paris 05, France.
    Pagnoux, Christian
    Mt Sinai Hospital, Canada.
    Haubitz, Marion
    Klinikum Fulda, Germany; Klinikum Fulda, Germany.
    de Groot, Kirsten
    Klinikum Offenbach, Germany.
    Puechal, Xavier
    Hop Cochin, France.
    Cohen Tervaert, Jan Willem
    Maastricht University, Netherlands.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Guillevin, Loic
    University of Paris 05, France; Hop Cochin, France.
    Jayne, David
    University of Cambridge, England.
    Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 10, p. 1662-1668Article in journal (Refereed)
    Abstract [en]

    Objectives A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)associated vasculitis (AAV). Methods Patients with AAV were recruited 18-24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1: 1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis. Results One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 mu mol/L (range 58-372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, pamp;lt;0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival. Conclusions Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV.

  • 337.
    Kechagias, Stergios
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Dernroth, Dženeta Nezirević
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgren, Anders
    Skåne University Hospital, Lund.
    Hansson, Therese
    Skåne University Hospital, Lund.
    Isaksson, Anders
    Skåne University Hospital, Lund.
    Walther, Lisa
    Skåne University Hospital, Lund.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Nystrom, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Phosphatidylethanol Compared with Other Blood Tests as a Biomarker of Moderate Alcohol Consumption in Healthy Volunteers: A Prospective Randomized Study.2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50, no 4, p. 399-406Article in journal (Refereed)
    Abstract [en]

    AIM: It is generally agreed that traditional alcohol biomarkers lack in sensitivity to detect hazardous alcohol consumption. The present study was undertaken to evaluate the ability of phosphatidylethanol (PEth) and traditional alcohol markers to detect moderate alcohol consumption and to distinguish between moderate alcohol consumption and abstinence.

    METHODS: Forty-four subjects, 32 females and 12 males, were included in the study. They were randomized to alcohol abstention or to alcohol consumption. Female participants consumed 150 ml of red wine (equivalent to 16 g of alcohol) per 24 h and the male participants double the amount. The study lasted for 3 months. Blood samples were drawn at the start and at the end of the study period. Blood samples were analysed for PEth, carbohydrate-deficient transferrin (CDT), mean corpuscular volume (MCV), γ-glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

    RESULTS: ROC curves for the various biochemical markers were plotted in order to assess their ability to discriminate between abstention and moderate daily consumption of alcohol. PEth and CDT were the only markers with AUROCs significantly higher than 0.5, and PEth was detected in all participants randomized to alcohol consumption.

    CONCLUSION: PEth was the only marker that could detect moderate intake and the present results also indicate that PEth probably can distinguish moderate alcohol consumption from abstinence.

  • 338.
    Kechagias, Stergios
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Lofti, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Läkemedelsorsakad leverskada av kosttillskottet Fortodol: Manipulerat preparat försenade diagnos2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 4, p. 186-188Article in journal (Refereed)
    Abstract [en]

    Summary:

    Pharmaceutical preparations are serious contributors to liver disease. The diagnostic approach of drug-induced liver injury is difficult and requires a high degree of suspicion and the exclusion of alternative causes of liver damage. Adulteration of food supplements is a potential cause of serious hepatotoxicity. A case of severe jaundice after consumption of Fortodol, which according to the manufacturer contained the active substances turmeric and phenylalanine, is reported. Several months later more patients experiencing hepatotoxicity from Fortodol was reported and it was discovered that the toxicity was related to adulteration by nimesulide.

  • 339.
    Kedia, George T.
    et al.
    Hannover Medical School, Germany.
    Ückert, Stefan
    Hannover Medical School, Germany; Institute for Biochemical Research and Analysis, Germany.
    Oelke, Matthias
    Hannover Medical School, Germany.
    Sonnenberg, Joachim E.
    Institute for Biochemical Research and Analysis, Germany.
    Sohn, Michael
    AGAPLESION Markus Hospital, Germany.
    Kuczyk, Markus A.
    Hannover Medical School, Germany.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. University Vita Salute San Raffaele, Italy.
    Expression and Distribution of Phosphodiesterase Isoenzymes in the Human Male Urethra2015In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 85, no 4, p. 964.e1-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To investigate the expression and distribution of phosphodiesterase (PDE) isoenzymes PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A in human urethral tissue. METHODS Specimens of penile urethra were obtained from male subjects who had undergone male-to-female sex reassignment surgery. Using immunohistochemistry (immunofluorescence), the occurrence of PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A, the neuronal nitric oxide synthase, calcitonin gene-related peptide, and vasoactive intestinal polypeptide was examined in urethral sections. Cytosolic supernatants prepared from isolated human urethral tissue were subjected to Western blot analysis using specific anti-PDE antibodies. RESULTS Immunosignals specific for PDE1A, 4A, 4B, and 5A were observed in the urethral smooth musculature. The smooth muscle bundles were seen innervated by slender nerve fibers, characterized by the expression of the neuronal nitric oxide synthase, calcitonin gene-related peptide, and vasoactive intestinal polypeptide. The expression of the PDE isoenzymes mentioned was confirmed by Western blotting. CONCLUSION The results provide evidence for a significance of both the cyclic adenosine monophosphate and cyclic guanosine monophosphate signaling in the control of human urethral smooth muscle. The selective inhibition of PDE isoenzymes might represent a pharmacologic option to influence the function of smooth musculature in the human outflow region.

  • 340.
    Khedidja, Hedna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Nordic School of Public Health NHV, Gothenburg, Sweden.
    Hakkarainen, Katja M.
    EPID Research, Espoo, Finland, Nordic School of Public Health NHV, Gothenburg, Sweden.
    Gyllensten, Hanna
    Nordic School of Public Health NHV, Gothenburg, Sweden, Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Jönsson, Anna K
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Andersson Sundell, Karolina
    Section of Social Medicine, University of Gothenburg, Gothenburg, Sweden.
    Petzold, Max
    Centre for Applied Biostatistics, University of Gothenburg, Gothenburg, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Jönköping County Council, Jönköping, Sweden.
    Adherence to Antihypertensive Therapy and Elevated Blood Pressure: Should We Consider the Use of Multiple Medications?2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0137451Article in journal (Refereed)
    Abstract [en]

    Background

    Although a majority of patients with hypertension require a multidrug therapy, this is rarely considered when measuring adherence from refill data. Moreover, investigating the association between refill non-adherence to antihypertensive therapy (AHT) and elevated blood pressure (BP) has been advocated.

    Objective

    Identify factors associated with non-adherence to AHT, considering the multidrug therapy, and investigate the association between non-adherence to AHT and elevated BP.

    Methods

    A retrospective cohort study including patients with hypertension, identified from a random sample of 5025 Swedish adults. Two measures of adherence were estimated by the proportion of days covered method (PDC≥80%): (1) Adherence to any antihypertensive medication and, (2) adherence to the full AHT regimen. Multiple logistic regressions were performed to investigate the association between sociodemographic factors (age, sex, education, income), clinical factors (user profile, number of antihypertensive medications, healthcare use, cardiovascular comorbidities) and non-adherence. Moreover, the association between non-adherence (long-term and a month prior to BP measurement) and elevated BP was investigated.

    Results

    Non-adherence to any antihypertensive medication was higher among persons < 65 years (Odds Ratio, OR 2.75 [95% CI, 1.18–6.43]) and with the lowest income (OR 2.05 [95% CI, 1.01–4.16]). Non-adherence to the full AHT regimen was higher among new users (OR 2.04 [95% CI, 1.32–3.15]), persons using specialized healthcare (OR 1.63, [95% CI, 1.14–2.32]), and having multiple antihypertensive medications (OR 1.85 [95% CI, 1.25–2.75] and OR 5.22 [95% CI, 3.48–7.83], for 2 and ≥3 antihypertensive medications, respectively). Non-adherence to any antihypertensive medication a month prior to healthcare visit was associated with elevated BP.

    Conclusion

    Sociodemographic factors were associated with non-adherence to any antihypertensive medication while clinical factors with non-adherence to the full AHT regimen. These differing findings support considering the use of multiple antihypertensive medications when measuring refill adherence. Monitoring patients' refill adherence prior to healthcare visit may facilitate interpreting elevated BP.

  • 341.
    Khedidja, Hedna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Nordic School of Public Health NHV, Gothenburg, Sweden.
    Hakkarainen, Katja M.
    Nordic School of Public Health NHV, Gothenburg, Sweden;EPID Research, Espoo, Finland.
    Gyllensten, Hanna
    Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Jönsson, Anna K
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Petzold, Max
    Centre for Applied Biostatistics, University of Gothenburg,, Gotenburg, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Potentially inappropriate prescribing and adverse drug reactions in the elderly: a population-based study2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 12, p. 1525-1533Article in journal (Refereed)
    Abstract [en]

    Purpose

    Potentially inappropriate prescriptions (PIPs) criteria are widely used for evaluating the quality of prescribing in elderly. However, there is limited evidence on their association with adverse drug reactions (ADRs) across healthcare settings. The study aimed to determine the prevalence of PIPs, defined by the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP) criteria, in the Swedish elderly general population and to investigate the association between PIPs and occurrence of ADRs.

    Method

    Persons ≥65 years old were identified from a random sample of 5025 adults drawn from the Swedish Total Population Register. A retrospective cohort study was conducted among 813 elderly with healthcare encounters in primary and specialised healthcare settings during a 3-month period in 2008. PIPs were identified from the Swedish Prescribed Drug Register, medical records and health administrative data. ADRs were independently identified by expert reviewers in a stepwise manner using the Howard criteria. Multivariable logistic regression examined the association between PIPs and ADRs.

    Results

    Overall, 374 (46.0 %) persons had ≥1 PIPs and 159 (19.5 %) experienced ≥1 ADRs during the study period. In total, 29.8 % of all ADRs was considered caused by PIPs. Persons prescribed with PIPs had more than twofold increased odds of experiencing ADRs (OR 2.47; 95 % CI 1.65–3.69). PIPs were considered the cause of 60 % of ADRs affecting the vascular system, 50 % of ADRs affecting the nervous system and 62.5 % of ADRs resulting in falls.

    Conclusion

    PIPs are common among the Swedish elderly and are associated with increased odds of experiencing ADRs. Thus, interventions to decrease PIPs may contribute to preventing ADRs, in particular ADRs associated with nervous and vascular disorders and falls.

  • 342.
    Kjölhede, Preben
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Bergdahl, Olga
    Region Östergötland.
    Borendal Wodlin, Ninnie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Nilsson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    Effect of intrathecal morphine and epidural analgesia on postoperative recovery after abdominal surgery for gynecologic malignancy: an open-label randomised trial2019In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 9, no 3, article id e024484Article in journal (Refereed)
    Abstract [en]

    Objectives We aimed to determine whether regional analgesia with intrathecal morphine (ITM) in an enhanced recovery programme (enhanced recovery after surgery [ERAS]) gives a shorter hospital stay with good pain relief and equal health-related quality of life (QoL) to epidural analgesia (EDA) in women after midline laparotomy for proven or assumed gynaecological malignancies. Design An open-label, randomised, single-centre study. Setting A tertiary referral Swedish university hospital. Participants Eighty women, 18-70 years of age, American Society of Anesthesiologists I and II, admitted consecutively to the department of Obstetrics and Gynaecology. Interventions The women were allocated (1: 1) to either the standard analgesic method at the clinic (EDA) or the experimental treatment (ITM). An ERAS protocol with standardised perioperative routines and standardised general anaesthesia were applied. The EDA or ITM started immediately preoperatively. The ITM group received morphine, clonidine and bupivacaine intrathecally; the EDA group had an epidural infusion of bupivacaine, adrenalin and fentanyl. Primary and secondary outcome measures Primary endpoint was length of hospital stay (LOS). Secondary endpoints were QoL and pain assessments. Results LOS was statistically significantly shorter for the ITM group compared with the EDA group (median [IQR] 3.3 [1.5-56.3] vs 4.3 [2.2-43.2] days; p=0.01). No differences were observed in pain assessment or QoL. The ITM group used postoperatively the first week significantly less opioids than the EDA group (median (IQR) 20 mg (14-35 mg) vs 81 mg (67-101 mg); pamp;lt;0.0001). No serious adverse events were attributed to ITM or EDA. Conclusions Compared with EDA, ITM is simpler to administer and manage, is associated with shorter hospital stay and reduces opioid consumption postoperatively with an equally good QoL. ITM is effective as postoperative analgesia in gynaecological cancer surgery.

  • 343.
    Klawonn, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Stanford Univ, CA 94305 USA.
    Wilhelms, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Lindström, Sarah
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Singh, Anand Kumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Baylor Coll Med, TX 77030 USA.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wess, Jurgen
    NIH, MD 20892 USA.
    Fritz, Michael
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Stanford Univ, CA 94305 USA.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity2018In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 139Article in journal (Refereed)
    Abstract [en]

    The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression (cFos and FosB) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

  • 344.
    Klionsky, Daniel J.
    et al.
    University of Michigan, Department of Molecular, Cellular, and Developmental Biology, Ann Arbor, MI, USA; University of Michigan, Life Sciences Institute, Ann Arbor, MI, USA .
    Boman, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Zughaier, Susu M.
    Emory University, School of Medicine, Department of Microbiology and Immunology, Atlanta, GA, USA.
    Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)2016In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 2, no 1, p. 1-222Article, review/survey (Refereed)
  • 345.
    Kollind, M.
    et al.
    Centalsjukhuset Kristianstad, Sweden.
    Wickbom, F.
    Hallands Sjukhus, Sweden.
    Wilkman, E.
    University of Helsinki, Finland.
    Snackestrand, M. S. C.
    Sahlgrenska University Hospital, Sweden.
    Holmen, A.
    Regional Halland, Sweden.
    Oldner, A.
    Karolinska University Hospital, Sweden.
    Perner, A.
    Rigshosp, Denmark.
    Aneman, A.
    University of New South Wales, Australia.
    Chew, Michelle
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Shock treatment in a cohort of Scandinavian intensive care units in 20142016In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 7, p. 945-957Article in journal (Refereed)
    Abstract [en]

    BackgroundShock is common in intensive care units, and treatment includes fluids, vasopressor and/or inotropic drugs, guided by hemodynamic monitoring. The aim of this study was to identify current practice for treatment of shock in Scandinavian intensive care units. MethodsSeven-day inception cohort study in 43 intensive care units in Scandinavia. Patients 15years old receiving more than 4h of cardiovascular acting drug infusion were included. The use of fluids, vasopressor and inotropic drugs, type of monitoring, and target values were recorded. ResultsOne hundred and seventy-one patients were included. At inclusion, 136/168 (81%) had received vasopressor and/or inotropic drug therapy for less than 24h, and 143/171 (84%) had received volume loading before the onset of vasoactive drug treatment. Ringers solution was given to 129/143 (90%) of patients and starches in 3/143 (2%) patients. Noradrenaline was the most commonly used cardiovascular acting drug, given in 168/171 (98%) of cases while dopamine was rarely used. Mean arterial pressure was considered the most important variable for hemodynamic monitoring. Invasive arterial blood pressure was monitored in 166/171 (97%) of patients, arterial pulse wave analysis in 11/171 (7%), and echocardiography in 50/171 (29%). ConclusionIn this survey, Ringers solution and noradrenaline were the most common first-line treatments in shock. The use of starches and dopamine were rare. Almost all patients were monitored with invasive arterial blood pressure, but comprehensive hemodynamic monitoring was used only in a minority of patients.

  • 346.
    Kreu, Simon
    et al.
    Lund University, Sweden; Örebro University Hospital, Sweden.
    Jazrawi, Allan
    Lund University, Sweden; Västmanland County Hospital, Sweden.
    Miller, Jan
    Lund University, Sweden.
    Baigi, Amir
    Gothenburg University, Sweden.
    Chew, Michelle
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Lund University, Sweden.
    Alkalosis in Critically III Patients with Severe Sepsis and Septic Shock2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0168563Article in journal (Refereed)
    Abstract [en]

    Introduction Although metabolic alkalosis is a common occurrence in intensive care units (ICUs), no study has evaluated its prevalence or outcomes in patients with severe sepsis or septic shock. Methods This is a retrospective cohort study of critically ill patients suffering from severe sepsis and septic shock admitted to the ICUs of Halmstad and Varberg County hospitals. From 910 patient records, 627 patients met the inclusion criteria. We investigated the relationship between metabolic alkalosis and mortality. Further, we studied the relationship between metabolic alkalosis and ICU length of stay (LOS). Results Metabolic alkalosis was associated with decreased 30-day and 12-month mortalities. This effect was however lost when a multivariate analysis was conducted, correcting for age, gender, pH on admission, base excess (BE) on admission, Simplified Acute Physiology Score III (SAPS III) and acute kidney injury (AKI). We then analyzed for any dose-response effect between the severity of metabolic alkalosis and mortality and found no relationship. Bivariate analysis showed that metabolic alkalosis had a significant effect on the length of ICU stay. When adjusting for age, sex, pH at admission, BE at admission, SAPS III and AKI in a multivariate analysis, metabolic alkalosis significantly contributed to prolonged ICU length of stay. In two separate sensitivity analyses pure metabolic alkalosis and late metabolic alkalosis (time of onset amp;gt; 48 hours) were the only significant predictor of increased ICU length of stay. Conclusion Metabolic alkalosis did not have any effect on 30-day and 12-month mortalities after adjusting for age, sex, SAPS III-score, pH and BE on admission and AKI in a multivariate analysis. The presence of metabolic alkalosis was independently associated with an increased ICU length of stay.

  • 347.
    Kreutzman, Anna
    et al.
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Yadav, Bhagwan
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Brummendorf, Tim H.
    Univ Klinikum RWTH Aachen, Germany.
    Gjertsen, Bjorn Tore
    Univ Bergen, Norway; Univ Bergen, Norway.
    Hee, Moon Lee
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Janssen, Jeroen
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    Kasanen, Tiina
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Koskenvesa, Perttu
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Markevarn, Berit
    Umea Univ Hosp, Sweden.
    Olsson-Stromberg, Ulla
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Stentoft, Jesper
    Aarhus Univ Hosp, Denmark.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Soderlund, Stina
    Uppsala Univ Hosp, Sweden.
    Udby, Lene
    Zealand Univ Hosp, Denmark.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Norway; Norwegian Univ Sci and Technol NTNU, Norway.
    Mustjoki, Satu
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line2019In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 9, article id e1638210Article in journal (Refereed)
    Abstract [en]

    Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naive and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.

  • 348.
    Kriikku, Pirkko
    et al.
    Vita Lab, Finland University of Helsinki, Finland .
    Wilhelm, Lars
    LADR GmbH Medical Versorgungszentrum, Germany .
    Jenckel, Stefan
    LADR GmbH Medical Versorgungszentrum, Germany .
    Rintatalo, Janne
    National Bur Invest Forens Lab, Finland .
    Hurme, Jukka
    Vita Lab, Finland .
    Kramer, Jan
    LADR GmbH Medical Versorgungszentrum, Germany University of Lubeck, Germany .
    Jones, A Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Ojanpera, Ilkka
    University of Helsinki, Finland .
    Comparison of breath-alcohol screening test results with venous blood alcohol concentration in suspected drunken drivers2014In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 239, p. 57-61Article in journal (Refereed)
    Abstract [en]

    Hand-held electronic breath-alcohol analyzers are widely used by police authorities in their efforts to detect drunken drivers and to improve road-traffic safety. Over a three month period, the results of roadside breath-alcohol tests of drivers apprehended in Finland were compared with venous blood alcohol concentration (BAC). The mean (median) time between sampling blood and breath was 0.71 h (0.58 h) with a range from 0 to 6 h. Some hand-held instruments gave results as the concentration of alcohol in breath and were converted into BAC assuming a blood-breath alcohol ratio (BBR) of 2260. The mean venous BAC (1.82 g/kg) in traffic offenders was higher than the result predicted by the hand-held breath analyzers (1.72 g/kg). In 1875 roadside tests, the relationship between venous BAC (x) and BrAC (y) was defined by the regression equation y = 0.18 + 0.85x. The coefficients show both a constant bias (y-intercept 0.18 g/kg) and a proportional bias (slope = 0.85). The residual standard deviation (SD), an indicator of random variation, was +/- 0.40 g/kg. After BAC results were corrected for the time elapsed between sampling blood and breath, the y-intercept decreased to 0.10 g/kg and 0.004 g/kg, respectively, when low (0.1 g/kg/h) and high (0.25 g/kg/h) rates of alcohol elimination were used. The proportional bias of 0.85 shows that the breath-alcohol test result reads lower than the actual BAC by 15% on average. This suggests that the BBR of 2260 used for calibration should be increased by about 15% to give closer agreement between BAC and BrAC. Because of the large random variation (SD +/- 0.40 g/kg), there is considerable uncertainty if and when results from the roadside screening test are used to estimate venous BAC. The roadside breath-alcohol screening instruments worked well for the purpose of selecting drivers above the statutory limit of 0.50 g/kg.

  • 349.
    Kronstrand, Christoffer
    et al.
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Nilsson, Gunnel
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Cherma, Maria D.
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Evaluating the hip-flask defence in subjects with alcohol on board: An experimental study2019In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 294, p. 189-195Article in journal (Refereed)
    Abstract [en]

    Driving under the influence of alcohol is a major problem for traffic-safety and a popular defence argument is alleged consumption after driving, commonly referred to as the hip-flask defence. Forensic toxicologists are often called as expert witnesses in drinking and driving cases where the suspect has claimed the hip-flask defence, to assess the credibility of the explanation. Several approaches to help the expert have been introduced but the scientific data used to support or challenge this is solely based on data from controlled single doses of ethanol administered during a short time and in abstinent subjects. In reality, we believe that even in drinking after driving cases, the subject many times has alcohol on board at time of the hip-flask drink. This questions the applicability of the data used as basis to investigate the hip-flask defence. To fill this knowledge gap, we aimed to investigate how blood and urine ethanol kinetics vary after an initial drinking session of beer and then a subsequent hip-flask drink of three different doses of whiskey. Fifteen subjects participated in the study and each provided 10 urine samples and 17 blood samples over 7 h. The initial drink was 0.51 g ethanol/kg and the second was either 0.25, 0.51, or 0.85 g/kg. Our data suggested that the difference between the ethanol concentrations in two consecutive urine samples is a more sensitive parameter than the ratio between urine and blood alcohol to detect a recent intake when ethanol from previous intakes are already present in the body. Twelve subjects presented results that fully supported a recent intake using the criteria developed from a single intake of ethanol. Three subjects showed unexpected results that did not fully support a recent intake. We conclude that data from one blood sample and two urine samples provide good evidence for investigating the hip-flask defence even if alcohol was on board at the time of the hip-flask drink. (C) 2018 Elsevier B.V. All rights reserved.

  • 350.
    Kronstrand, Robert
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Brinkhagen, Linda
    National Board for Forensic Medicine, Linkoping, Sweden .
    Birath-Karlsson, Carolina
    National Board for Forensic Medicine, Linkoping, Sweden .
    Roman, Markus
    National Board for Forensic Medicine, Linkoping, Sweden .
    Josefsson, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine2014In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 406, no 15, p. 3599-3609Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to compare the performance of an immunoassay screening for synthetic cannabinoids with a newly developed confirmation method using liquid chromatography quadrupole time-of-flight mass spectrometry. The screening included metabolites from JWH-018, JWH-073, and AM-2201. The confirmation included metabolites from AM-2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, JWH-398, MAM-2201, RCS-4, and UR-144. The immunoassay was tested and found to have no cross-reactivity with UR-144 metabolites but considerable cross-reactivity with MAM-2201 and JWH-122 metabolites. Sensitivity and specificity for the immunoassay were evaluated with 87 authentic urine samples and found to be 87 % and 82 %, respectively. With a cutoff at 2 ng/ml, the confirmation showed 80 positive findings in 38 cases. The most common finding was JWH-122 5-OH-pentyl, followed by JWH-018 5-OH-pentyl. There were 9 findings of UR-144 metabolites and 3 of JWH-073 metabolites. In summary, the immunoassay performed well, presenting both high sensitivity and specificity for the synthetic cannabinoids present in the urine samples tested. The rapid exchange of one cannabinoid for another may pose problems for immunoassays as well as for confirmation methods. However, we consider time-of-flight mass spectrometry to be superior since new metabolites can be quickly included and identified.

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