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  • 1.
    Abbott, T. E. F.
    et al.
    Queen Mary Univ London, England.
    Ahmad, T.
    Queen Mary Univ London, England.
    Phull, M. K.
    Barts Hlth NHS Trust, England.
    Fowler, A. J.
    Guys and St Thomass NHS Fdn Trust, England.
    Hewson, R.
    Barts Hlth NHS Trust, England.
    Biccard, B. M.
    Univ Cape Town, South Africa.
    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.
    Gillies, M.
    Univ Edinburgh, Scotland.
    Pearse, R. M.
    Queen Mary Univ London, England.
    The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis2018In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 120, no 1, p. 146-155Article, review/survey (Refereed)
    Abstract [en]

    Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained amp;gt;= 1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32-0.77); Pamp;lt;0.01], but no difference in complication rates [OR 1.02 (0.88-1.19); P = 0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62-0.92); Pamp;lt;0.01; I-2 = 87%] and reduced complication rates [OR 0.73 (0.61-0.88); Pamp;lt;0.01; I-2 = 89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine.

  • 2.
    Abednazari, Hossin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. PEAS Institute, Linköping.
    Brudin, Lars
    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.
    Almroth, Gabriel
    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.
    Nilsson, Ingela
    Kalmar County Hospital, Sweden.
    Nayeri, Fariba
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Hepatocyte growth factor is a reliable marker for efficient anti-bacterial therapy within the first day of treatment2014In: Advances in Bioscience and Biotechnology, ISSN 2156-8456, E-ISSN 2156-8502, Vol. 5, no 10, p. 823-830Article in journal (Refereed)
    Abstract [en]

    Rapid diagnosis and choice of appropriate antibiotic treatment might be life-saving in serious infectious diseases. Still the available markers that can evaluate and monitor the diagnosis and treatment are few. Hepatocyte growth factor (HGF) has been studied as a potent regenerative factor produced and released during injuries such as infectious diseases. Monitoring of HGF levels might predict therapy results better than C-reactive protein (CRP) within the first day of treatment in pneumonia. For further investigation of previous observations we aimed to study HGF as a first-day marker in over-representing infectious diseases in comparison to procalcitonin (PCT), CRP and body temperature. Fifty-one patients with community acquired infectious diseases were included consequently at admittance and the serum samples were collected before and within 18 - 24 hours of treatment. HGF levels decreased significantly in case of efficient antibiotic therapy and HGF was shown to be better than PCT, CRP and body temperature to evaluate treatment. In patients with pneumonia, monitoring of HGF was most reasonable. HGF might be used as a therapeutic marker within the first day of empiric antibiotic treatment during infection.

  • 3.
    Abrate, Alberto
    et al.
    IRCCS Osped San Raffaele, Italy.
    Buono, Roberta
    IRCCS Osped San Raffaele, Italy.
    Canu, Tamara
    IRCCS Osped San Raffaele, Italy.
    Esposito, Antonio
    IRCCS Osped San Raffaele, Italy.
    Del Maschio, Alessandro
    IRCCS Osped San Raffaele, Italy.
    Luciano, Roberta
    IRCCS Osped San Raffaele, Italy; IRCCS Osped San Raffaele, Italy.
    Bettiga, Arianna
    IRCCS Osped San Raffaele, Italy.
    Colciago, Giorgia
    IRCCS Osped San Raffaele, Italy.
    Guazzoni, Giorgio
    IRCCS Osped San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Hedlund, Petter
    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. IRCCS Osped San Raffaele, Italy.
    Altaner, Cestmir
    Slovak Academic Science, Slovakia; St Elisabeth Cancer Institute, Slovakia.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy.
    Cavarretta, Ilaria T. R.
    IRCCS Osped San Raffaele, Italy.
    Mesenchymal stem cells expressing therapeutic genes induce autochthonous prostate tumour regression2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 14, p. 2478-2488Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSC) as vehicles of therapeutic genes represent a unique tool to activate drugs within a neoplastic mass due to their property to home and engraft into tumours. In particular, MSC expressing the cytosine deaminase:: uracil phosphoribosyltransferase (CD-MSC) have been previously demonstrated to inhibit growth of subcutaneous prostate cancer xenografts thanks to their ability to convert the non-toxic 5-fluorocytosine into the antineoplastic 5-fluorouracil. Since both the immune system and the tumour microenvironment play a crucial role in directing cancer progression, in order to advance towards clinical applications, we tested the therapeutic potential of this approach on animal models that develop autochthonous prostate cancer and preserve an intact immune system. As cell vectors, we employed adipose-tissue and bone-marrow MSC. CD-MSC toxicity on murine prostate cancer cells and tumour tropism were verified in vitro and ex-vivo before starting the preclinical studies. Magnetic Resonance Imaging was utilised to follow orthotopic tumour progression. We demonstrated that intravenous injections of CD-MSC cells, followed by intraperitoneal administration of 5-fluorocytosine, caused tumour regression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which develops aggressive and spontaneous prostate cancer. These results add new insights to the therapeutic potential of specifically engineered MSC in prostate cancer disease.

  • 4.
    Adolfsson, Per I
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Bloth, Björn
    Department of Clinical Neuroscience, Laboratory of Translational Neuropharmacology, Center of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Hägg, Staffan
    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 Health Sciences. Futurum Academy for Health and Care, Jönköping County Council, Sweden.
    Svensson, Samuel P S
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zinc Induces a Bell-shaped Proliferative Dose-response Effect in Cultured Smooth Muscle Cells From Benign Prostatic Hyperplasia.2015In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 85, no 3, p. 704.e15-704.e19Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the effects of zinc (Zn(2+)) concentrations on cultured benign prostatic hyperplasia (BPH) smooth muscle cell (SMC) proliferation.

    METHODS: The effects of Zn(2+) were studied in primary cultures of human BPH SMC, stimulated with either 10-μM lysophosphatidic acid (LPA) or LPA in combination with 100-nM testosterone. Deoxyribonucleic acid replication and protein synthesis using [(3)H]-thymidine and [(35)S]-methionine incorporation were measured. Furthermore, studies were performed to evaluate if Zn(2+) could potentiate the inhibitory effect of phosphodiesterase-5 blockers, on BPH SMC proliferation.

    RESULTS: Zn(2+) generated a bell-shaped concentration response, both regarding deoxyribonucleic acid replication and protein synthesis in cultured BPH SMC. Below a threshold value (approximately 200 μM), a significant mitogenic effect was seen, whereas higher concentrations inhibited SMC proliferation after stimulation with LPA. This effect was even more pronounced after stimulation of LPA in combination with testosterone. Moreover, phosphodiesterase-5 inhibitors, that is, sildenafil blocked LPA-stimulated BPH SMC proliferation. This antiproliferative effect, was significantly potentiated by coincubation with Zn(2+) in an additative manner.

    CONCLUSION: The bell-shaped concentration response of Zn(2+) on cultured BPH SMC proliferation suggests that changes in prostate Zn(2+) concentrations, during aging, diet, or inflammatory conditions, may be of importance in the pathogenesis of BPH.

  • 5.
    Ahlner, Johan
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Swedish National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Holmgren, Anita
    Swedish National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Jones, A Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Swedish National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Demographics and post-mortem toxicology findings in deaths among people arrested multiple times for use of illicit drugs and/or impaired driving2016In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 265, p. 138-143Article in journal (Refereed)
    Abstract [en]

    Background: Multiple arrests for use of illicit drugs and/or impaired driving strongly suggests the existence of a personality disorder and/or a substance abuse problem. Methods: This retrospective study (1993-2010) used a national forensic toxicology database (TOXBASE), and we identified 3943 individuals with two or more arrests for use of illicit drugs and/or impaired driving. These individuals had subsequently died from a fatal drug poisoning or some other cause of death, such as trauma. Results: Of the 3943 repeat offenders 1807 (46%) died from a fatal drug overdose and 2136 (54%) died from other causes (p amp;lt; 0.001). The repeat offenders were predominantly male (90% vs 10%) and mean age of drug poisoning deaths was 5 y younger (mean 35 y) than other causes of death (mean 40 y). Significantly more repeat offenders (46%) died from drug overdose compared with all other forensic autopsies (14%) (p amp;lt; 0.001). Four or more drugs were identified in femoral blood in 44% of deaths from poisoning (drug overdose) compared with 18% of deaths by other causes (p amp;lt; 0.001). The manner of death was considered accidental in 54% of deaths among repeat offenders compared with 28% for other suspicious deaths (p amp;lt; 0.001). The psychoactive substances most commonly identified in autopsy blood from repeat offenders were ethanol, morphine (from heroin), diazepam, amphetamines, cannabis, and various opioids. Conclusions: This study shows that people arrested multiple times for use of illicit drugs and/or impaired driving are more likely to die by accidentally overdosing with drugs. Lives might be saved if repeat offenders were sentenced to treatment and rehabilitation for their drug abuse problem instead of conventional penalties for drug-related crimes. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 6.
    Ahlner, Johan
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Holmgren, Anita
    National Board for Forensic Medicine, Linkoping, Sweden .
    Jones, A Wayne
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Prevalence of alcohol and other drugs and the concentrations in blood of drivers killed in road traffic crashes in Sweden2014In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 42, no 2, p. 177-183Article in journal (Refereed)
    Abstract [en]

    Background: Drunk or drug-impaired drivers represent a major public health and societal problem worldwide. Because over 95% of drivers killed on the roads in Sweden are autopsied, reliable information is available about the use of alcohol and/or other drug before the crash. Methods: This retrospective 4-year study (2008-2011) used a forensic toxicology database (TOXBASE) to evaluate the concentrations of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes. Results: The mean age of all victims (N = 895) was 48 +/- 20 years, and the majority were male (86%). In 504 drivers (56%), the results of toxicological analysis were negative and these victims were older; mean age (+/- SD) 47 +/- 20 years, than alcohol positive cases (35 +/- 14 years) and illicit drug users (34 +/- 15 years). In 21% of fatalities, blood-alcohol concentration (BAC) was above the statutory limit for driving (0.2 g/L), although the median BAC was appreciably higher (1.72 g/L). Illicit drugs (mainly amphetamine and cannabis) were identified in similar to 7% of victims, either alone (2.5%), together with alcohol (1.8%) or a prescription drug (2%). The psychoactive prescription drugs identified were mainly benzodiazepines, z-hypnotics and tramadol, which were found in the blood of 7.6% of crash victims. Conclusions: The high median BAC in fatally-injured drivers speaks strongly towards alcohol-induced impairment as being responsible for the crash. Compared with alcohol, the prevalence of illicit and psychoactive prescription drugs was fairly low despite a dramatic increase in the number of drug-impaired drivers arrested by the police after a zero-tolerance law was introduced in 1999.

  • 7.
    Ahrén, Maria
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Selegård, Linnéa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Klasson, Anna
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Abrikossova, Natalia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, The Institute of Technology.
    Engström, Maria
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Käll, Per-Olov
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Synthesis and Characterization of PEGylated Gd2O3 Nanoparticles for MRI Contrast Enhancement2010In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, no 8, p. 5753-5762Article in journal (Refereed)
    Abstract [en]

    Recently, much attention has been given to the development of biofunctionalized nanoparticles with magnetic properties for novel biomedical imaging. Guided, smart, targeting nanoparticulate magnetic resonance imaging (MRI) contrast agents inducing high MRI signal will be valuable tools for future tissue specific imaging and investigation of molecular and cellular events. In this study, we report a new design of functionalized ultrasmall rare earth based nanoparticles to be used as a positive contrast agent in MRI. The relaxivity is compared to commercially available Gd based chelates. The synthesis, PEGylation, and dialysis of small (3−5 nm) gadolinium oxide (DEG-Gd2O3) nanoparticles are presented. The chemical and physical properties of the nanomaterial were investigated with Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, and dynamic light scattering. Neutrophil activation after exposure to this nanomaterial was studied by means of fluorescence microscopy. The proton relaxation times as a function of dialysis time and functionalization were measured at 1.5 T. A capping procedure introducing stabilizing properties was designed and verified, and the dialysis effects were evaluated. A higher proton relaxivity was obtained for as-synthesized diethylene glycol (DEG)-Gd2O3 nanoparticles compared to commercial Gd-DTPA. A slight decrease of the relaxivity for as-synthesized DEG-Gd2O3 nanoparticles as a function of dialysis time was observed. The results for functionalized nanoparticles showed a considerable relaxivity increase for particles dialyzed extensively with r1 and r2 values approximately 4 times the corresponding values for Gd-DTPA. The microscopy study showed that PEGylated nanoparticles do not activate neutrophils in contrast to uncapped Gd2O3. Finally, the nanoparticles are equipped with Rhodamine to show that our PEGylated nanoparticles are available for further coupling chemistry, and thus prepared for targeting purposes. The long term goal is to design a powerful, directed contrast agent for MRI examinations with specific targeting possibilities and with properties inducing local contrast, that is, an extremely high MR signal at the cellular and molecular level.

  • 8.
    Aizawa, Naoki
    et al.
    University of Tokyo, Japan.
    Gandaglia, Giorgio
    IRCCS, Italy; Lund University, Sweden.
    Hedlund, Petter
    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.
    Fujimura, Tetsuya
    University of Tokyo, Japan.
    Fukuhara, Hiroshi
    University of Tokyo, Japan.
    Montorsi, Francesco
    IRCCS, Italy.
    Homma, Yukio
    University of Tokyo, Japan.
    Igawa, Yasuhiko
    University of Tokyo, Japan.
    URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E-2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 117, no 5, p. 821-828Article in journal (Refereed)
    Abstract [en]

    Objective To determine if inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) can counteract the changes in urodynamic variables and bladder afferent activities induced by intravesical prostaglandin E-2 (PGE(2)) instillation in rats. Materials and methods In female Sprague-Dawley rats we studied the effects of URB937, a peripherally restricted FAAH inhibitor, on single-unit afferent activity (SAA) during PGE(2)-induced bladder overactivity (BO). SAA measurements were made in urethane-anaesthetised rats and Ad-and C-fibres were identified by electrical stimulation of the pelvic nerve and by bladder distention. Cystometry (CMG) in conscious animals and during SAA measurements was performed during intravesical instillation of PGE(2) (50 or 100 mu M) after intravenous administration of URB937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB1 and CB2, in microsurgically removed L6 dorsal root ganglion (DRG) were studied by immunofluorescence. Results During CMG, 1 mg/kg URB937, but not vehicle or 0.1 mg/kg URB937, counteracted the PGE(2)-induced changes in urodynamic variables. PGE(2) increased the SAAs of C-fibres, but not Ad-fibres. URB937 (1 mg/kg) depressed Ad-fibre SAA and abolished the facilitated C-fibre SAA induced by PGE(2). The DRG nerve cells showed strong staining for FAAH, CB1 and CB2, with a mean (SEM) of 77 (2)% and 87 (3)% of FAAH-positive nerve cell bodies co-expressing CB1 or CB2 immunofluorescence, respectively. Conclusion The present results show that URB937, a peripherally restricted FAAH inhibitor, reduces BO and C-fibre hyperactivity in the rat bladder provoked by PGE(2), suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.

  • 9.
    Aizawa, Naoki
    et al.
    University of Tokyo, Japan.
    Hedlund, Petter
    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.
    Fuellhase, Claudius
    University of Munich, Germany.
    Ito, Hiroki
    University of Tokyo, Japan.
    Homma, Yukio
    University of Tokyo, Japan.
    Igawa, Yasuhiko
    University of Tokyo, Japan .
    Inhibition of Peripheral FAAH Depresses Activities of Bladder Mechanosensitive Nerve Fibers of the Rat2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 192, no 3, p. 956-963Article in journal (Refereed)
    Abstract [en]

    Purpose: FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats. Materials and Methods: Female Sprague Dawley (R) rats were anesthetized. Single unit afferent activity of A delta or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP in the L6 dorsal root ganglion were compared by immunofluorescence. Results: A total of 102 single afferent fibers (48 A delta and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean +/- SEM of 78% +/- 9% and of A delta-fibers to a mean of 67% +/- 7% while increasing bladder compliance to a mean of 116% +/- 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity of each fiber type but SR144528 affected only A delta-fiber activity. CGRP positive L6 dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining. Conclusions: To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Ad and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.

  • 10.
    Alehagen, Urban
    et al.
    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 Cardiology in Linköping.
    Johansson, Peter
    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 Cardiology in Linköping.
    Aaseth, Jan
    Innlandet Hospital Trust, Norway; Hedmark University of Coll, Norway.
    Alexander, Jan
    Norwegian Institute Public Heatlh, Norway; Norwegian University of Life Science NMBU, Norway.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Significant changes in circulating microRNA by dietary supplementation of selenium and coenzyme Q10 in healthy elderly males. A subgroup analysis of a prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0174880Article in journal (Refereed)
    Abstract [en]

    Background Selenium and coenzyme Q10 is essential for important cellular functions. A low selenium intake is reported from many European countries, and the endogenous coenzyme Q10 production is decreasing in the body with increasing age. Supplementation with selenium and coenzyme Q10 in elderly have shown reduced cardiovascular mortality and reduced levels of markers of inflammation. However, microRNA analyses could give important information on the mechanisms behind the clinical effects of supplementation. Methods Out of the 443 healthy elderly participants that were given supplementation with 200 mu g Se/ day as organic selenium yeast tablets, and 200 mg/day of coenzyme Q10 capsules, or placebo for 4 years, 25 participants from each group were randomized and evaluated regarding levels of microRNA. Isolation of RNA from plasma samples and quantitative PCR analysis were performed. Volcano- and principal component analyses (PCA)-plots were used to illustrate the differences in microRNA expression between the intervention, and the placebo groups. Serum selenium concentrations were measured before intervention. Findings On average 145 different microRNAs out of 172 were detected per sample. In the PCA plots two clusters could be identified indicating significant difference in microRNA expression between the two groups. The pre-treatment expression of the microRNAs did not differ between active treatment and the placebo groups. When comparing the post- treatment microRNAs in the active and the placebo groups, 70 microRNAs exhibited significant differences in expression, also after adjustment for multiple measurements. For the 20 microRNAs with the greatest difference in expression the difference was up to more than 4 fold and with a P-value that were less than 4.4e(-8). Conclusions Significant differences were found in expression of more than 100 different microRNAs with up to 4 fold differences as a result of the intervention of selenium and coenzyme Q10 combined. The changes in microRNA could be a part of mechanisms underlying the clinical effects earlier reported that reduced cardiovascular mortality, gave better cardiac function, and showed less signs of inflammation and oxdative stress following the intervention. However, more research is needed to understand biological mechanisms of the protective effects of selenium and Q10 supplementation.

  • 11.
    Alehagen, Urban
    et al.
    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 Cardiology in Linköping.
    Slind Olsen, Renate
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Ryhov, Sweden.
    Länne, Toste
    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 Thoracic and Vascular Surgery. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Matussek, Andreas
    County Hospital Ryhov, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    PDGF-D gene polymorphism is associated with increased cardiovascular mortality in elderly men2016In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, no 62Article in journal (Refereed)
    Abstract [en]

    Background: Platelet-derived growth factor (PDGF) D has been reported to be active in fibroblasts, and in areas of myocardial infarction. In this longitudinal study we evaluated the association between PDGF-D polymorphism and cardiovascular mortality, and attempted to discover whether specific genotype differences regarding risk could be observed, and if gender differences could be seen. Methods: Four hundred seventy-six elderly community participants were included in this study. All participants underwent a clinical examination, echocardiography, and blood sampling including PDGF-D single nucleotide polymorphism (SNP) analyses of the rs974819 A/A, G/A and G/G SNP. The follow-up time was 6.7 years. Results: No specific genotype of rs974819 demonstrated increased cardiovascular mortality in the total population, however, the male group with genotypes A/A and G/A demonstrated an increased risk that persisted in a multivariate evaluation where adjustments were made for well-known cardiovascular risk factors (2.7 fold compared with the G/G genotype). No corresponding finding was observed in the female group. Conclusion: We report here for the first time that the genotypes G/A or A/A of the SNP rs974819 near PDGF-D exhibited a 2.7 fold increased cardiovascular mortality risk in males. Corresponding increased risk could not be observed in either the total population and thus not in the female group. However, the sample size is was small and the results should be regarded as hypothesis-generating, and thus more research in the field is recommended.

  • 12.
    Alehagen, Urban
    et al.
    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 Cardiology in Linköping.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Ljungberg, Liza
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Länne, Toste
    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 Thoracic and Vascular Surgery.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gender difference in adiponectin associated with cardiovascular mortality2015In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 16, no 9Article in journal (Refereed)
    Abstract [en]

    Background: It is important to identify cardiovascular diseases in patients at high risk. To include genetics into routine cardiological patients has therefore been discussed recently. We wanted to evaluate the association between high-molecular weight adiponectin and cardiovascular risk, and secondly in the same population evaluate if specific genotype differences regarding risk could be observed, and thirdly if gender differences could be seen. Method: Four hundred seventy-six elderly participants recruited from a rural community were included. All participants underwent a clinical examination, echocardiography, and blood sampling and the single nucleotide polymorphism (SNP) (rs266729) of adiponectin was analysed. Follow-up time was 6.7 years. Results: Those with high serum concentration of adiponectin had a more 2 fold increased cardiovascular risk, and it might be that females exhibits even higher risk where a more than 5 fold increased risk could be seen. The result could be demonstrated even in a multivariate model adjusting for well-known clinical risk factors. However, as the sample size was small the gender differences should be interpreted with caution. In the genotype evaluation the C/C carriers of the female group had a more than 9-fold increased risk of cardiovascular mortality, however the confidence interval was wide. Such genotype difference could not be found in the male group. Conclusion: High level of adiponectin was associated with increased cardiovascular risk. Also a gender difference in the genotype evaluation could be seen where the C/C carriers obtained higher risk in the female group but not in the male group. Thus, in order to identify patients at risk early, genetic analyses may add to the armamentarium used in the clinical routine. However, information should be regarded as hypothesis generating as the sample size was small and should stimulate further research in individualized cardiovascular prevention and treatment.

  • 13.
    Almroth, Gabriel
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Lönn, Johanna
    Örebro Universitet, Sweden.
    Uhlin, Fredrik
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Physiology, County Hospital, Kalmar, Sweden.
    Andersson, Bengt Andersson
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Hahn-Zoric, Mirjana
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Sclerostin, TNF-alpha and Interleukin-18 Correlate and are Together with Klotho Related to Other Growth Factors and Cytokines in Haemodialysis Patients2016In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 83, no 1, p. 58-63Article in journal (Refereed)
    Abstract [en]

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

  • 14.
    Amundstuen Reppe, Linda
    et al.
    Nordic University, Norway; Norwegian University of Science and Technology, Norway; St Olays Hospital, Norway.
    Lydersen, Stian
    Norwegian University of Science and Technology, Norway.
    Schjott, Jan
    Haukeland Hospital, Norway; University of Bergen, Norway; Haukeland Hospital, Norway.
    Damkier, Per
    Odense University Hospital, Denmark.
    Rolighed Christensen, Hanne
    Bispebjerg and Frederiksberg University Hospital, Denmark.
    Peter Kampmann, Jens
    Bispebjerg and Frederiksberg University Hospital, Denmark.
    Böttiger, Ylva
    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.
    Spigset, Olav
    Norwegian University of Science and Technology, Norway; St Olays Hospital, Norway.
    Relationship Between Time Consumption and Quality of Responses to Drug-related Queries: A Study From Seven Drug Information Centers in Scandinavia2016In: Clinical Therapeutics, ISSN 0149-2918, E-ISSN 1879-114X, Vol. 38, no 7, p. 1738-1749Article in journal (Refereed)
    Abstract [en]

    Purpose: The aims of this study were to assess the quality of responses produced by drug information centers (DICs) in Scandinavia, and to study the association between time consumption processing queries and the quality of the responses. Methods: We posed six identical drug-related queries to seven DICs in Scandinavia, and the time consumption required for processing them was estimated. Clinical pharmacologists (internal experts) and general practitioners (external experts) reviewed responses individually. We used mixed model linear regression analyses to study the associations between time consumption on one hand and the summarized quality scores and the overall impression of the responses on the other hand. Findings: Both expert groups generally assessed the quality of the responses as "satisfactory" to "good." A few responses were criticized for being poorly synthesized and less relevant, of which none were quality-assured using co-signatures. For external experts, an increase in time consumption was statistically significantly associated with a decrease in common quality score (change in score, -0.20 per hour of work; 95% CI, -0.33 to -0.06; P = 0.004), and overall impression (change in score, -0.05 per hour of work; 95% CI, -0.08 to -0.01; P = 0.005). No such associations were found for the internal experts assessment. Implications: To our knowledge, this is the first study of the association between time consumption and quality of responses to drug-related queries in DICs. The quality of responses were in general good, but time consumption and quality were only weakly associated in this setting. (C) 2016 The Authors. Published by Elsevier HS Journals, Inc.

  • 15.
    Amundstuen Reppe, Linda
    et al.
    Nordic University, Norway; Norwegian University of Science and Technology, Norway; St Olavs Hospital, Norway.
    Spigset, Olav
    Norwegian University of Science and Technology, Norway; St Olavs Hospital, Norway.
    Kampmann, Jens Peter
    Bispebjerg Hospital, Denmark.
    Damkier, Per
    Odense University Hospital, Denmark.
    Rolighed Christensen, Hanne
    Bispebjerg Hospital, Denmark.
    Böttiger, Ylva
    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.
    Schjott, Jan
    Haukeland Hospital, Norway; University of Bergen, Norway; Haukeland Hospital, Norway.
    Quality assessment of structure and language elements of written responses given by seven Scandinavian drug information centres2017In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 73, no 5, p. 623-631Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify structure and language elements affecting the quality of responses from Scandinavian drug information centres (DICs). Six different fictitious drug-related queries were sent to each of seven Scandinavian DICs. The centres were blinded for which queries were part of the study. The responses were assessed qualitatively by six clinical pharmacologists (internal experts) and six general practitioners (GPs, external experts). In addition, linguistic aspects of the responses were evaluated by a plain language expert. The quality of responses was generally judged as satisfactory to good. Presenting specific advice and conclusions were considered to improve the quality of the responses. However, small nuances in language formulations could affect the individual judgments of the experts, e.g. on whether or not advice was given. Some experts preferred the use of primary sources to the use of secondary and tertiary sources. Both internal and external experts criticised the use of abbreviations, professional terminology and study findings that was left unexplained. The plain language expert emphasised the importance of defining and explaining pharmacological terms to ensure that enquirers understand the response as intended. In addition, more use of active voice and less compressed text structure would be desirable. This evaluation of responses to DIC queries may give some indications on how to improve written responses on drug-related queries with respect to language and text structure. Giving specific advice and precise conclusions and avoiding too compressed language and non-standard abbreviations may aid to reach this goal.

  • 16.
    Andersson Hagiwara, Magnus
    et al.
    University of Boras, Sweden.
    Nilsson, Lena
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Norrköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Stromsoe, Anneli
    Malardalens Hogskola, Sweden.
    Axelsson, Christer
    University of Boras, Sweden.
    Kangstrom, Anna
    University of Boras, Sweden.
    Herlitz, Johan
    University of Boras, Sweden.
    Patient safety and patient assessment in pre-hospital care: a study protocol2016In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 24, no 14Article in journal (Refereed)
    Abstract [en]

    Background: Patient safety issues in pre-hospital care are poorly investigated. The aim of the planned study is to survey patient safety problems in pre-hospital care in Sweden. Methods/Design: The study is a retro-perspective structured medical record review based on the use of 11 screening criteria. Two instruments for structured medical record review are used: a trigger tool instrument designed for pre-hospital care and a newly development instrument designed to compare the pre-hospital assessment with the final hospital assessment. Three different ambulance organisations are participating in the study. Every month, one rater in each organisation randomly collects 30 medical records for review. With guidance from the review instrument, he/she independently reviews the record. Every month, the review team meet for a discussion of problematic reviews. The results will be analysed with descriptive statistics and logistic regression. Discussion: The findings will make an important contribution to knowledge about patient safety issues in prehospital care.

  • 17.
    Andersson, Henrik
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, 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.
    Björnström-Karlsson, Karin
    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. Linköping University, Faculty of Medicine and Health Sciences.
    Eintrei, Christina
    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.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Orexin A Phosphorylates the gamma-Aminobutyric Acid Type A Receptor beta(2) Subunit on a Serine Residue and Changes the Surface Expression of the Receptor in SH-SY5Y Cells Exposed to Propofol2015In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 93, no 11, p. 1748-1755Article in journal (Refereed)
    Abstract [en]

    Propofol activates the gamma-aminobutyric acid type A receptor (GABA(A)R) and causes a reversible neurite retraction, leaving a thin, thread-like structure behind; it also reverses the transport of vesicles in rat cortical neurons. The awakening peptide orexin A (OA) inhibits this retraction via phospholipase D (PLD) and protein kinase CE (PKCE). The human SH-SY5Y cells express both GABA(A)Rs and orexin 1 and 2 receptors. These cells are used to examine the interaction between OA and the GABAAR. The effects of OA are studied with flow cytometry and immunoblotting. This study shows that OA stimulates phosphorylation on the serine residues of the GABA(A)R beta(2) subunit and that the phosphorylation is caused by the activation of PLD and PKCE. OA administration followed by propofol reduces the cell surface expression of the GABA(A)R, whereas propofol stimulation before OA increases the surface expression. The GABA(A)R beta(2) subunit is important for receptor recirculation, and the effect of OA on propofol-stimulated cells may be due to a disturbed recirculation of the GABA(A)R. (C) 2015 Wiley Periodicals, Inc.

  • 18.
    Andersson, Maria
    et al.
    NIDA, MD 21224 USA.
    Diao, Xingxing
    NIDA, MD 21224 USA.
    Wohlfarth, Ariane
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. NIDA, MD 21224 USA; National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Scheidweiler, Karl B.
    NIDA, MD 21224 USA.
    Huestis, Marilyn A.
    NIDA, MD 21224 USA.
    Metabolic profiling of new synthetic cannabinoids AMB and 5F-AMB by human hepatocyte and liver microsome incubations and high-resolution mass spectrometry2016In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, no 8, p. 1067-1078Article in journal (Refereed)
    Abstract [en]

    RationaleAMB (methyl (1-pentyl-1H-indazole-3-carbonyl)-L-valinate)) and its fluoro analog 5F-AMB (methyl (1-(5-fluoropentyl)-1H-indazole-3-carbonyl)-L-valinate) are two new synthetic cannabinoids that are structural analogs of AB-PINACA and 5F-AB-PINACA, respectively. 5F-AMB is scheduled as an illicit drug in China, Germany, Singapore and Japan, and no metabolism data are currently available for either drug. The aim of the present work was to investigate the metabolism of AMB and 5F-AMB and propose appropriate markers to identify their intake in clinical or forensic cases. MethodsAMB and 5F-AMB were incubated in human hepatocytes (10 mol/L) to generate phase I and II metabolites, which were identified with a TripleTOF 5600(+) high-resolution mass spectrometer. AMB and 5F-AMB metabolic stability studies also were performed with human liver microsomes (HLM) to evaluate metabolic clearances, and to adequately design the human hepatocyte experiment. ResultsAMB and 5F-AMB were quickly metabolized in HLM with a 1.1 0.1 and 1.0 +/- 0.2min T-1/2, respectively. The predominant metabolic pathway for AMB and 5F-AMB in hepatocytes was ester hydrolysis, and further oxidation and/or glucuronidation. In total, 19 metabolites were identified for AMB and 17 for 5F-AMB. We describe metabolites to differentiate AMB from 5F-AMB, and metabolites that are common to both analytes due to oxidative defluorination of 5F-AMB. ConclusionsFor the first time, AMB and 5F-AMB metabolism profiles were characterized, providing valuable data for identifying these two novel psychoactive substances. The difficulties of differentiating AMB and 5F-AMB from AB-PINACA/5F-AB-PINACA metabolites also were examined. These data improve the interpretation of urinary markers after AMB and 5F-AMB intake. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA

  • 19.
    Andersson, Marine L.
    et al.
    Karolinska University, Sweden.
    Böttiger, Ylva
    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.
    Bastholm-Rahmner, Pia
    Karolinska Institute, Sweden.
    Ovesjo, Marie-Louise
    Karolinska University, Sweden.
    Veg, Aniko
    Karolinska Institute, Sweden.
    Eiermann, Birgit
    Karolinska University, Sweden.
    Evaluation of usage patterns and user perception of the drug-drug interaction database SFINX2015In: International Journal of Medical Informatics, ISSN 1386-5056, E-ISSN 1872-8243, Vol. 84, no 5, p. 327-333Article in journal (Refereed)
    Abstract [en]

    Purpose: The aim of the present study was to investigate how prescribers and pharmacists use and perceive the drug-drug interaction database SFINX in their clinical work. Methods: A questionnaire was developed with questions aimed at the usage of SFINX, and the perceptions of the database. The questionnaire was sent out to all registered users of the web application of SFINX. The anonymous answers from the target users, prescribers and pharmacists were summarized using descriptive statistics. Statistical analysis was performed on age and gender differences for some questions regarding different usage patterns. Results: The questionnaire was sent to 11,763 registered SFINX users. The response rate was 23%, including 1871 answers from prescribers or pharmacists. SFINX was reported to be used at least weekly or more often by 45% of the prescribers and 51% of the pharmacists. Many prescribers reported using the database during the patient consultation (60%) or directly before or after (56%). Among the prescribers, 74% reported that the information received made them change their action at least sometimes. About 20% of the prescribers and 25% of the pharmacists considered the information as irrelevant sometimes or more often. Conclusion: Most prescribers and pharmacists reported using SFINX in direct association with a patient consultation. Information received by using SFINX makes prescribers and pharmacists change their handling of patients. DDI databases with relevant information about patient handling might improve drug treatment outcome. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

  • 20.
    Andersson, Marine L
    et al.
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm,.
    Böttiger, Ylva
    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.
    Kockum, Henrik
    3Department of.
    Eiermann, Birgit
    Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm,.
    High Prevalence of Drug-Drug Interactions in Primary Health Care is Caused by Prescriptions from other Healthcare Units.2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 122, no 5, p. 512-516Article in journal (Refereed)
    Abstract [en]

    Drug-drug interactions are increasingly common, as patients are getting older and the number of drugs per patient is increasing. In this study, we investigated to which extent potential drug-drug interactions originated from single or multiple prescribers. All patients attending any of 20 primary healthcare centres were included in a retrospective observational cohort study. Data on all prescriptions to these patients, irrespectively of the prescriber, were collected for two 4-month periods. Potential drug interactions were identified using the drug-drug interaction database SFINX. Interactions were classified with respect to the workplace of the prescriber, and the prevalence of interactions according to origin was analysed. We found that the drug interactions were significantly more common when the drugs were prescribed from different healthcare centres, compared with drugs prescribed from the patients' primary healthcare centre only. One explanation for this increased risk of drug interactions could be that the prescribers at different primary healthcare centres do not share the same information concerning the total medication list of the patient.

  • 21.
    Andersson Sundell, K.
    et al.
    University of Gothenburg, Sweden.
    Jönsson, Anna K.
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Beliefs about medicines are strongly associated with medicine-use patterns among the general population2016In: International journal of clinical practice (Esher), ISSN 1368-5031, E-ISSN 1742-1241, Vol. 70, no 3, p. 277-285Article in journal (Refereed)
    Abstract [en]

    AimsTo investigate self-reported beliefs and perceived sensitivity to medicines and their effects in relation to self-reported use of medicines and herbal remedies. MethodsA survey sent to 13,931 randomly selected Swedish adults included the Beliefs about Medicines Questionnaire-General (BMQ-General) Questionnaire and the Perceived Sensitivity to Medicines Scale (PSM). The survey also asked about individuals use of prescribed and over-the-counter (OTC) medicines and herbal remedies in the past month. We examined all associations between scores on the BMQ-General subscales and PSM in relation to the use of medicines and herbal remedies, using analysis of covariance adjusted for potential confounders. ResultsAmong 7099 respondents, those using herbal remedies exclusively believed strongly that prescription and OTC medicines are harmful and overprescribed. Respondents using prescription and OTC medicines reported more positive beliefs [coefficient 0.67 (95% CI 0.47-0.87) and 0.70 (95% CI 0.51-0.90)] on the benefits of medicines compared with those using herbal remedies [-0.18 (95% CI -0.57-0.20)]. Perceived sensitivity to medicines was higher among those using herbal remedies only [1.25 (95% CI 0.46-2.03)] compared with those using no medicines (reference 0) or prescription [-0.44 (95% CI -0.84 to -0.05)] or OTC [-0.27 (95% CI -0.66-0.12)] medicines alone. ConclusionRespondents using prescription and/or OTC medicines reported stronger positive beliefs about the benefits of medicines in general, supporting the hypothesis that beliefs influence medicine use. Therefore, addressing beliefs and concerns about medicines during patient counselling may influence medicine use, particularly regarding unintentional non-adherence.

  • 22.
    Apellaniz-Ruiz, Maria
    et al.
    Spanish National Cancer Research Centre CNIO, Spain.
    Sanchez-Barroso, Lara
    Spanish National Cancer Research Centre CNIO, Spain.
    Gutierrez-Gutierrez, Gerardo
    Hospital University of Infanta Sofia, Spain.
    Sereno, Maria
    Hospital University of Infanta Sofia, Spain.
    Garcia-Donas, Jesus
    CIOCC, Spain.
    Åvall Lundqvist, Elisabeth
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Royal Institute Technology, Sweden; National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Brosen, Kim
    University of Southern Denmark, Denmark.
    Bergmann, Troels K.
    University of Southern Denmark, Denmark.
    Rodriguez-Antona, Cristina
    Spanish National Cancer Research Centre CNIO, Spain; ISCIII Centre Biomed Research Rare Disease CIBERER, Spain.
    Letter: Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel-Letter in CLINICAL CANCER RESEARCH, vol 21, issue 13, pp 3092-30932015In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 13, p. 3092-3093Article in journal (Other academic)
    Abstract [en]

    n/a

  • 23.
    Apellániz-Ruiz, Maria
    et al.
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Tejero, Héctor
    Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
    Inglada-Pérez, Lucía
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
    Sánchez-Barroso, Lara
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Gutiérrez-Gutiérrez, Gerardo
    Neurology Section, Hospital Universitario Infanta Sofía, Madrid, Spain.
    Calvo, Isabel
    Medical Oncology Department, Hospital Montepríncipe, Madrid, Spain. Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain.
    Castelo, Beatriz
    Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
    Redondo, Andrés
    Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
    García-Donás, Jesus
    Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
    Romero-Laorden, Nuria
    Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
    Sereno, Maria
    Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
    Merino, María
    Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
    Currás-Freixes, Maria
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Montero-Conde, Cristina
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Mancikova, Veronika
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    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 and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Al-Shahrour, Fatima
    Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
    Cascon, Alberto
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
    Robledo, Mercedes
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain .
    Rodriguez-Antona, Cristina
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain .
    Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 5, p. 1227-1235Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for inter-individual differences remain unexplained. In this study we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.

    EXPERIMENTAL DESIGN: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/ gene-based analyses were used to compare variant frequencies among neuropathy groups and Cox regression models were used to analyze neuropathy evolution along treatment.

    RESULTS: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low frequency non-synonymous variants in EPHA6 were present exclusively in patients with high neuropathy and all affected the ligand binding domain. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency non-synonymous variant carriers (HR=14.60, 95%CI=2.33-91.62, P=0.0042) and an independent cohort confirmed an increased neuropathy risk (HR=2.07, 95%CI=1.14-3.77, P=0.017). Combining the series gave an estimated 2.50-fold higher risk of neuropathy (95%CI=1.46-4.31; P=9.1x10(-4)).

    CONCLUSION: This first study sequencing EPHA genes revealed that low frequency variants in EPHA6, EPHA5 and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHAs neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.

  • 24.
    Appelgren, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson, Per
    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 Rheumatology.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    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. Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2242Article in journal (Refereed)
    Abstract [en]

    In mice, B1 and marginal zone (MZ) B-cells play an important role in prevention of autoimmunity through production of regulatory cytokines and natural antibodies. There is limited knowledge about the human counterparts of these cells. We therefore investigated functions of MZ-like B-cells and the frequency of circulating MZ-like and Bl-like B-cells in healthy controls (HC), as well as in patients with autoimmune vasculitis to learn more about the role of these cells in autoimmune disease. After stimulation with CpG oligodeoxynucleotides (ODN) of class B in vitro, MZ-like B-cells were the main producers of IgM whereas switched memory B-cells primarily produced IgG and IgA. TNF and IL-10 were produced by both MZ-like and switched memory B-cells. Neither antibody nor TNF/IL-10 production by the B-cell subsets differed between patients and HC. Patients with autoimmune vasculitis, irrespective of disease activity, had lower percentage and absolute numbers of circulating MZ-like B-cells, and lower absolute numbers of B1-like B-cells. The percentage of B1-like B-cells was reduced during active disease. These findings remained significant when the analysis was confined to active treatment-naive patients (disease onset).Our results suggest that human innate-like B-cells might have a physiological role in prevention of autoimmunity.

  • 25.
    Aronsson, Patrik
    et al.
    Department Pharmacology, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Booth, Shirley
    Department Pedagogical, Curricular and Professional Studies, Faculty of Education, University of Gothenburg, Gothenburg, Sweden; School of Education, University of the Witwatersrand, Johannesburg, South Africa.
    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.
    Kjellgren, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Zetterqvist, Ann
    Department Pedagogical, Curricular and Professional Studies, Faculty of Education, University of Gothenburg, Gothenburg, Sweden.
    Tobin, Gunnar
    Department Pharmacology, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Reis, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    The understanding of core pharmacological concepts among health care students in their final semester2015In: BMC Medical Education, ISSN 1472-6920, E-ISSN 1472-6920, Vol. 15, no 1, article id 235Article in journal (Refereed)
    Abstract [en]

    Background

    The overall aim of the study was to explore health care students´ understanding of core concepts in pharmacology.

    Method

    An interview study was conducted among twelve students in their final semester of the medical program (n = 4), the nursing program (n = 4), and the specialist nursing program in primary health care (n  = 4) from two Swedish universities. The participants were individually presented with two pharmacological clinically relevant written patient cases, which they were to analyze and propose a solution to. Participants were allowed to use the Swedish national drug formulary. Immediately thereafter the students were interviewed about their assessments. The interviews were audio-recorded and transcribed verbatim. A thematic analysis was used to identify units of meaning in each interview. The units were organized into three clusters: pharmacodynamics, pharmacokinetics, and drug interactions. Subsequent procedure consisted of scoring the quality of students´ understanding of core concepts. Non-parametric statistics were employed.

    Results

    The study participants were in general able to define pharmacological concepts, but showed less ability to discuss the meaning of the concepts in depth and to implement these in a clinical context. The participants found it easier to grasp concepts related to pharmacodynamics than pharmacokinetics and drug interactions.

    Conclusion

    These results indicate that education aiming to prepare future health care professionals for understanding of more complex pharmacological reasoning and decision-making needs to be more focused and effective.

  • 26.
    Arund, Jurgen
    et al.
    Tallinn University of Technology, Estonia.
    Luman, Merike
    North Estonia Medical Centre, Estonia.
    Uhlin, Fredrik
    Region Östergötland, Heart and Medicine Center, Department of Nephrology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Tallinn University of Technology, Estonia.
    Tanner, Risto
    Tallinn University of Technology, Estonia.
    Fridolin, Ivo
    Tallinn University of Technology, Estonia.
    Is Fluorescence Valid to Monitor Removal of Protein Bound Uremic Solutes in Dialysis?2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0156541Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate the contribution and removal dynamics of the main fluorophores during dialysis by analyzing the spent dialysate samples to prove the hypothesis whether the fluorescence of spent dialysate can be utilized for monitoring removal of any of the protein bound uremic solute. A high performance liquid chromatography system was used to separate and quantify fluorophoric solutes in the spent dialysate sampled at the start and the end of 99 dialysis sessions, including 57 hemodialysis and 42 hemodiafiltration treatments. Fluorescence was acquired at excitation 280 nm and emission 360 nm. The main fluorophores found in samples were identified as indole derivatives: tryptophan, indoxyl glucuronide, indoxyl sulfate, 5-hydroxy-indoleacetic acid, indoleacetyl glutamine, and indoleacetic acid. The highest contribution (35 +/- 11%) was found to arise from indoxyl sulfate. Strong correlation between contribution values at the start and end of dialysis (R-2 = 0.90) indicated to the stable contribution during the course of the dialysis. The reduction ratio of indoxyl sulfate was very close to the decrease of the total fluorescence signal of the spent dialysate (49 +/- 14% vs 51 +/- 13% respectively, P = 0.30, N = 99) and there was strong correlation between these reduction ratio values (R-2 = 0.86). On-line fluorescence measurements were carried out to illustrate the technological possibility for real-time dialysis fluorescence monitoring reflecting the removal of the main fluorophores from blood into spent dialysate. In summary, since a predominant part of the fluorescence signal at excitation 280 nm and emission 360 nm in the spent dialysate originates from protein bound derivatives of indoles, metabolites of tryptophan and indole, the fluorescence signal at this wavelength region has high potential to be utilized for monitoring the removal of slowly dialyzed uremic toxin indoxyl sulfate.

  • 27.
    Asklöf, Madeleine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Kjölhede, Preben
    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.
    Borendal Wodlin, Ninnie
    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.
    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.
    Bioelectrical impedance analysis; a new method to evaluate lymphoedema, fluid status, and tissue damage after gynaecological surgery - A systematic review2018In: European Journal of Obstetrics, Gynecology, and Reproductive Biology, ISSN 0301-2115, E-ISSN 1872-7654, Vol. 228, p. 111-119Article, review/survey (Refereed)
    Abstract [en]

    The aim of this descriptive review is to summarise the current knowledge of non-invasive bioelectrical impedance analysis (BIA) used with gynaecological surgical patients in regard to postoperative development of lymphoedema and determination of perioperative fluid balance, and as a prognostic factor in cancer mortality and a predictor of postoperative complications. The databases PubMed, MEDLINE, Scopus Web of Science, the Cochrane Library, and reference lists of selected articles were searched for relevant articles published during the period January 2008-April 2018. Only papers published in English were retrieved. Thirty-seven articles were evaluated. Where gynaecological studies were lacking, studies with a study population from neighbouring clinical fields were used instead. Studies on the clinical use of BIA with gynaecological surgical patients were divided into three categories: the postoperative development of lower limb lymphoedema (n = 7), perioperative hydration measuring (n = 3), and the BIA parameter phase angle as a prognostic factor in cancer survival and as predictive for postoperative complications (n = 6). Of these 16 studies only three used a pure gynaecological study population. Three different methods of BIA were used in these articles: single frequency-BIA, multifrequency-BIA and bioimpedance spectroscopy. BIA was found to detect lymphoedema with a sensitivity of 73% and a specificity of 84%. Studies indicated that BIA was able to detect lower limb lymphoedema at an early stage even before it became clinically detectable. During postoperative hydration measurements, an increase in extracellular fluid volume and extracellular fluid volume in relation to total body fluid volume, as well as a decrease in phase angle, were associated with higher frequencies of postoperative complications. Moreover, low values for the phase angle have been associated with increased mortality in cancer patients. However, the number of studies in this field was limited. From our review, BIA seems to be a useful tool for use in the clinical setting of the gynaecological surgical patient. The theoretical approach of using bioelectrical impedance values to measure the fluid distribution in the body compartments offers wide opportunities in the clinical setting. However, so far, all studies have set up cut-off limits within the study population, and reference values for a general population need to be defined. There are also rather few studies on a gynaecological study population. Hence, there is a need for further studies within gynaecological surgery focusing on early detection of lower limb lymphoedema, perioperative fluid balance, and postoperative complications in order to establish the value of BIA in clinical praxis. (C) 2018 Elsevier B.V. All rights reserved.

    The full text will be freely available from 2019-06-18 12:44
  • 28.
    Avall-Lundqvist, E H
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Department of Gynecologic Oncology, Karolinska Hospital, Stockholm, Sweden.
    Peterson, C O
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Serum cholesterol and apolipoprotein B levels may reflect disease activity in ovarian cancer patients.1996In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 35, no 8, p. 1007-10Article in journal (Refereed)
    Abstract [en]

    Data in the literature demonstrates increased receptor-mediated uptake of low density lipoprotein (LDL) in many types of malignant cells compared with normal cells. In acute leukemia, an inverse correlation has been demonstrated between disease activity and plasma cholesterol. To explore whether this is true also for ovarian cancer a case-control study was performed. We serially collected blood samples and assayed serum cholesterol and apolipoprotein B (the receptor recognizing moiety of LDL) in 10 patients with ovarian cancer. At diagnosis, the patients had lower mean cholesterol levels compared with 6 healthy women. An increase was found after primary surgery and after successful initial chemotherapy. The 5 patients who are in complete remission after a mean follow-up time of 79 months had higher cholesterol and apolipoprotein B levels at their last visit than at diagnosis. In contrast, a reduction of the two analytes was found in the patients who died from their ovarian cancer 15 to 28 months after diagnosis. The results may open a possibility for targetted chemotherapy in ovarian cancer with LDL as a drug carrier.

  • 29.
    Bahlmann, Hans
    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.
    Stewarts blodgastolkning ger djupare insikt i syra–basrubbning2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114Article in journal (Refereed)
  • 30.
    Bahlmann, Hans
    et al.
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Hahn, R. G.
    Sodertalje Hospital, Sweden.
    Nilsson, Lena
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Norrköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Agreement between Pleth Variability Index and oesophageal Doppler to predict fluid responsiveness2016In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 2, p. 183-192Article in journal (Refereed)
    Abstract [en]

    Background: Optimisation of stroke volume using oesophageal Doppler is an established technique to guide intraoperative fluid therapy. The method has practical limitations and therefore alternative indices of fluid responsiveness, such as ventilator-induced variation in the pulse oximetric signal (Pleth Variability Index (PVI)) could be considered. We hypothesised that both methods predict fluid responsiveness in a similar way. Methods: Seventy-five patients scheduled for open major abdominal surgery were randomised to fluid optimisation using fluid bolus algorithms based on either PVI (n = 35) or Doppler (n = 39). All patients were monitored with both methods; the non-guiding method was blind. Primary endpoint was the concordance between the methods to predict fluid responsiveness. We also analysed the ability of each method to predict a stroke volume increase >= 10% after a fluid bolus, as well as the accumulated intraoperative bolus fluid volume. Results: PVI indicated a need for fluid in one-third of the situations when Doppler did so, Cohens kappa = 0.03. A fluid bolus indicated by the PVI algorithm increased stroke volume by >= 10% in half the situations. The same was found for the Doppler algorithm. The mean total bolus volume given was 878 ml when the fluid management was governed by PVI compared to 826 ml with Doppler (P = 0.71). Conclusion: PVI-and Doppler-based stroke volume optimisations agreed poorly, which did not affect the amount of fluid administered. None of the algorithms showed a good ability to predict fluid responsiveness. Our results do not support the fluid responsiveness concept.

  • 31.
    Bahlmann, Hans
    et al.
    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.
    Hahn, Robert
    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. Sodertalje Hosp, Sweden.
    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.
    Pleth variability index or stroke volume optimization during open abdominal surgery: a randomized controlled trial2018In: BMC Anesthesiology, ISSN 1471-2253, E-ISSN 1471-2253, Vol. 18, article id 115Article in journal (Refereed)
    Abstract [en]

    Background: The impact of Goal Directed Fluid Therapy (GDFT) based on the non-invasive Pleth Variability Index (PVI) on clinical outcome after abdominal surgery has only sparingly been explored. The purpose of this study was to compare the effect of intraoperative GDFT guided by PVI to a control group using esophageal Doppler on the incidence of complications and length of hospital stay after major abdominal surgery. We hypothesized that there would be no difference between the groups. Methods: This was a randomized controlled trial in a Swedish university hospital between November 2011 and January 2015; 150 patients scheduled for open abdominal surgery lasting 2 h or more were included. Exclusion criteria included hepatic resection or severe cardiac arrhythmia. The patients were randomized 1: 1 to either the intervention group or the control group. The intervention group received intraoperative GDFT by administering fluid boluses of 3 ml/kg tetrastarch aiming at a PVI value below 10%, while GDFT in the control group aimed for optimization of stroke volume as assessed with esophageal Doppler. Blinded observers assessed complications until postoperative day 30 using pre-defined definitions, as well as length of hospital stay. Results: One hundred and-fifty patients were randomized and 146 patients were available for the final data analysis. Median duration of surgery was 3 h. A total of 64 complications occurred in the PVI group (N = 74) and 70 in the Doppler group (N = 72) (p = 0.93). Median (IQR) length of stay was 8.0 (8.0) days in the PVI group and 8.0 (9.5) in the Doppler group (P = 0.57). Conclusions: No difference in clinical outcome, as defined by number of postoperative complications, and length of hospital stay, was found when goal directed fluid therapy was applied using PVI as an alternative to esophageal Doppler. PVI appears to be an acceptable alternative to esophageal Doppler for goal directed fluid therapy during major open abdominal surgery.

  • 32.
    Barbu, Andreea
    et al.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Jansson, Leif
    Uppsala University, Sweden.
    Sandberg, Monica
    Uppsala University, Sweden.
    Quach, My
    Uppsala University, Sweden.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Uppsala University, Sweden.
    The use of hydrogen gas clearance for blood flow measurements in single endogenous and transplanted pancreatic islets2015In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 97, p. 124-129Article in journal (Refereed)
    Abstract [en]

    The blood perfusion of pancreatic islets is regulated independently from that of the exocrine pancreas, and is of importance for multiple aspects of normal islet function, and probably also during impaired glucose tolerance. Single islet blood flow has been difficult to evaluate due to technical limitations. We therefore adapted a hydrogen gas washout technique using microelectrodes to allow such measurements. Platinum micro-electrodes monitored hydrogen gas clearance from individual endogenous and transplanted islets in the pancreas of male Lewis rats and in human and mouse islets implanted under the renal capsule of male athymic mice. Both in the rat endogenous pancreatic islets as well as in the intra-pancreatically transplanted islets, the vascular conductance and blood flow values displayed a highly heterogeneous distribution, varying by factors 6-10 within the same pancreas. The blood flow of human and mouse islet grafts transplanted in athymic mice was approximately 30% lower than that in the surrounding renal parenchyma. The present technique provides unique opportunities to study the islet vascular dysfunction seen after transplantation, but also allows for investigating the effects of genetic and environmental perturbations on islet blood flow at the single islet level in vivo. (C) 2014 The Authors. Published by Elsevier Inc.

  • 33.
    Bastami, Salumeh
    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 Chemistry.
    Practical and clinical use of opioids2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pain is a common symptom of a number of conditions including cancer and one of the most frequent reasons for seeking healthcare. Acute and chronic pain result in considerable discomfort with a detrimental impact on the quality of life. Opioids are the mainstay of pain management for many patients with severe pain. Opioids are, unfortunately, also commonly abused drugs, and are well-represented in forensic toxicology investigations.

    Side effects related to the central nervous system are the major reasons fordiscontinuation of opioid treatment. In this thesis, we tested the hypothesis that local analgesic treatment by opioids, without the usual opioid-related side effects, could be a potential alternative to systemic opioid treatment. We examined the analgesic effect of topically applied morphine in a randomized, double blind, cross over study in patients with painful leg ulcers. Significant reduction of pain was obtained after application of both morphine and placebo gel. Morphine reduced pain more than placebo but the difference was not statistically significant. However, morphine could reduce pain considerably more than placebo in those cases where VAS (Visual analog scale) was higher initially.

    Another issue with opioid therapy is the substantial individual variability in response to opioids including morphine and tramadol. We investigated the significance of UGT2B7, CYP2D6, OPRM1 and ABCB1 polymorphisms for pharmacokinetic and pharmacodynamic properties of morphine and tramadol. We showed that genetic variants in CYP2D6 and UGT2B7 have an important role in the metabolism of tramadol and morphine respectively. While the role of SNPs in ABCB1 remained unclear, genetic variants in OPRM1 gene were correlated with the required dose of morphine. Taken together, these findings suggest that genotypes should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results.

    Opioids, besides their analgesic properties, have other pharmacological effects including effects on immune system. We evaluated potential differences between commonly used opiates with regard to their effect on the immune system. We found an inhibition of cytokine release, in the order of potency as follows: tramadol > ketobemidone >morphine >fentanyl. All opioids with the exception of fentanyl were capable of inhibiting production of mRNAs for TNF-alpha and IL-8. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of opioids and to improve opioid treatment strategies in patients with cancer.

    Here, we have found that individual genotype matters and affects the individual response. Further research is warranted to tailor individualized treatment. Personalized medicine has increased in importance and will hopefully in the near future become standard procedure to improve and predict the outcome of treatment by opioids.

    List of papers
    1. Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study
    Open this publication in new window or tab >>Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study
    2012 (English)In: International Wound Journal, ISSN 1742-4801, E-ISSN 1742-481X, Vol. 9, no 4, p. 419-427Article in journal (Refereed) Published
    Abstract [en]

    Chronic painful wounds, a major health problem, have a detrimental impact on the quality of life due to associated pain. Some clinical reports have suggested that local administration of morphine could be beneficial. The aim of this study was to evaluate the analgesic effect of topically applied morphine on chronic painful leg ulcers. Twenty-one patients were randomly assigned to receive either morphine or placebo in a randomised, placebo-controlled, crossover pilot study. Each patient was treated four times in total. Pain was measured by the visual analogue score (VAS) before application of gel, directly after and after 2, 6, 12 and 24 hours. Although an overall, clinically relevant, reduction of pain was observed upon treatment with morphine, the difference was not statistically significant. Morphine reduced pain scores more than placebo on treatment occasions 1 and 2. The difference was statistically significant only 2 hours after dressing on the first treatment occasion. Thus, our study did not demonstrate a consistent and globally significant difference in nociception in patients treated with morphine. However, the relatively small number of patients included in our study and other methodological limitations makes it difficult for us to draw general conclusions regarding efficacy of topically applied morphine as an effective treatment for some painful ulcers. Further studies are warranted to evaluate the value of topically applied morphine in the treatment of patients with chronic painful leg ulcers.

    Place, publisher, year, edition, pages
    Blackwell Publishing, 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-75512 (URN)10.1111/j.1742-481X.2011.00901.x (DOI)000306406000011 ()22151619 (PubMedID)
    Available from: 2012-03-05 Created: 2012-03-05 Last updated: 2017-12-07
    2. Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use
    Open this publication in new window or tab >>Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use
    Show others...
    2014 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 5, p. 423-431Article in journal (Refereed) Published
    Abstract [en]

    Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in, both, effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsy cases as morphine is also a very commonly abused drug

    Blood samples were collected from 40 patients following abdominal hysterectomy, 24 hours after initiation of analgesia through a PCA pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsy cases found positive for morphine in routine forensic analysis.

    Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. Dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood.

    Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients.

    We conclude that gene polymorphisms contribute significantly to the variation in morphine levels observed in individual patients.

    Place, publisher, year, edition, pages
    Wiley, 2014
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96791 (URN)10.1111/bcpt.12248 (DOI)000344015300008 ()24703092 (PubMedID)
    Available from: 2013-08-27 Created: 2013-08-27 Last updated: 2017-12-06Bibliographically approved
    3. Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics
    Open this publication in new window or tab >>Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.

    Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.

    Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the  variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.

    Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-96792 (URN)
    Available from: 2013-08-27 Created: 2013-08-27 Last updated: 2013-08-27Bibliographically approved
    4. Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
    Open this publication in new window or tab >>Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
    Show others...
    2013 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 5, p. 1022-1033Article in journal (Refereed) Published
    Abstract [en]

    Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

    Place, publisher, year, edition, pages
    Informa Healthcare, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-89960 (URN)10.3109/0284186X.2012.737932 (DOI)23145506 (PubMedID)
    Available from: 2013-03-12 Created: 2013-03-12 Last updated: 2017-12-06
  • 34.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Gupta, A.
    Department of Anesthesia and Intensive Care, Örebro University, Örebro, Sweden.
    Zackrisson, Anna Lena
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden .
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use2014In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 5, p. 423-431Article in journal (Refereed)
    Abstract [en]

    Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in, both, effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsy cases as morphine is also a very commonly abused drug

    Blood samples were collected from 40 patients following abdominal hysterectomy, 24 hours after initiation of analgesia through a PCA pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsy cases found positive for morphine in routine forensic analysis.

    Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. Dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood.

    Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients.

    We conclude that gene polymorphisms contribute significantly to the variation in morphine levels observed in individual patients.

  • 35.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Haage, Pernilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Kugelberg, Fredrik C.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamicsManuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.

    Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.

    Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the  variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.

    Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.

  • 36.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Haage, Pernilla
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Kugelberg, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Zackrisson, Anna-Lena
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose2014In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, p. 125-132Article in journal (Refereed)
    Abstract [en]

    The major purpose of this study was to elucidate if genotyping can facilitate interpretations of tramadol (TRA) in forensic case work, with special regard to the estimation of the time of drug intake and drug related symptoms (DRS). The association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA was studied. Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report DRS during the experimental day. We found a positive correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA and the time after drug intake for both CYP2D6 intermediate metabolizers and extensive metabolizers. For the only poor metabolizer with detectable ODT levels the metabolic ratio was almost constant. Significant associations were found between the area under the concentration-time curve (AUC) and three of the investigated ABCB1 single nucleotide polymorphisms for TRA, but not for ODT and only in the 50 mg dosage group. There was great interindividual variation in DRS, some subjects exhibited no symptoms at all whereas one subject both fainted and vomited after a single therapeutic dose. However, no associations could be found between DRS and investigated polymorphisms. We conclude that the metabolic ratio of ODT/TRA may be used for estimation of the time of drug intake, but only when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study.

  • 37.
    Benkirane, Raja
    et al.
    Moroccan Pharmacovigilance Centre, Rabat, Morocco; Centre AntiPoison et de Pharmacovigilance, Rabat, Morocco.
    Soulaymani-Bencheikh, Rachida
    Faculty of Medicine, Mohamed V, Rabat, Morocco.
    Khattabi, Asmae
    Institut National Administration Sanitaire, Rabat, Morocco.
    Benabdallah, Ghita
    Moroccan Pharmacovigilance Centre, Rabat, Morocco.
    Alj, Loubna
    Moroccan Pharmacovigilance Centre, Rabat, Morocco.
    Sefiani, Houda
    Moroccan Pharmacovigilance Centre, Rabat, Morocco.
    Hedna, Khedidja
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Ouammi, Lahcen
    Moroccan Pharmacovigilance Centre, Rabat, Morocco.
    Olsson, Sten
    Uppsala Monitoring Centre, Uppsala, Sweden.
    Pal, Shanti N
    World Health Organization, Geneva, Switzerland.
    Assessment of a New Instrument for Detecting Preventable Adverse Drug Reactions.2015In: Drug safety, ISSN 0114-5916, Vol. 38, no 4, p. 383-393Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pharmacovigilance centres (PVCs) in the World Health Organization (WHO) Programme for International Drug Monitoring have demonstrated their ability to detect preventable adverse drug reactions (ADRs) in their databases. In this field, there is no gold-standard method for detecting medication errors and evaluating ADR preventability. Therefore, we developed, from existing tools, a preventability assessment method: the 'P Method' (PM).

    OBJECTIVE: To present the PM and to evaluate its inter-rater reliability.

    METHODS: The PM includes 20 explicit criteria for assessing ADR preventability. This approach is based on identification of any potentially preventable risk factor that increases the likelihood of ADR occurrence. The outcome of the preventability assessment results in one of three possible scores: 'preventable', 'non-preventable' or 'not assessable'. The PM was tested in a multicentre study involving nine national PVCs. Two experienced reviewers at each participating PVC independently analysed the preventability of 183 ADRs, applying the PM.

    RESULTS: The overall agreement between all reviewers for assessment of ADR preventability was 'fair', with a kappa value of 0.27 [95 % confidence interval (CI) 0.21-0.40]. The level of agreement between reviewer pairs ranged from 'slight', with a kappa value of 0.12 (95 % CI -0.03 to 0.27), to 'substantial', with a kappa value of 0.69 (95 % CI 0.48-0.89).

    CONCLUSION: The analysis of the agreements and disagreements between reviewers highlighted where improvements might be made. Given that no standard assessment tool exists in the WHO Programme, the transparency of the assessment process in this method provides a substantial basis for further development and for support in signalling possible preventability.

  • 38.
    Bergek, Christian
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Zdolsek, Joachim H.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Hahn, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Research Unit, Södertälje Hospital, Södertälje, Sweden.
    Non-invasive blood haemoglobin and plethysmographic variability index during brachial plexus block2015In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 114, no 5, p. 812-817Article in journal (Refereed)
    Abstract [en]

    Background Plethysmographic measurement of haemoglobin concentration (SpHb  ), pleth variability index (PVI), and perfusion index (PI) with the Radical-7 apparatus is growing in popularity. Previous studies have indicated that SpHb  has poor precision, particularly when PI is low. We wanted to study the effects of a sympathetic block on these measurements.

    Methods Twenty patients underwent hand surgery under brachial plexus block with one Radical-7 applied to each arm. Measurements were taken up to 20 min after the block had been initiated. Venous blood samples were also drawn from the non-blocked arm.

    Results During the last 10 min of the study, SpHb  had increased by 8.6%. The PVI decreased by 54%, and PI increased by 188% in the blocked arm (median values). All these changes were statistically significant. In the non-blocked arm, these parameters did not change significantly.

    Conclusions Brachial plexus block significantly altered SpHb  , PVI, and PI, which indicates that regional nervous control of the arm greatly affects plethysmographic measurements obtained by the Radical-7. After the brachial plexus block, SpHb  increased and PVI decreased.

  • 39.
    Bergström, G
    et al.
    University of Gothenburg / Sahlgrenska University Hospital.
    Berglund, G
    Lund University.
    Blomberg, A
    Umeå University.
    Brandberg, J
    Sahlgrenska University Hospital / University of Gothenburg.
    Engström, G
    Lund University.
    Engvall, Jan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Eriksson, M
    Karolinska University Hospital, Stockholm.
    de Faire, U
    Karolinska Institutet, Stockholm / Karolinska University Hospital, Stockholm.
    Flinck, A
    Sahlgrenska University Hospital, Stockholm / University of Gothenburg.
    Hansson, M G
    Uppsala University.
    Hedblad, B
    Lund University.
    Hjelmgren, O
    University of Gothenburg / Sahlgrenska University Hospital, Gothenburg.
    Janson, C
    Uppsala University.
    Jernberg, T
    Karolinska University Hospital, Stockholm / Karolinska Institutet, Stockholm.
    Johnsson, Å
    Sahlgrenska University Hospital, Gothenburg / University of Gothenburg.
    Johansson, L
    Unit of Radiology.
    Lind, L
    Uppsala University.
    Löfdahl, C-G
    Lund University / Lund University Hospital.
    Melander, O
    Lund University / Skåne University Hospital, Malmö.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Primary Health Care in Motala.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Persson, M
    Lund University / Skåne University Hospital, Malmö.
    Sandström, A
    Umeå University.
    Schmidt, C
    University of Gothenburg.
    Söderberg, S
    Umeå University.
    Sundström, J
    Uppsala University / Uppsala Clinical Resarch Centre.
    Toren, K
    University of Gothenburg.
    Waldenström, A
    Umeå University Hospital.
    Wedel, H
    Nordic School of Public Health, Gothenburg.
    Vikgren, J
    Sahlgrenska University Hospital, Gothenburg / University of Gothenburg.
    Fagerberg, B
    University of Gothenburg.
    Rosengren, A
    University of Gothenburg.
    The Swedish CArdioPulmonary BioImage Study: objectives and design2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 6, p. 645-659Article in journal (Refereed)
    Abstract [en]

    Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

  • 40.
    Bertorello, Alejandro M.
    et al.
    Karolinska Institute, Sweden.
    Pires, Nuno
    Bial Portela and Ca SA, Portugal.
    Igreja, Bruno
    Bial Portela and Ca SA, Portugal.
    Joao Pinho, Maria
    University of Porto, Portugal.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    Wikstrom, Johannes
    AstraZeneca RandD, Sweden.
    Behrendt, Margareta
    AstraZeneca RandD, Sweden.
    Hamsten, Anders
    Karolinska Institute, Sweden.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Soares-da-Silva, Patricio
    Bial Portela and Ca SA, Portugal; University of Porto, Portugal.
    Brion, Laura
    Karolinska Institute, Sweden.
    Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)2015In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 116, no 4, p. 642-U190Article in journal (Refereed)
    Abstract [en]

    Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-beta 1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1+/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-beta 1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-beta 1-signaling inhibition.

  • 41.
    Bettiga, Arianna
    et al.
    IRCCS Osped San Raffaele, Italy.
    Aureli, Massimo
    University of Milan, Italy.
    Colciago, Giorgia
    IRCCS Osped San Raffaele, Italy.
    Murdica, Valentina
    University of Milan, Italy.
    Moschini, Marco
    IRCCS Osped San Raffaele, Italy.
    Luciano, Roberta
    IRCCS Osped San Raffaele, Italy.
    Canals, Daniel
    SUNY Stony Brook, NY 11794 USA.
    Hannun, Yusuf
    SUNY Stony Brook, NY 11794 USA.
    Hedlund, Petter
    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. IRCCS Osped San Raffaele, Italy.
    Lavorgna, Giovanni
    IRCCS Osped San Raffaele, Italy.
    Colombo, Renzo
    IRCCS Osped San Raffaele, Italy.
    Bassi, Rosaria
    University of Milan, Italy.
    Samarani, Maura
    University of Milan, Italy.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    Salonia, Andrea
    University of Vita Salute San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 42157Article in journal (Refereed)
    Abstract [en]

    The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour. Both cell lines expressed similar CB2. Exposure to CB2 agonists inhibited BC growth, down-modulated Akt, induced caspase 3-activation and modified SL metabolism. Baseline SL analysis in cell lines showed differences linked to unique migratory behaviours and cytoskeletal re-arrangements. CB2 activation changed the SL composition of more aggressive RT112 cells by reducing (p amp;lt; 0.01) Gb3 ganglioside (-50 +/- 3%) and sphingosine 1-phosphate (S1P, -40 +/- 4%), which ended up to reduction in cell motility (-46 +/- 5%) with inhibition of p-SRC. CB2-selective antagonists, gene silencing and an inhibitor of SL biosynthesis partially prevented CB2 agonist-induced effects on cell viability and motility. CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility.

  • 42.
    Bironaite, Daiva
    et al.
    State Research Institute Centre Innovat Med, Lithuania .
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Venalis, Algirdas
    State Research Institute Centre Innovat Med, Lithuania .
    Protective Induction of Hsp70 in Heat-Stressed Primary Myoblasts: Involvement of MAPKs2013In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 114, no 9, p. 2024-2031Article in journal (Refereed)
    Abstract [en]

    The involvement of extracellular signal-regulated kinases 1 and 2 (ERK1,2), stress kinase p38 and c-Jun NH2-terminal kinases 1 and 2 (JNK1,2) on Hsp70-upregulation following mild heat shock, and resulting cell protection, was studied on rabbit primary myoblasts. Cells subjected to heat stress (42 degrees C; 60min) showed a significantly enhanced amount of heat-shock-induced protein 70 (Hsp70), correlating with sustained phosphorylation of MAP kinases ERK1,2, inhibition of p38 and JNK1,2 activation. Induced Hsp70 did not autocrinally suppress activation of transcription factor c-Jun, suggesting involvement of the latter in the protection of myoblasts following heat shock. The inhibition of stress kinases p38, JNK1,2, and MEK1,2 by SP600125, SB203580, and UO126, respectively, established the involvement of JNK1,2 and p38 as upstream, and ERK1,2 as downstream targets of Hsp70 induction. Moreover, the effect of the MEK1,2 inhibitor UO126 revealed a new pathway of c-Jun activation by ERK1,2 in myogenic heat-stressed stem cells. The presented data show that transient activation of JNK1, JNK2, and p38 is necessary for Hsp70 induction and ensuing cell protection. In conclusion, affecting myogenic stem cell protective mechanisms might be a useful strategy in improving stem cell survival and their expanded application in therapy.

  • 43.
    Björn, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vergote, Ignace
    Leuven Canc Inst, Belgium.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 3, p. 277-287Article in journal (Refereed)
    Abstract [en]

    The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199Gamp;gt;A (rs2229109), 1236Camp;gt;T (rs1128503), 2677Gamp;gt;T/A (rs2032582), 3435Camp;gt;T (rs1045642) in ABCB1, and 1196Aamp;gt;G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol((R)) (Arm B, n=265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR=0.590) and in Arm B (HR=0.627), as well as increased OS in All (HR=0.443) and in Arm A (HR=0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p=0.039) and less neutrophil decrease in All (p=0.048) and in Arm B (p=0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.

    The full text will be freely available from 2019-03-05 17:31
  • 44.
    Björnström-Karlsson, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Turina, Dean
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Eintrei, Christina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Orexin A Inhibits Propofol-Induced Neurite Retraction by a Phospholipase D/Protein Kinase C-epsilon-Dependent Mechanism in Neurons2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e0097129-Article in journal (Refereed)
    Abstract [en]

    Background: The intravenous anaesthetic propofol retracts neurites and reverses the transport of vesicles in rat cortical neurons. Orexin A (OA) is an endogenous neuropeptide regulating wakefulness and may counterbalance anaesthesia. We aim to investigate if OA interacts with anaesthetics by inhibition of the propofol-induced neurite retraction. Methods: In primary cortical cell cultures from newborn rats brains, live cell light microscopy was used to measure neurite retraction after propofol (2 mu M) treatment with or without OA (10 nM) application. The intracellular signalling involved was tested using a protein kinase C (PKC) activator [phorbol 12-myristate 13-acetate (PMA)] and inhibitors of Rho-kinase (HA-1077), phospholipase D (PLD) [5-fluoro-2-indolyl des-chlorohalopemide (FIPI)], PKC (staurosporine), and a PKC epsilon translocation inhibitor peptide. Changes in PKC epsilon Ser(729) phosphorylation were detected with Western blot. Results: The neurite retraction induced by propofol is blocked by Rho-kinase and PMA. OA blocks neurite retraction induced by propofol, and this inhibitory effect could be prevented by FIPI, staurosporine and PKC epsilon translocation inhibitor peptide. OA increases via PLD and propofol decreases PKC epsilon Ser(729) phosphorylation, a crucial step in the activation of PKC epsilon. Conclusions: Rho-kinase is essential for propofol-induced neurite retraction in cortical neuronal cells. Activation of PKC inhibits neurite retraction caused by propofol. OA blocks propofol-induced neurite retraction by a PLD/PKC epsilon-mediated pathway, and PKC epsilon maybe the key enzyme where the wakefulness and anaesthesia signal pathways converge.

  • 45.
    Boiso, Samuel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Karlsson, Louise
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Carlsson, Björn
    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.
    Tillmar, Andreas
    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 Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    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.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    ABCB1 gene polymorphisms are associated with suicide in forensic autopsies2013In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, no 9, p. 463-469Article in journal (Refereed)
    Abstract [en]

    Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

  • 46.
    Borendal Wodlin, Ninnie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping.
    Kjölhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Snabbspår har fördelar vid elektiv gynekologisk kirurgi.2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 25-26, p. 2-7Article in journal (Refereed)
    Abstract [en]

    Fast-track is a multimodal strategy aimed at achieving an improved and accelerated postoperative recovery. The strategy combines unimodal evidence-based interventions concerning preoperative preparation, peroperative principles and postoperative care. There is substantial evidence for the benefits of following fast-track concepts in general elective surgery to enhance postoperative recovery. The main findings of this review are that there are benefits likewise within elective gynecological surgery, but studies of quality of life, patient satisfaction and health economics are needed. Studies of fast-track within non-elective surgery and gynaecological oncology surgery are lacking. Widespread information and education is needed to improve the rate of implementation of fast-track. Comprehensive involvement of the entire staff dealing with the patient in the perioperative period is crucial to ensure implementation and development of surgical care aiming for enhanced postoperative recovery.

  • 47.
    Bragde, Hanna
    et al.
    Ryhov County Hospital, Sweden.
    Jansson, Ulf
    Ryhov County Hospital, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Soederman, Jan
    Ryhov County Hospital, Sweden.
    Potential blood-based markers of celiac disease2014In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 14, no 176Article in journal (Refereed)
    Abstract [en]

    Background: Blood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers. Methods: We investigated the levels of messenger RNA (mRNA) in whole blood (n = 49) and protein in plasma (n = 22) from cases with active CD (n = 20), with confirmed CD and normalized histology (n = 15), and without a CD diagnosis (n = 14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann-Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis. Results: CXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-kappa B complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone. Conclusions: The CD markers identified in this study further emphasize the significance of components related to NF-kappa B regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-kappa B interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD.

  • 48.
    Bragde, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Jansson, Ulf
    Ryhov Cty Hosp, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. 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.
    Söderman, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies2018In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 75, no 23, p. 4385-4401Article in journal (Refereed)
    Abstract [en]

    Establishing a celiac disease (CD) diagnosis can be difficult, such as when CD-specific antibody levels are just above cutoff or when small intestinal biopsies show low-grade injuries. To investigate the biological pathways involved in CD and select potential biomarkers to aid in CD diagnosis, RNA sequencing of duodenal biopsies from subjects with either confirmed Active CD (n=20) or without any signs of CD (n=20) was performed. Gene enrichment and pathway analysis highlighted contexts, such as immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. Twenty-nine potential CD biomarkers were selected based on differential expression and biological context. The biomarkers were validated by real-time polymerase chain reaction of eight RNA sequencing study subjects, and further investigated using an independent study group (n=43) consisting of subjects not affected by CD, with a clear diagnosis of CD on either a gluten-containing or a gluten-free diet, or with low-grade intestinal injury. Selected biomarkers were able to classify subjects with clear CD/non-CD status, and a subset of the biomarkers (CXCL10, GBP5, IFI27, IFNG, and UBD) showed differential expression in biopsies from subjects with no or low-grade intestinal injury that received a CD diagnosis based on biopsies taken at a later time point. A large number of pathways are involved in CD pathogenesis, and gene expression is affected in CD mucosa already in low-grade intestinal injuries. RNA sequencing of low-grade intestinal injuries might discover pathways and biomarkers involved in early stages of CD pathogenesis.

  • 49.
    Brinkman, D. J.
    et al.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Tichelaar, J.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Schutte, T.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Benemei, S.
    University of Florence, Italy.
    Böttiger, Ylva
    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.
    Chamontin, B.
    University of Toulouse, France.
    Christiaens, T.
    University of Ghent, Belgium.
    Likic, R.
    University of Zagreb, Croatia.
    Maciulaitis, R.
    Lithuanian University of Health Science, Lithuania.
    Marandi, T.
    University of Tartu, Estonia.
    Monteiro, E. C.
    NOVA Medical Sch, Portugal.
    Papaioannidou, P.
    Aristotle University of Thessaloniki, Greece.
    Pers, Y. M.
    University of Montpellier, France.
    Pontes, C.
    Autonomous University of Barcelona, Spain.
    Raskovic, A.
    University of Novi Sad, Serbia.
    Regenthal, R.
    University of Leipzig, Germany.
    Sanz, E. J.
    University of La Laguna, Spain.
    Tamba, B. I.
    Gr T Popa University of Medical and Pharm, Romania.
    Wilson, K.
    University of Manchester, England.
    de Vries, T. P.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Richir, M. C.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    van Agtmael, M. A.
    Vrije University of Amsterdam, Netherlands; Research and Expertise Centre Pharmacotherapy Educ RECIPE, Netherlands.
    Essential Competencies in Prescribing: A First European Cross-Sectional Study Among 895 Final-Year Medical Students2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 101, no 2, p. 281-289Article in journal (Refereed)
    Abstract [en]

    European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.

  • 50.
    Brodin, Ola
    et al.
    Karolinska Institute, Sweden.
    Eksborg, Staffan
    Karolinska Institute, Sweden.
    Wallenberg, Marita
    Karolinska Institute, Sweden.
    Asker-Hagelberg, Charlotte
    Medical Prod Agency, Sweden; Karolinska Institute, Sweden.
    Larsen, Erik H.
    Technical University of Denmark, Denmark.
    Mohlkert, Dag
    Karolinska University Hospital Sodersjukhuset, Sweden.
    Lenneby-Helleday, Clara
    Karolinska Institute, Sweden.
    Jacobsson, Hans
    Karolinska University Hospital, Sweden.
    Linder, Stig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Misra, Sougat
    Karolinska Institute, Sweden.
    Bjornstedt, Mikael
    Karolinska Institute, Sweden.
    Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study2015In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 7, no 6, p. 4978-4994Article in journal (Refereed)
    Abstract [en]

    Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.

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