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  • 101.
    Gustafsson, Åsa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. FOI.
    Jonasson, Sofia
    FOI.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Lorentzen, Johnny
    KI, IMM.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. FOI.
    Genetic variation influences immune responses in sensitive rats following exposure to TiO2 nanoparticles2014Ingår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 326, s. 74-85Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    This study examines the immunological responses in rats following inhalation to titanium dioxide nanoparticles (TiO2 NPs), in naïve rats and in rats with induced allergic airway disease. The responses of two different inbred rat strains were compared: the Dark Aguoti (DA), susceptible to chronic inflammatory disorders, and the Brown Norwegian (BN), susceptible to atopic allergic inflammation. Naïve rats were exposed to an aerosol of TiO2 NPs once daily for 10 days. Another subset of rats was sensitized to the allergen ovalbumin (OVA) in order to induce airway inflammation. These sensitized rats were exposed to TiO2 NPs before and during the allergen challenge. Naïve rats exposed to TiO2 NPs developed an increase of neutrophils and lymphocytes in both rat strains. Airway hyperreactivity and production of inflammatory mediators typical of a T helper 1 type immune response were significantly increased, only in DA rats. Sensitization of the rats induced a prominent OVA-specific-IgE and IgG response in the BN rat while DA rats only showed an increased IgG response. Sensitized rats of both strains developed airway eosinophilia following allergen challenge, which declined upon exposure to TiO2 NPs. The level of neutrophils and lymphocytes increased upon exposure to TiO2 NPs in the airways of DA rats but remained unchanged in the airways of BN rats. In conclusion, the responses to TiO2 NPs were strain-dependent, indicating that genetics play a role in both immune and airway reactivity. DA rats were found to be higher responder compared to BN rats, both when it comes to responses in naïve and sensitized rats. The impact of genetically determined factors influencing the inflammatory reactions pinpoints the complexity of assessing health risks associated with nanoparticle exposures.

  • 102.
    Gustafsson, Åsa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Lindstedt, Elsa
    Elfsmark Svensson, Linda
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat2011Ingår i: Journal of Immunotoxicology, ISSN 1547-691X, E-ISSN 1547-6901, Vol. 8, nr 2, s. 111-121Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nanomaterial of titanium dioxide (TiO(2)) is manufactured in large-scale production plants, resulting in risks for accidental high exposures of humans. Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects. By using the Dark Agouti (DA) rat, a strain disposed to develop chronic inflammation following exposure to immunoactivating adjuvants, we investigated local and systemic inflammatory responses after lung exposure of nanosized TiO(2) particles up to 90 days after intratracheal instillation. TiO(2) induced a transient response of proinflammatory and T-cell-activating cytokines (interleukin [IL]-1α, IL-1β, IL-6, cytokine-induced neutrophil chemoattractant [CINC]-1, granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-2) in airways 1-2 days after exposure, accompanied by an influx of eosinophils and neutrophils. Neutrophil numbers remained elevated for 30 days, whereas the eosinophils declined to baseline levels at Day 8, simultaneously with an increase of dendritic cells and natural killer (NK) cells. The innate immune activation was followed by a lymphocyte expansion that persisted throughout the 90-day study. Lymphocytes recruited to the lungs were predominantly CD4(+) helper T-cells, but we also demonstrated presence of CD8(+) T-cells, B-cells, and CD25(+) T-cells. In serum, we detected both an early cytokine expression at Days 1-2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon-gamma [IFN-γ] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-α), indicating systemic late-phase effects in addition to the local response in airways. In summary, these data demonstrate a dynamic response to TiO(2) nanoparticles in the lungs of DA rats, beginning with an innate immune activation of eosinophils, neutrophils, dendritic cells, and NK cells, followed by a long-lasting activation of lymphocytes involved in adaptive immunity. The results have implications for the assessment of risks for adverse and persistent immune stimulation following nanoparticle exposures in sensitive populations.

  • 103.
    Gustafsson, Åsa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Svensson-Elfsmark, Linda
    Lorentzen, Johnny C
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats2014Ingår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 34, nr 3, s. 272-280Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2days after exposure and a second peak dominated by macrophages 29days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude.

    Copyright (c) 2013 John Wiley & Sons, Ltd.

  • 104. Gutierrez, Lia
    et al.
    Booth, Helen
    Dedman, Daniel
    Crellin, Elizabeth
    Kaye, James A.
    Franzoni, Carla
    Arana, Alejandro
    Schmitt-Egenolf, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Sundström, Anders
    Byström, Camilla
    Case validation of cutaneous lymphoma to minimize protopathic bias2019Ingår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 28, nr S2, s. 315-315Artikel i tidskrift (Övrigt vetenskapligt)
  • 105.
    Harlid, Sophia
    et al.
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Adgent, Margaret
    Jefferson, Wendy N.
    Panduri, Vijayalakshmi
    Umbach, David M.
    Xu, Zongli
    Stallings, Virginia A.
    Williams, Carmen J.
    Rogan, Walter J.
    Taylor, Jack A.
    Soy formula and epigenetic modifications: analysis of vaginal epithelial cells from infant girls in the IFED study2017Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 125, nr 3, s. 447-452Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations.

    OBJECTIVES: Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls.

    METHODS: Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula-fed and six cow formula-fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula-fed and 22 cow formula-fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue.

    RESULTS: The epigenome-wide scan suggested differences in methylation between soy formula-fed and cow formula-fed infants at three CpGs in the gene proline rich 5 like (PRR5L) (p < 10(4)). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls.

    CONCLUSIONS: Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene.

  • 106. Hebels, Dennie G. A. J.
    et al.
    Georgiadis, Panagiotis
    Keun, Hector C.
    Athersuch, Toby J.
    Vineis, Paolo
    Vermeulen, Roel
    Portengen, Lützen
    Bergdahl, Ingvar A.
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Palli, Domenico
    Bendinelli, Benedetta
    Krogh, Vittorio
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Kleinjans, Jos C. S.
    de Kok, Theo M. C. M.
    Smith, Martyn T.
    Kyrtopoulos, Soterios A.
    Performance in omics analyses of blood samples in long-term storage: opportunities for the exploitation of existing biobanks in environmental health research2013Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 121, nr 4, s. 480-487Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The suitability for omic analysis of biosamples collected in previous decades and currently stored in biobanks is unknown.

    Objectives: We evaluated the influence of handling and storage conditions of blood-derived biosamples on transcriptomic, epigenomic (CpG methylation), plasma metabolomic [UPLC-ToFMS (ultra performance liquid chromatography-time-of-flight mass spectrometry)], and wide-target proteomic profiles.

    Methods: We collected fresh blood samples without RNA preservative in heparin, EDTA, or citrate and held them at room temperature for ≤ 24 hr before fractionating them into buffy coat, erythrocytes, and plasma and freezing the fractions at -80oC or in liquid nitrogen. We developed methodology for isolating RNA from the buffy coats and conducted omic analyses. Finally, we analyzed analogous samples from the EPIC-Italy and Northern Sweden Health and Disease Study biobanks.

    Results: Microarray-quality RNA could be isolated from buffy coats (including most biobank samples) that had been frozen within 8 hr of blood collection by thawing the samples in RNA preservative. Different anticoagulants influenced the metabolomic, proteomic, and to a lesser extent transcriptomic profiles. Transcriptomic profiles were most affected by the delay (as little as 2 hr) before blood fractionation, whereas storage temperature had minimal impact. Effects on metabolomic and proteomic profiles were noted in samples processed ≥ 8 hr after collection, but no effects were due to storage temperature. None of the variables examined significantly influenced the epigenomic profiles. No systematic influence of time-in-storage was observed in samples stored over a period of 13-17 years.

    Conclusions: Most samples currently stored in biobanks are amenable to meaningful omics analysis, provided that they satisfy collection and storage criteria defined in this study.

  • 107. Hellgren, Dennis
    et al.
    Wu, Jianyao
    Roos, Robert
    Westerholm, Emma
    Adfeldt-Still, Oliver
    Andersson, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Halldin, Krister
    Håkansson, Helen
    The PCB effect database: a tool for translational research and health risk assessment2013Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 221, nr Suppl., s. S229-S229Artikel i tidskrift (Övrigt vetenskapligt)
  • 108.
    Hellström, Gustav
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Klaminder, Jonatan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Finn, Fia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Persson, Lo
    Alanärä, Anders
    Jonsson, Micael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brodin, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    GABAergic anxiolytic drug in water increases migration behaviour in salmon2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 13460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Migration is an important life-history event in a wide range of taxa, yet many migrations are influenced by anthropogenic change. Although migration dynamics are extensively studied, the potential effects of environmental contaminants on migratory physiology are poorly understood. In this study we show that an anxiolytic drug in water can promote downward migratory behaviour of Atlantic salmon (Salmo salar) in both laboratory setting and in a natural river tributary. Exposing salmon smolt to a dilute concentration of a GABAA receptor agonist (oxazepam) increased migration intensity compared with untreated smolt. These results implicate that salmon migration may be affected by human-induced changes in water chemical properties, such as acidification and pharmaceutical residues in wastewater effluent, via alterations in the GABAA receptor function.

  • 109. Henrohn, Dan
    et al.
    Sandqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Egeröd, Hanna
    Hedeland, Mikael
    Wernroth, Lisa
    Bondesson, Ulf
    Wikström, Gerhard
    Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension2015Ingår i: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 73, s. 71-77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine.

    PATIENTS AND METHODS: ADMA, SDMA, and arginine were measured (0-540min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60min.

    RESULTS: A reduction in ADMA was observed at 30 and 45min with a median change of -11.1% (P=0.021) and -12.5% (P=0.002). SDMA decreased with a median -5.3% change (P=0.032) at 45min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed.

    CONCLUSIONS: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

  • 110. Henrohn, Dan
    et al.
    Sandqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Hedeland, Mikael
    Egerod, Hanna
    Bondesson, Ulf
    Wikstrom, Gerhard
    Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension2012Ingår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 74, nr 6, s. 990-998Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS To evaluate the acute haemodynamic effects of a single oral dose of vardenafil and to study the drug concentration in relation to haemodynamic effects in patients with pulmonary hypertension (PH). METHODS Sixteen patients with PH (aged 29-85\ years), received one single oral dose of vardenafil (5, 10 or 20 mg). The haemodynamic effect was assessed over a 60 min period. Vardenafil plasma concentrations were measured after 15, 30, 45 and 60 min using liquid chromatography-tandem mass spectrometry. RESULTS At 60 min a reduction in mPAP with a median % decrease of -20.3% (range -48.3 to 3.0; P < 0.001) and an increase in cardiac output and the cardiac index with a median % change of 10.6% (range -25.0 to 88.1; P = 0.015) and 12.1% (range -24.0 to 94.4; P = 0.01) respectively was observed. The pulmonary vascular resistance (PVR) was reduced with a median % decrease of -28.9% (range -61.5 to -5.9; P < 0.001), and pulmonary selectivity was reflected by a median percent reduction of -16.9% (range -49.0 to 16.5; P = 0.002; n = 14) in the PVR/ systemic vascular resistance ratio. There was a correlation between the plasma concentrations of vardenafil and change in mPAP (r = -0.579, P = 0.019) and between vardenafil concentrations and change in PVR (r = -0.662, P = 0.005). CONCLUSIONS Vardenafil causes rapid changes in cardiopulmonary haemodynamics and there is a correlation between plasma vardenafil drug concentration and the acute changes in mPAP as well as PVR in patients with PH.

  • 111.
    Heynen, Martina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Backstrom, Tobias
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jonsson, Micael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Klaminder, Jonatan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Brodin, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Home alone: the effects of isolation on uptake of a pharmaceutical contaminant in a social fish2016Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 180, s. 71-77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A wide range of biologically active pharmaceutical residues is present in aquatic systems worldwide. As uptake potential and the risk of effects in aquatic wildlife are directly coupled, the aim of this study was to investigate the relationships between stress by isolation, uptake and effects of the psychiatric pharmaceutical oxazepam in fish. To do this, we measured cortisol levels, behavioral stress responses, and oxazepam uptake under different stress and social conditions, in juvenile perch (Percafluviatilis) that were either exposed (1.03 mu gl(-1)) or not exposed to oxazepam. We found single exposed individuals to take up more oxazepam than individuals exposed in groups, likely as a result of stress caused by isolation. Furthermore, the bioconcentration factor (BCF) was significantly negatively correlated with fish weight in both social treatments. We found no effect of oxazepam exposure on body cortisol concentration or behavioral stress response. Most laboratory experiments, including standardized bioconcentration assays, are designed to minimize stress for the test organisms, however wild animals experience stress naturally. Hence, differences in stress levels between laboratory and natural environments can be one of the reasons why predictions from artificial laboratory experiments largely underestimate uptake of oxazepam, and other pharmaceuticals, in the wild.

  • 112. Hiremathad, Asha
    et al.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Keri, Rangappa S.
    Development of coumarin-benzofuran hybrids as versatile multitargeted compounds for the treatment of Alzheimer's Disease2018Ingår i: Chemical Biology and Drug Design, ISSN 1747-0277, E-ISSN 1747-0285, Vol. 92, nr 2, s. 1497-1503Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition. The evidenced multifactorial nature of AD has been considered the main reason for the absence of cure so far. Therefore, the development of novel hybrids to treat the disease is very much essential. Focusing on this, a novel series of coumarin-benzofuran hybrids have been designed and screened as anti-Alzheimer's disease agents. The strategy is to obtain an effective mimetic of donepezil, which is acetylcholinesterase inhibitor. Herein, the two main scaffolds namely coumarin and benzofuran are known pharmacophore moieties and we have performed their molecular design, pharmacokinetic descriptor studies for drug-likeliness. Further, in vitro studies such as antioxidant capacity, acetylcholinesterase (AChE) inhibition and amyloid-beta (A beta) self-aggregation inhibition have also been performed. Most importantly, these studies revealed that the newly synthesized hybrids can be versatile and promising drug-like moieties as efficient anti-AD agents.

  • 113. Holl, Katsiaryna
    et al.
    Rosenlund, Mats
    Giaquinto, Carlo
    Silfverdal, Sven-Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Carmona, Alfonso
    Larcombe, James
    Garcia-Sicilia, Jose
    Fuat, Ahmet
    Eulalia Munoz, Maria
    Luisa Arroba, Maria
    Sloesen, Brigitte
    Vollmar, Jens
    Pircon, Jean-Yves
    Liese, Johannes G.
    The Impact of Childhood Acute Otitis Media on Parental Quality of Life in a Prospective Observational Cohort Study2015Ingår i: Clinical drug investigation, ISSN 1173-2563, E-ISSN 1179-1918, Vol. 35, nr 10, s. 613-624Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute otitis media (AOM) not only affects childhood quality of life (QoL), but can also affect parental QoL. We adapted a previously published questionnaire on the effect of childhood recurrent ear, nose and throat infections on parental QoL for use with AOM and used it in an observational, multicentre, prospective study of children with AOM. The AOM-specific parental QoL questionnaire grouped 15 items into emotional, daily disturbance, total and overall parental QoL impact scores. The questionnaire was assessed using item-convergent and item-discriminant validity criteria and internal consistency reliability; and then used with parents of children aged < 6 years diagnosed with AOM at 73 practices in Germany, Italy, Spain, Sweden and the UK. Bivariate analyses explored the differences in mean parental QoL impact scores by various characteristics. The questionnaire demonstrated good to excellent internal consistency reliability for the various components (Cronbach's alpha 0.82-0.97). There were 1419 AOM episodes among 5882 healthy children over 1 year, of which 1063 episodes (74.9 %) among 852 children had a questionnaire. Parents reported interrupted sleep (68.4 %), worry (51.0 %), altered daily schedule (44.6 %) and less leisure time (41.5 %) with a score a parts per thousand yen3 (1 = least to 5 = most impact). Factors that adversely affected parental QoL included: increased parental perception of AOM severity, younger child age and multiple AOM episodes. The AOM-specific parental QoL questionnaire demonstrated good performance across five European countries. Parental QoL was affected by childhood AOM proportionally to severity, number of episodes and younger child age.

  • 114. Holler, James S.
    et al.
    Nordberg, Gunnar F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Fowler, Bruce A.
    Silver2007Ingår i: Handbook on the Toxicology of Metals, 3rd edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, s. 809-814Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Silver compounds may be absorbed through inhalation, but there are no quantitative human data on the extent of this phenomenon. Silver salts may be absorbed by up to 10-20% after ingestion. The highest concentrations of silver are usually found in the liver and spleen, and to some extent in the muscles, skin, and brain after ingestion. The biological half-time for silver ranges from a few days for animals up to approximately 50 days for the human liver; it is possible that skin deposits have an even longer half-time, but there are no quantitative data on this for man. Silver binds to high-molecular-weight proteins and metallothionein in tissue cytosol fractions. Excretion of silver from the body is primarily biliary. Water-soluble silver compounds such as the nitrate have a local corrosive effect and may cause fatal poisoning if swallowed accidentally. Chronic exposure of humans leads to argyria, a clinical entity characterized by grey-blue pigmentation of the skin and other body viscera. Repeated exposure of animals to silver may produce anemia, cardiac enlargement, growth retardation, and degenerative changes in the liver.

  • 115. Holme, Oyvind
    et al.
    Loberg, Magnus
    Kalager, Mette
    Bretthauer, Michael
    Hernan, Miguel A.
    Aas, Eline
    Eide, Tor J.
    Skovlund, Eva
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Tveit, Kjell Magne
    Hoff, Geir
    Effect of Flexible Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality A Randomized Clinical Trial2014Ingår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 312, nr 6, s. 606-615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    IMPORTANCE

    Colorectal cancer is a major health burden. Screening is recommended in many countries. OBJECTIVE To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 100 210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry.

    INTERVENTIONS

    Participants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1: 1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp >= 10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention.

    MAIN OUTCOMES AND MEASURES

    Colorectal cancer incidence and mortality.

    RESULTS

    A total of 98 792 participants were included in the intention-to-screen analyses, of whom 78 220 comprised the control group and 20 572 comprised the screening group (10 283 randomized to receive a flexible sigmoidoscopy and 10 289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100 000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100 000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50-to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55-to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups.

    CONCLUSIONS AND RELEVANCE

    In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50-to 54-year and the 55-to 64-year age groups.

  • 116. Holmgren, Helena M
    et al.
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Acetylsalicylsyra i låg dos plus naproxen: liten interaktionsrisk i praktiken2011Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, nr 26-28, s. 1374-1374Artikel i tidskrift (Övrigt vetenskapligt)
  • 117.
    Holmgren, Helena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    [NSAID can increase the risk of cardiovascular incidents. The risk increase is usually connected to dosage and the length of treatment].2012Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, nr 4, s. 164-164Artikel i tidskrift (Övrigt vetenskapligt)
  • 118.
    Holt, Sandra
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Farmakologi.
    Fatty acid amide hydrolase - A target for anti-inflammatory therapies?2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Anti-inflammatory drugs are a widely used class of therapeutic agents, but the use of non-steroidal anti-inflammatory drugs (NSAID) is hampered by their gastrointestinal side-effects. Recent reports that cyclooxygenase-2 inhibitors may cause cardiovascular events underline the importance of identifying new therapeutic strategies for the treatment of inflammation. One such target could be agents modifying the endogenous cannabinoid (endocannabinoid) system, since there is evidence that this system plays a role in our natural defence against inflammation. The levels of the endocannabinoid anandamide (arachidonoyl ethanolamide, AEA) are low under normal conditions, and stand under strict regulatory control of synthesising and degrading enzymes. Fatty acid amide hydrolase (FAAH) is the main enzyme degrading AEA, hydrolysing it to ethanolamine and arachidonic acid. The focus of this thesis lies in exploring the pharmacology of FAAH to evaluate its possibilities as a target for new anti-inflammatory drugs.

    In Papers I and II, the effects of the ambient pH on the properties of FAAH were investigated, since tissue pH is known to decrease under inflammatory conditions. In homogenates, it was found that the activity of FAAH decreased as the assay pH was decreased, consistent with the known pH profile of the enzyme. More importantly, the sensitivity of the enzyme to inhibition by FAAH inhibitors changed. In particular, the sensitivity of the enzyme to inhibition by the NSAID ibuprofen increased seventeen-fold as the assay pH decreased from 8.37 to 5.28. A similar pattern was found using intact C6 glioma cells when the extracellular, but not the intracellular pH was reduced. Thus, at an extracellular pH value of 6.2, (R)-ibuprofen, (S)-flurbiprofen and (R,S)-flurbiprofen inhibited the metabolism of AEA with IC50 values of 26, 14 and 15 µM, respectively. These values are in theory reachable upon normal dosing of the compounds. In Paper III, the effect of the selective FAAH inhibitor URB597 and the NSAID indomethacin were investigated in vivo upon the oedema response to carrageenan administration in the paw of anaesthetised mice. Both compounds reduced the oedema in a manner completely blocked by the CB2 receptor antagonist SR144528. In Paper IV, the effect of inflammation upon endocannabinoid synthesis was investigated in mice. Lipopolysaccharide-induced pulmonary inflammation was found not to affect the release of AEA to any obvious extent, and did not change the activities of the AEA synthesising enzymes N-acyl transferase or N-acyl phosphatidylethanolamine phospholipase D, or of FAAH in lung tissue.

    The results of this thesis would suggest that FAAH inhibitors can produce anti-inflammatory effects, and that the endocannabinoid system contributes to the actions of the NSAID indomethacin in the carrageenan model of inflammation, but that an increased endocannabinoid synthesis (a prerequisite for FAAH inhibition as a therapeutic strategy) is not an obligatory response to an inflammatory stimulus.

  • 119. Hulpia, Fabian
    et al.
    Mabille, Dorien
    Campagnaro, Gustavo D.
    Schumann, Gabriela
    Maes, Louis
    Roditi, Isabel
    Hofer, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    de Koning, Harry P.
    Caljon, Guy
    Van Calenbergh, Serge
    Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness2019Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikel-id 5564Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    African trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3'-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3'-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3'-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness.

  • 120.
    Hunter, Amanda
    et al.
    University of Edinburgh.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bosson, Jenny A
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Langrish, Jeremy P
    University of Edinburgh.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Raftis, Jennifer B
    University of Edinburgh.
    Miller, Mark R
    University of Edinburgh.
    Lucking, Andrew J
    University of Edinburgh.
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Nyström, Robin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Donaldson, Kenneth
    University of Edinburgh.
    Flapan, Andrew D
    University of Edinburgh.
    Pung, Louis
    University of Edinburgh.
    Sadiktsis, Ioannis
    Stockholm University.
    Masala, Silvia
    Stockholm University.
    Westerholm, Roger
    Stockholm University.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Newby, David E
    University of Edinburgh.
    Mills, Nicholas L
    University of Edinburgh.
    Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters2014Ingår i: Particle and Fibre Toxicology, ISSN 1743-8977, E-ISSN 1743-8977, Vol. 11, artikel-id 62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. Methods: In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m3 particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4–6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. Results: Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P < 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P > 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P < 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P > 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P > 0.05 for all). Conclusions: Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.

  • 121.
    Hägg, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi. Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Marie
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Schmitt-Egenolf, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Sundström, Anders
    Psoriasis Patients New to Specialist Care in Sweden 2007-2009: A Two-Year Follow-Up of Treatment Allocation2016Ingår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, s. 4-5Artikel i tidskrift (Övrigt vetenskapligt)
  • 122.
    Jensen, Ninnie
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Biomedicinprogrammet.
    Effects of interleukin-1B upon anandamide metabolism in a human neuroblastoma cell line2014Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
  • 123.
    Jin, Taiyi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin. Fudan University, School of Public Health, Department of Occupational Health, Shanghai 200032, Peoples Republic of China.
    Chen, Liang
    Lei, Lijian
    Nordberg, Monica
    Nordberg, Gunnar F
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    An invited paper presented in the symposium "Health effects of low dose exposure to toxic metals"2008Ingår i: Cell Biology and Toxicology, ISSN 0742-2091, E-ISSN 1573-6822, Vol. 24, nr 5, s. 451-455Artikel i tidskrift (Refereegranskat)
  • 124.
    Johansson, Susanne M C
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Multivalent HSA conjugates of 3 '-siallyllactose are potent inhibitors of adenoviral cell attachment and infection2005Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 6, nr 2, s. 358-364Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adenoviruses of serotypes 8, 19 and 37 are the major cause of the severe eye infection EKC (epidemic keratoconjunctivitis). In general, all adenoviruses interact with their cellular receptors through the fibre proteins, which extend from the virus particle. Recently, adenovirus type 37 (Ad37) was found to bind and infect human corneal cells through attachment to carbohydrate structures that carry terminal alpha-(2-3)-linked sialic acids. Herein we present a synthetic route to a 3'-sialyllactose derivative and corresponding multivalent HSA conjugates with varying orders of valency. The potential of these compounds as inhibitors of EKC causing adenovirus of serotype Ad37, was studied with both binding assay and an infectivity assay. The results revealed that these compounds effectively prevent Ad37 from binding to and infecting human corneal epithelial (HCE) cells. Moreover, the inhibition is significantly increased with higher orders of multivalency.

  • 125. Jonasson, Sofia
    et al.
    Gustafsson, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Koch, Bo
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Inhalation exposure of nano-scaled titanium dioxide (TiO2) particles alters the inflammatory responses in asthmatic mice2013Ingår i: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 25, nr 4, s. 179-191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Titanium dioxide (TiO2) nanoparticles (NPs) are regarded as relatively non-toxic in concentrations occurring in occupational environments. Nevertheless, it is conceivable that adverse health effects may develop in sensitive populations such as individuals with respiratory diseases.

    Objective: We investigated whether single or repeated exposure to TiO2 could aggravate inflammatory responses in naive mice and mice with ovalbumin (OVA)-induced airway inflammation.

    Methods: Exposure to aerosolized TiO2 was performed during OVA sensitization, before, or during the OVA challenge period. The effects on respiratory physiology, inflammatory cells in bronchoalveolar lavage (BAL) and inflammatory mediators in BAL and serum were assessed 24 h after the last OVA challenge or TiO2 exposure.

    Results: A single exposure of TiO2 had a marked effect on responses in peripheral airways and increasing infiltration of neutrophils in airways of naive animals. Marked aggravation of airway responses was also observed in animals with allergic disease provided that the single dose TiO2 was given before allergen challenge. Repeated exposures to TiO2 during sensitization diminished the OVA-induced airway eosinophilia and airway hyperresponsiveness but concomitant exposure to TiO2 during the OVA challenge period resulted in neutrophilic airway inflammation and a decline in general health condition as indicated by the loss of body weight.

    Conclusion: We conclude that inhalation of TiO2 may aggravate respiratory diseases and that the adverse health effects are highly dependent on dose and timing of exposure. Our data imply that inhalation of NPs may increase the risk for individuals with allergic airway disease to develop symptoms of severe asthma.

  • 126.
    Jonsson, Kent-Olov
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Farmakologi.
    Pharmacology of Palmitoylethanolamide and Related Compounds2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Anandamide (AEA) is an endogenous fatty acid which activates the same cannabinoid receptors as ∆9-tetrahydrocannabinol, the psychoactive substance in marijuana. In vivo, anandamide exerts a number of actions including effects upon pain and inflammation. However, AEA has a short duration of action since it is rapidly metabolised, primarily by the intracellular enzyme fatty acid amide hydrolase (FAAH).

    The general aim of this thesis has been to identify and characterize compounds capable of preventing the metabolism of anandamide. The chemical approach was based on the endogenous anti-inflammatory compound palmitoylethanolamide (PEA), a compound related to anandamide with the ability to inhibit anandamide degradation by substrate competition, but without the ability to directly activate cannabinoid receptors.

    A number of compounds were identified as inhibitors of rat brain FAAH in the initial in vitro studies, without having major affinity for the cannabinoid receptors. In particular, palmitoylisopropylamide (PIA) was found to reduce the metabolism of AEA in intact C6 glioma cells with potency similar to the prototypical AEA reuptake inhibitor AM404. This compound was in addition found to exert less effect upon C6 glioma cell proliferation than either AM404 or the closely related uptake inhibitor VDM11. To evaluate if PIA was effective in vivo, a model of mast cell dependent inflammation, oedema of the ear following local injection of compound 48/80, was set up using anaesthetised mice. Initially, a CB2 cannabinoid receptor selective agonist was used to probe the model and demonstrated to produce an anti-oedema effect. In contrast, the compound was inactive in vitro in skin slice preparations. PIA showed a similar pattern, although there was a large variation in responses which affected the significance of the result obtained, as did the vehicle used to dissolve the compound.

    Taken together, the present data would suggest that PIA can inhibit the degradation of AEA without having deleterious effects upon cell proliferation or affinity for the cannabinoid receptors. Further experimentation is necessary to elucidate the usefulness of this compound in vivo.

  • 127. Jonsson, L.
    et al.
    Holmen, C.
    Hillert, J.
    Nilsson, P.
    Dahle, C.
    Feltelius, N.
    Sveningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lycke, J.
    Landtblom, A-M
    Burman, J.
    Walentin, F.
    Martin, C.
    Piehl, F.
    Olsson, T.
    A Swedish nationwide pharmaco-epidemiological and genetic study (IMSE) of the long-term safety and efficacy of natalizumab2014Ingår i: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, s. 166-166Artikel i tidskrift (Övrigt vetenskapligt)
  • 128.
    Järvholm, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Carcinogens in the construction industry2006Ingår i: Living in a chemical world: framing the future in light of the past, Oxford: Blackwell Publishing, 2006, s. 421-428Konferensbidrag (Refereegranskat)
    Abstract [en]

    The construction industry is a complex work environment. The work sites are temporary and rapidly changing. Asbestos has been widely used in construction industry, but the risks were primarily detected in specialized trades, such as insulation workers and plumbers. Today, the majority of cases related to asbestos exposure will occur in other occupational groups in the construction industry. In a large cohort of Swedish construction workers, insulators and plumbers constituted 37% of all cases of pleural mesothelioma between 1975 and 1984 while they constituted 21% of the cases between 1998 and 2002. It is estimated that 25-40% of all male cases of pleural mesothelioma in Sweden are caused by asbestos exposure in the construction trades. There are many other known carcinogens occurring in the construction industry, including PAHs, diesel exhausts, silica, asphalt fumes, solvents, etc., but it is difficult to estimate exposures and thus the size of the risk. The risk of cancer is less easy to detect with traditional epidemiological methods in the construction industry than in other industrial sectors. It is not sufficient to rely upon broad epidemiological data to estimate the risk of cancer due chemicals in the construction industry. Thus, a strategy to decrease exposure, e.g., to dust, seems a feasible way to reduce the risk.

  • 129.
    Järvinen, Kristiina
    et al.
    Department of Pharmacy, University of Eastern Finland, Kuopio, Finland.
    Jokiniemi, Jorma
    Deaprtment of Environmental Science.
    Lammi, Mikko
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Lappalainen, Reijo
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Närvänen, Ale
    Department of Pharmacy, University of Eastern Finland.
    Pakkanen, Tapani
    Department of Chemistry, University of Eastern Finland, Kuopio,Finland.
    Lehto, Vesa-Pekka
    Department ofApplied Physics, University of Eastern Finalnd, Kuopio, Finland.
    Nanoteknologia biomateriaalien ja lääkkeiden kantaja-aineiden pintojen räätälöinnissä [Nanoscale tailoring of the surface properties of biomaterials and drug carriers]2012Ingår i: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 128, nr 20, s. 2085-2092, artikel-id 23167167Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Functionalities of biomaterials and drug delivery systems are improved by tailoring their surface properties using modern nanotechnology. Orthopedic implants and invasive electrodes are examples of implantable biomaterials. Biological interactions of orthopedic implants can be optimized by the synergetic effect of surface micro- and nanotexturing with a chemical composition of coating. Further, mechanical flexibility and electrochemical characteristics of invasive electrodes are improved by using micro- and nanotechnology. In nano-size drug delivery systems, surface properties of nanocarriers strongly affect their safety and efficacy. Mesoporous silicon nanoparticles are example of nanocarriers those properties can be tailored for drug delivery applications.

  • 130.
    Jóhannesson, Gauti
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik. Department of Ophthalmology, National University Hospital, University of Iceland, Reykjavik, Iceland.
    Moya-Ortega, Maria D
    Ásgrímsdóttir, Gudrun Marta
    Agnarsson, Bjarni A
    Lund, Sigrún H
    Loftsson, Thorsteinn
    Stefánsson, Einar
    Dorzolamide cyclodextrin nanoparticle suspension eye drops and trusopt in rabbit2014Ingår i: Journal of Ocular Pharmacology and Therapeutics, ISSN 1080-7683, E-ISSN 1557-7732, Vol. 30, nr 6, s. 464-467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Abstract Purpose: Dorzolamide nanoparticle γ-cyclodextrin eye drops may prolong the effect of dorzolamide on intraocular pressure. We test whether the nanoparticle drops have an irritating or toxic effect on the eye in an in vivo rabbit model. Methods: Eighteen pigmented rabbits were divided into 4 groups receiving dorzolamide nanoparticle γ-cyclodextrin eye drops×1/day or×2/day, Trusopt(®) (dorzolamide HCl)×3/day, and untreated controls that received no drops. The rabbits received treatment for 1 month. After sacrifice, 33 eyes and 25 Harderian glands were evaluated for histopathology in a masked way. Results: Mild inflammation was seen in 19/31 eyes and 13/23 Harderian glands. The difference in inflammation (n=eyes/n=glands)between the γ-cyclodextrin nanoparticle eye drops×1/day (n=5/5),×2/day (n=5/3), Trusopt (n=7/4), or untreated control (n=2/0) groups was nonsignificant in both eyes and glands (P=0.87 and P=0.92) Acute inflammation was seen in 1 Harderian gland that received γ-cyclodextrin nanoparticle eye drops×2/day. The difference in conjunctival injection between the groups was nonsignificant (P=0.30). Conclusions: Dorzolamide γ-cyclodextrin nanoparticle eye drops are no more locally toxic or irritating to the eye than Trusopt.

  • 131. Kamte, Stephane L. Ngahang
    et al.
    Ranjbarian, Farahnaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Cianfaglione, Kevin
    Sut, Stefania
    Dall'Acqua, Stefano
    Bruno, Maurizio
    Afshar, Fariba Heshmati
    Iannarelli, Romilde
    Benelli, Giovanni
    Cappellacci, Loredana
    Hofer, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Maggi, Filippo
    Petrelli, Riccardo
    Identification of highly effective antitrypanosomal compounds in essential oils from the Apiaceae family2018Ingår i: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 156, s. 154-165Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Apiaceae family encompasses aromatic plants of economic importance employed in foodstuffs, beverages, perfumery, pharmaceuticals and cosmetics. Apiaceae are rich sources of essential oils because of the wealth of secretory structures (ducts and vittae) they are endowed with. The Apiaceae essential oils are available on an industrial level because of the wide cultivation and disposability of the bulky material from which they are extracted as well as their relatively cheap price. In the fight against protozoal infections, essential oils may represent new therapeutic options. In the present work, we focused on a panel of nine Apiaceae species (Siler montamon, Sison amomum, Echinophora spinosa, Kundmannia sicula, Crithmum maritimum, Helosciadium nodiforum, Pimpinella anisum, Heracleum sphondylium and Trachyspermum cunmi) and their essential oils as a model for the identification of trypanocidal compounds to be used as alternative/integrative therapies in the treatment of Human African trypanosomiasis (HAT) and as starting material for drug design. The evaluation of inhibitory effects of the Apiaceae essential oils against Trypanosoma brucei showed that some of them (E. spinosa, S. amomum, C. maritimwn and H. nodifloruin) were active, with EC50 in the range 2.7-10.7 mu g/mL. Most of these oils were selective against T. brucei, except the one from C. maritimum that was highly selective against the BALB/3T3 mammalian cells. Testing nine characteristic individual components (a-pinene, sabinene, alpha-phellandrene, p-cymene, limonene, beta-ocimene, gamma-terpinene, terpinolene, and myristicin) of these oils, we showed that some of them had much higher selectivity than the oils themselves. Terpinolene was particularly active with an EC50 value of 0.035 mu g/rnL (0.26 mu M) and a selectivity index (SI) of 180. Four other compounds with EC50 in the range 1.0-6.0 mu g/mL (7.4-44 mu M) had also good SI: a-pinene (> 100), beta-ocimene (> 91), limonene (> 18) and sabinene ( > 17). In conclusion, these results highlight that the essential oils from the Apiaceae family are a reservoir of substances to be used as leading compounds for the development of natural drugs for the treatment of HAT.

  • 132. Karlsson, Britt M.
    et al.
    Koch, Mona
    Koskinen, Lars-Owe D.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Neurovetenskaper.
    Nimodipine affects the microcirculation and modulates the vascular effects of acetylcholinesterase inhibition2003Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 108, nr 2, s. 141-149Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The present investigation was undertaken in order to study whether microvascular effects of the calcium antagonist nimodipine induces changes that can explain an increased detoxification of the highly toxic cholinesterase inhibitor soman. Anaesthetised, tracheotomised and artificially ventilated rats were treated intra-peritoneally (ip) with nimodipine, 10 mg kg(-1) or vehicle followed one hour later by the exposure to 45 microg kg(-1) soman (iv). Nimodipine per se induced a vasodilation in the intestine, myocardium and other muscles. In the abdominal skin soman elicited a significant vasoconstriction that was turned into an increased blood flow after nimodipine pre-treatment. A slight vasoconstriction in diaphragm of soman intoxicated rats was turned into a significant vasodilation by nimodipine pre-treatment. In the intestinal parts no effect of soman was detected. However, in nimodipine pretreated animals soman induced a significant vasoconstriction. The capacity of soman detoxifying processes, i.e. enzymatic hydrolysis and covalent binding to different esterases, is unequally distributed throughout the body. Together with the knowledge of the detoxifying processes of cholinesterase inhibition the results support our theory, that nimodipine alters the peripheral blood flow in a beneficial way resulting in improved detoxification ability.

  • 133.
    Karlsson, Britt M.
    et al.
    Defence Research Establishment, Division of NBC Defence, 5‐907 82 Umeå, Sweden.
    Waara, Lena M.
    Defence Research Establishment, Division of NBC Defence, 5‐907 82 Umeå, Sweden.
    Fredriksson, Sten-Åke
    Koskinen, Lars-Owe D.
    Department of Neurosurgery, University Hospital of Umeå, S‐901 85 Umeå, Sweden.
    The effect of the calcium antagonist nimodipine on the detoxification of soman in anaesthetized rabbits.1997Ingår i: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 49, nr 3, s. 296-300Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effect of nimodipine, a vasoactive calcium antagonist, on the disappearance of soman from blood was studied in anaesthetized rabbits intoxicated with soman (10.8 micrograms kg-1 i.v.). Blood samples from the left heart ventricle and femoral artery were used to investigate soman detoxification. The concentrations of the soman isomers C+P- and C-P- in blood samples were determined by gas chromatography coupled with high-resolution mass spectrometry. During the sampling, 15-300 s after soman injection, the soman concentration in control animals decreased from 50 to 0.029 ng mL-1; in animals pre-treated with nimodipine (10 mg kg-1) it decreased from 15 to 0.033 ng mL-1. In animals pre-treated with nimodipine the soman concentration was significantly reduced during the first minute of sampling. No differences were detected between soman concentrations in samples from the heart and femoral artery. Acetylcholinesterase inhibition was also used as an indicator of soman activity; there was no difference between the activity of this enzyme in different peripheral organs of control and nimodipine-treated animals. Nimodipine reduces the initial concentration of soman in the blood, which might be of significance in the treatment of soman intoxication.

  • 134.
    Karlsson, Jessica
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Endocannabinoid metabolism: the impact of inflammatory factors and pharmacological inhibitors2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The endocannabinoid (eCB) system is an endogenous signaling system consisting of ligands (referred to as endocannabinoids, eCBs), receptors and metabolic enzymes. The eCB system is involved in homeostatic control of a variety of biological functions such as neuronal signaling, mood, appetite and pathological conditions such as pain, inflammation and tumour progression. The main eCBs N- arachidonoylethanolamine (AEA, anandamide) and 2-arachidonoylglycerol (2-AG) are synthesised upon stimuli when and where their action is demanded. The signaling is brief and the eCBs are quickly degraded. The enzyme primarily responsible for eCB degradation is fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MAGL) for 2-AG. In addition, both substances are substrates for cyclooxygenase-2 (COX-2). COX-2 is upregulated in inflammation, pain and in several tumours including prostate cancers, but it is not known whether COX-2 contribute significantly to eCB metabolism under these conditions.

    Increasing endogenous levels of eCBs by inhibiting their degradation is exploited as a future therapy for pain conditions. One suggested therapeutic strategy is dual inhibition of enzymes FAAH and COX-2 to raise AEA levels. Paper I and II of this thesis investigates FAAH and COX inhibitory effects of: the major metabolites and enantiomers of derivatives (flu-AM1 and ibu-AM5) of the current clinically used NSAIDs ibuprofen and flurbiprofen. The metabolites 3 ́hydroxyibuprofen and 4 ́hydroxyflurbiprofen retained the FAAH and COX- inhibitory effects seen by the parent compounds although at lower potencies. Both enantiomers of flu-AM1 were equally potent as FAAH inhibitors and displayed a useful substrate selective COX-2 inhibition profile, favoring eCBs as substrates rather than arachidonic acid.

    Paper III explores the impact of COX-2 and the effect of (R)-flu-AM1 upon AEA levels and degradation in mouse leukemic macrophage RAW264.7 cells. Despite the high inhibitory potency in enzyme assays, neither (R)-flu-AM1 nor the combination of a FAAH inhibitor with flurbiprofen increased AEA levels in the intact cells to any great extent. This suggests that the eCB turnover in these cells is rather slow. Further, in paper IV, induction of COX-2 did not unmask an ability of this enzyme to “gate” the uptake of AEA analogous to that seen with FAAH.

    Paper IV and V focus upon the role of the eCB system in prostate cancer. The eCB system is altered in cancer and is linked to the progression and prognosis of prostate cancer. How and whereby this change occurs is unknown. This thesis explores the impact of the inflammatory factors TNFα, IL-6 and lactic acid induced low pH upon the mRNA levels of eCB related enzymes and the functional impact upon AEA degradation in human DU145 and rat AT-1 prostate cancer cells. TNFα treatment of DU145 and IL-6 and lactic acid induced low pH exposure of AT-1 changed the mRNA levels of 2-AG related enzymes leaving AEA rather unaffected other than for a substantial induction of COX-2 mRNA in DU145 cells. Thus, AEA homeostasis was not shifted in prostate cancer cell lines exposed to inflammatory factors. The results suggest that COX-2 does not gate the uptake of AEA and is a minor contributor to AEA degradation in intact cells. 

  • 135.
    Karlsson, Jessica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fowler, Christopher
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 7, s. e103589-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. Methodology/Principal Findings:COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. Conclusions/Significance: It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  • 136.
    karlsson, jessica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Metabolism of N-acylethanolamines: To Phase II and Back Again2017Ingår i: eLS, ISSN 1618-2863Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    N-acylethanolamines (NAEs) are a family of endogenous signalling molecules involved in various effects of the body including pain, inflam- mation, appetite and sleep. NAEs are mainly degraded by fatty acid amide hydrolase (FAAH) andN-acylethanolamine acid amidase (NAAA). FAAH inhibitors have shown promising results in pre- clinical studies of pain, inflammation and anxiety, mediating effects mainly via increased cannabi- noid receptor activity. However, FAAH inhibitors have failed in clinical pain trials, and in a recent phase I trial, an irreversible compound caused one death and sustained impairments in healthy vol- unteers. The latter is most likely due to off-target effects of that compound, rather than an FAAH-mediated effect, and design of dual-action FAAH-NAAA, -TRPV1 or -cyclooxygenase-2 inhibitory compounds may solve the pain efficacy issue. NAAA inhibitors are still in preclinical testing and show a promising anti-inflammatory profile mainly due to increased palmitoylethanolamide and oleoylethanolamide levels.

  • 137.
    Karlsson, Jessica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Gouveia-Figueira, Sandra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Swedish Univ Agr Sci, Umea, Sweden.
    Alhouayek, Mireille
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Effects of tumour necrosis factor alpha upon the metabolism of the endocannabinoid anandamide in prostate cancer cells2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 9, artikel-id e0185011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tumour necrosis factor a (TNF alpha) is involved in the pathogenesis of prostate cancer, a disease where disturbances in the endocannabinoid system are seen. In the present study we have investigated whether treatment of DU145 human prostate cancer cells affects anandamide (AEA) catabolic pathways. Additionally, we have investigated whether cyclooxygenase- 2 (COX-2) can regulate the uptake of AEA into cells. Levels of AEA synthetic and catabolic enzymes were determined by qPCR. AEA uptake and hydrolysis in DU145 and RAW264.7 macrophage cells were assayed using AEA labeled in the arachidonic and ethanolamine portions of the molecule, respectively. Levels of AEA, related N-acylethanolamines (NAEs), prostaglandins (PG) and PG-ethanolamines (PG-EA) in DU145 cells and medium were quantitated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. TNF alpha treatment of DU145 cells increased mRNA levels of PTSG2 (gene of COX-2) and decreased the mRNA of the AEA synthetic enzyme N-acylphosphatidylethanolamine selective phospholipase D. mRNA levels of the AEA hydrolytic enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase were not changed. AEA uptake in both DU145 and RAW264.7 cells was inhibited by FAAH inhibition, but not by COX-2 inhibition, even in RAW264.7 cells where the expression of this enzyme had greatly been induced by lipopolysaccharide + interferon. treatment. AEA and related NAEs were detected in DU145 cells, but PGs and PGE(2)-EA were only detected when the cells had been preincubated with 100 nM AEA. The data demonstrate that in DU145 cells, TNFa treatment changes the relative expression of the enzymes involved in the hydrolytic and oxygenation catabolic pathways for AEA. In RAW264.7 cells, COX-2, in contrast to FAAH, does not regulate the cellular accumulation of AEA. Further studies are necessary to determine the extent to which inflammatory mediators are involved in the abnormal endocannabinoid signalling system in prostate cancer.

  • 138. Karlsson, Sofia A.
    et al.
    Jacobsson, Ingela
    Boman, Marit Danell
    Division of Clinical Pharmacology, University Hospital of Umeå, Umeå, Sweden.
    Hakkarainen, Katja M.
    Lovborg, Henrik
    Hagg, Staffan
    Jonsson, Anna K.
    The impact of a changed legislation on reporting of adverse drug reactions in Sweden, with focus on nurses' reporting2015Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, nr 5, s. 631-636Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 139.
    Kauppi, Karolina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Gani, Osman
    Sanyal, Nilotpal
    Bettella, Francesco
    Smeland, Olav
    Andreassen, Ole
    Chen, Chi-Hua
    PREDICTING ANTIPSYCHOTIC RESPONSE COMBINING POLYGENIC RISK WITH PROTEIN-PROTEIN NETWORKS2019Ingår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S27-S27Artikel i tidskrift (Övrigt vetenskapligt)
  • 140.
    Kling, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    5-HT2A: a serotonin receptor with a possible role in joint diseases2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background

    Serotonin (5-HT), an amino acid derivative and neurotransmitter, has for long been studied in relation to inflammation. It is an endogenous ligand for several different types of serotonin receptors. The serotonin receptor 5-HT2A has been reported to have a role in the pathophysiology of arthritis in animal experiment models. However, no studies into this subject have been reported in man.

    Objective

    The objectives of this project were firstly, to examine possible associations for the 5-HT2A receptor and also for the gene (HTR2A) encoding for the receptor with arthritis in man and secondly, to explore possible mechanisms underlying such associations.

    Methods

    The density and affinity of platelet 5-HT2A receptors were determined in 43 patients with a common inflammatory joint disease, i. e., rheumatoid arthritis (RA), in comparison with matched controls using a radio-ligand assay. The effects of treatment with prednisolone on 5-HT2A density and affinity were also examined in 27 individuals diagnosed with polymyalgia rheumatica before and after start of treatment. In addition, possible candidate HTR2A genes were studied in relation to RA in two Swedish cohorts incorporating a total of 2450 RA patients. Furthermore, a register study using reports of joint symptoms as adverse drug reactions (ADRs) in the Swedish and the WHO ADR databases was undertaken. The proportion of reports concerning joint symptoms in relation to all ADR reports and to sales figures was analysed for 5-HT2A blocking atypical antidepressant substances compared with another group of antidepressants, i. e., selective serotonin re-uptake inhibitors (SSRIs), used for similar clinical indications.

    Results

    The mean density of 5-HT2A receptors in RA patients was significantly lower than in controls, 45.3 versus 57.4 fmol/mg protein (p = 0.004). There was no significant difference in affinity. Variation of four single nucleotide polymorphisms (SNPs) (rs6314, rs1328674, rs6313 and rs6311) in the HTR2A gene was associated with RA, although not significantly so for all SNPs after testing for multiple comparisons. The proportion of joint symptoms reported as ADRs, relative to all ADRs was significantly higher for the 5-HT2A blocking antidepressants compared with the SSRIs in both databases (p< 0.001). In the Swedish material the comparison of ADRs was also related to sales figures, showing a considerable higher frequency of joint symptoms for the 5-HT2A antagonists (p< 0.001). The density of 5-HT2A receptors increased after treatment with prednisolone in 23 out of 27 individuals. The mean density at baseline was 45.2 versus 64.9 fmol/mg protein at the end of the study (p=0.001). There were no significant differences in affinity during the treatment period, although a low affinity at baseline was a predictor for higher density following treatment with prednisolone.

    Conclusions

    The density of 5-HT2A receptors, reflecting the number of receptors, was markedly reduced in a cohort of patients with RA from Northern Sweden. This may depend, at least in part, on an association between RA and certain HTR2A SNPs. Genetically determined or acquired low levels of accessible 5-HT2A receptors may contribute to susceptibility for development of joint symptoms, not only in RA but more generally, e. g., joint ADRs caused by 5-HT2A blocking atypical antidepressants. The benefits of treatment with glucocorticoids may, at least partially, be mediated by an effect on 5-HT2A receptors.

  • 141.
    Kling, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Mjörndal, Tom
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Glucocorticoid treatment increases density of serotonin 5-HT2A receptors in humans2012Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, nr 7, s. 1014-1020Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Interactions between the serotonergic system and the hypothalamic–pituitary–adrenal axis have been suggested, albeit the details for such interactions have yet to be established. Animal studies have shown that the density of serotonin 5-HT2A receptors is increased after administration of exogenous glucocorticoids.

    Objective: The objective of this study was to explore possible changes in the pattern of density and affinity of 5-HT2A receptors in humans after treatment with glucocorticoids.

    Methods: Using a radioactive binding assay, the density and affinity (measured as Bmax and Kd) of 5-HT2A serotonin receptors were measured in blood samples drawn from 27 individuals diagnosed with polymyalgia rheumatica and/or giant cell arteritis before and after start of an oral treatment with prednisolone. For each patient Bmax and Kd at baseline before prednisolone treatment were compared with Bmax and Kd in samples drawn at a first and second follow-up clinic visit at an average of 8.8 (±2.5) days and 33.6 (±6.8) days, respectively.

    Results: The density of 5-HT2A receptors increased after treatment in 23 individuals. The mean Bmax value at baseline for all patients was 45.2 fmol/mg protein compared with 64.9 fmol/mg protein in the corresponding samples drawn at the second follow-up visit (p = 0.001). There also was an association between individuals accumulated prednisolone dose and the magnitude of change in Bmax between baseline and the first follow-up visit. Erythrocyte sedimentation rate, platelet count or gender had no influence on the results. There were no significant differences in Kd during the treatment period. However, a low Kd value at baseline was a predictor for an increase in Bmax following treatment.

    Conclusions: The results of this study showed that the density of 5-HT2A serotonin receptors in man is increased after a subchronic treatment with glucocorticoids. The magnitude of the increase appears to be associated with the affinity of 5-HT2A receptors before treatment and the accumulated dose of glucocorticoid early in the treatment period.

  • 142. Klingström, Jonas
    et al.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Hantavirus protein interactions regulate cellular functions and signaling responses2011Ingår i: Expert Review of Anti-Infective Therapy, ISSN 1478-7210, E-ISSN 1744-8336, Vol. 9, nr 1, s. 33-47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rodent-borne pathogenic hantaviruses cause two severe and often lethal zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Currently, no US FDA-approved therapeutics or vaccines are available for HFRS/HCPS. Infections with hantaviruses are not lytic, and it is currently not known exactly why infections in humans cause disease. A better understanding of how hantaviruses interfere with normal cell functions and activation of innate and adaptive immune responses might provide clues to future development of specific treatment and/or vaccines against hantavirus infection. In this article, the current knowledge regarding immune responses observed in patients, hantavirus interference with cellular proteins and signaling pathways, and possible approaches in the development of therapeutics are discussed.

  • 143. Koch, Bo L.
    et al.
    Edvinsson, Åsa A.
    Koskinen, Lars-Owe D.
    University Hospital of Northern Sweden, Department of Neurosurgery, SE‐901 85 Umeå, Sweden.
    Inhalation of substance P and thiorphan: acute toxicity and effects on respiration in conscious guinea pigs.1999Ingår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 19, nr 1, s. 19-23Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Substance P is a tachykinin and a biologically active neuropeptide. The peptide produces salivation, neuronal excitation, vasodilatation, increased vascular permeability and contraction of smooth muscles in the respiratory tract. The study was designed to evaluate the acute effects in guinea pigs of inhaled aerosolized Substance P (SP). Apart from the acute toxic effect of the peptide, the distribution in different organs was also investigated. The acute inhalation toxicity of SP (LC50, 15 min) when co-administrated with the neutral endopeptidase inhibitor thiorphan was 368 microg m(-3). The peptide caused an increase in respiratory rate proceeding a decrease in tidal volume. As the exposure proceeded, a decrease in both respiratory rate and further decreases in tidal volume were observed until either the animal died or the exposure was terminated. The decreases in respiratory rate and tidal volume were probably due to bronchoconstriction caused by SP. Eighteen per cent of the inhaled amount of radioactive SP was retained in the body, and the highest concentrations of radioactivity were found in the kidney, lung and liver. Substance P in combination with thiorphan administered as an aerosol is extremely toxic and highly potent. Exposure to the substance at extremely low air concentrations may result in incapacitation in humans.

  • 144.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap. Umeå University and Defence Reearch Etablishment, Division of NBC Defence, Department och Biomedicine, Umeå, Sweden.
    Collin, Ola
    University Hosptial of Umeå and Departments och Anatomy and Pathalogy, Umeå University, Sweden.
    Bergh, A.
    University Hosptial of Umeå and Departments och Anatomy and Pathalogy, Umeå University, Sweden.
    Cigarette smoke and hypoxia induce acute changes in the testicular and cerebral microcirculation2000Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 105, nr 3, s. 215-226Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The acute effects of cigarette smoking and hypoxia on the cerebral and testicular microcirculation were studied in anestethised adult rats. Smoking for 2 min did not influence arterial pO2, pCO2 or pH but it induced an increase in cerebral blood flow by 34% and inhibited vasomotion in the testis for about 1 h. One hour after smoke exposure apnea induced a slight increase in arterial pCO2, a significant decrease in pO2, and an increase in cerebral blood flow (CBF) by 54%. In animals not previously exposed to cigarette smoke apnea increased CBF by 121%, demonstrating that a short-term exposure to tobacco smoke influences the cerebrovascular reactivity for more than one hour. In the testis, apnea resulted in a decreased blood flow by 39% and a complete depression of vasomotion. Breathing 10% O2/90% N2 resulted in moderate hypoxia, a total disappearance of the vasomotion in the testis, a 24% decrease in testicular blood flow, but a 23% increase in CBF.

    Our results indicate that short-term exposure to tobacco smoke induces marked acute vascular effects in both the brain and the testis. Apnea and moderate hypoxia elicited totyally different effects in the brain and testis, inicating different vascular control mechanisms. 

  • 145.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap. Institution of Threat Assessment, Division of NBC Defence, Swedish Defence Research Agency, Umeå, Sweden.
    Koch, Mona L.
    Institution of Threat Assessment, Division of NBC Defence, Swedish Defence Research Agency, Umeå, Sweden.
    Nitric oxide inhibition by L-NAME but not 7-NI induces a transient increase in cortical cerebral blood flow and affects the cerebrovasodilation induced by TRH2003Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 24, nr 4, s. 579-583Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The tripeptide thyrotropin releasing hormone (TRH) has multiple interesting and complex physiological effects. One of these is the cerebrovasodilating effect, which has been described under several different conditions. The final mechanism for this effect is unknown. In the present study, we found an initial atropine-resistant cerebral vasodilation (24%) elicited by the NOS inhibitor L-NAME in the rat. D-NAME and 7-NI did not produce this effect. TRH (300 microg kg(-1), i.v.) induced an increase in cerebral blood flow by 62%. L-NAME reduced this effect significantly. The cerebrovasodilating mechanism of TRH, at least in part, is endothelial NO dependent as the neuronal 7-NI NOS inhibitor does not affect the TRH response.

  • 146.
    Koskinen, Lars-Owe D.
    et al.
    Department of Biomedicine, Defense Research Establishment, Umeå, Sweden. Department of Neurosurgery, Umeå University Hospital, Umeå, Sweden.
    Koch, Mona L.
    Puu, Gertrud
    The neuropeptide TRH has a minor effect on the enzymatic activity of acetylcholinesterase in vitro.1998Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 19, nr 10, s. 1675-1677Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The neuropeptide thyrotropin-releasing hormone (TRH) elicits a variety of physiological effects of which some are due to cholinergic mechanisms. TRH modulates in vivo the effects of compounds affecting acetylcholinesterase (AChE). In the present study the in vitro effects of TRH on the activity of AChE were explored. TRH has no effect at physiologically relevant concentrations. At unphysiologically high concentrations (>5 mM) a slight inhibition was found. This was noticed also when the enzyme was exposed to the amide-free tripeptide analog p-Glu-His-Pro. We conclude that any cholinergic effect of TRH observed in vivo is unlikely to be due to a direct interaction of the peptide with AChE.

  • 147.
    Koskinen, Lars-Owe D.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Runnerstam, Magnus
    Koch, Mona
    FOI, Swedish Defence Research Agency, SE-901 82 Umeå, Sweden.
    Karlsson, Britt M.
    FOI, Swedish Defence Research Agency, SE-901 82 Umeå, Sweden.
    Cerebral microvascular effects of nimodipine in combination with soman2012Ingår i: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 34, nr 3, s. 905-910Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nimodipine, a calcium antagonist, has been shown to increase the detoxification of soman. In this study the cerebral microcirculatory effects of nimodipine and the acetylcholinesterase inhibitor soman was studied. Anaesthetised rats were administered nimodipine, 10 mg kg(-1) or vehicle intra-peritoneally, and 1 h later exposed to 45 mu g kg(-1) soman intravenously. The regional blood flows were measured using the microsphere method. Nimodipine and soman markedly increased the cerebral blood flow (CBF) and reduced the vascular resistance. Total CBF increased by 146% after nimodipine and by 105% after soman administration. Combined administration of nimodipine and soman caused additional but not fully additive effects on CBF and vascular resistance, indicating possible different mechanisms of the two agents. A part of the nimodipine induced increased detoxification after AChE-inhibition may be associated with this cerebral vasodilation. (C) 2012 Elsevier B.V. All rights reserved.

  • 148.
    Kouokam, J Clavin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Outer membrane vesicle-mediated export of a pore-forming cytotoxin from Escherichia coli2006Ingår i: Journal of toxicology. Toxin reviews, ISSN 0731-3837, E-ISSN 1525-6057, Vol. 25, nr 1, s. 31-46Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ClyA, also called SheA or HlyE, is a four-helix bundle cytotoxic protein expressed by Escherichia coli and other enterobacteria. The expression of ClyA was shown to be controlled by the nucleoid protein H-NS and could be activated by overproduction of several different transcriptional regulators such as SlyA, MprA, HlyX, and FnrP. The ClyA protein contains two hydrophobic potential transmembrane domains. Lipid bilayer experiments and electron microscopic studies have led to the conclusion that ClyA forms stable pores in target membranes by assembling into ring-shaped toxin oligomers, but little or no effect was found on the bacterial cell membranes from which it is produced, presumably because the lytic activity of the protein is stimulated by cholesterol. Several studies have revealed that the ClyA toxin, which does not have any canonical signal sequence, nevertheless is secreted to the medium. It has become evident that a vesicle-mediated transport mechanism is responsible for the activation and delivery of ClyA protein, seemingly independent of the previously described type I-V secretion systems.

  • 149.
    Kronstrand, Robert
    et al.
    National Board of Forensic Medicine.
    Roman, Markus
    National Board of Forensic Medicine.
    Thelander, Gunilla
    National Board of Forensic Medicine.
    Eriksson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rättsmedicin.
    Unintentional fatal intoxications with mitragynine and O-Desmethyltramadol from the herbal blend krypton2011Ingår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 35, nr 4, s. 242-247Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The leaves of Kratom, a medicinal plant in Southeast Asia, have been used as an herbal drug for a long time. At least one of the alkaloids present in Kratom, mitraynine, is a mu-receptor agonist. Both Kratom and an additional preparation called Krypton are available via the internet. It seems to consist of powdered Kratom leaves with another mu-receptor agonist, O-desmethyltramadol added. O-desmethyltramadol is an acitve metabolite of tramadol, a commonly prescribed analgesic. We present nine cases of intoxication, occurring in a period of less than one year, where both mitragynine and O-desmethyltramadol were detected in the postmortem blood samples. neither tramadol nor N-desmethyltramadol was present in these samples, which implies that the ingested drug was O-desmethyltramadol. The blood concentrations of mitragynine, determined by ultra-performance liquid chromatography-tandem mass spectrometry, ranged from 0.02 to 0.18 μg/g, and O-desmethyltramadol concentrations, determined by gas chromatogtraphy with nitrogen-specific detection, ranged from 0.4 to 4.3 μg/g. We believe that the addition of the potent mu-receptor agonist O-desmethyltramadol to powdered leaves from Kratom contributed to the unintentional death of the nine cases presented and conclude that intake of Krypton is not as harmless as it often is described on internet websites.  

  • 150. Kvarnryd, Moa
    et al.
    Grabic, Roman
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brandt, Ingvar
    Berg, Cecilia
    Early life progestin exposure causes arrested oocyte development, oviductal agenesis and sterility in adult Xenopus tropicalis frogs2011Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 103, nr 1-2, s. 18-24Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Levonorgestrel (LNG) is a commonly used pharmaceutical progestin found in the environment. Information on the long-term toxicity of progestins following early life exposure is scant. We investigated the effects of developmental LNG exposure on sex differentiation, reproductive organ development and fertility in the model frog Xenopus tropicalis. Tadpoles were exposed to 0, 0.06 or 0.5 nM LNG via the water from hatching until metamorphosis. At metamorphosis effects on gonadal differentiation were evaluated using a subsample of frogs. Remaining animals were held unexposed for nine months, at which time reproductive organ structure, function and fertility were determined. LNG exposure severely impaired oviduct and ovary development and fertility. All adult females in the 0.5 nM group (n =10) completely lacked oviducts. They also displayed a significantly larger fraction of immature oocytes, arrested in meiotic prophase, than control females. Upon mating with unexposed males, only one of 11 LNG-exposed females laid eggs, whereas all control females did. No effects on testicular development, sperm count or male fertility were observed. At metamorphosis, no effects on sex ratio or gonadal histology were evident. The effects on ovarian and oviductal development were detected at adult age but not at metamorphosis, emphasising the importance of investigating the long-term consequences of developmental exposure. This is the first developmental reproductive toxicity study of a progestin in an aquatic vertebrate. Considering that several progestins are present in contaminated surface waters, further investigation into the sensitivity of frogs to progestins is warranted to understand the risk such compounds may pose to wild frog populations.

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