liu.seSearch for publications in DiVA
Change search
Refine search result
1234 1 - 50 of 185
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Ahlenius, Sven
    et al.
    Göteborgs universitet.
    Heimann, Mikael
    Göteborgs universitet.
    Larsson, Knut
    Göteborgs universitet.
    Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine.1979In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 65, no 2, p. 137-140Article in journal (Refereed)
    Abstract [en]

    Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.

  • 2.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Frick, Anna
    State Alaska Dept Hlth & Social Serv, AK USA.
    Pongratz, Catherine
    State Alaska Dept Hlth & Social Serv, AK USA.
    Spink, Kimberly
    State Alaska Dept Hlth & Social Serv, AK USA.
    Xavier, Catherine
    State Alaska Dept Hlth & Social Serv, AK USA.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Council, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Genomic comparison of carbapenem-resistant Enterobacteriaceae from humans and gulls in Alaska2021In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 25, p. 23-25Article in journal (Refereed)
    Abstract [en]

    Objectives: Wildlife may harbour clinically important antimicrobial-resistant bacteria, but the role of wildlife in the epidemiology of antimicrobial-resistant bacterial infections in humans is largely unknown. In this study, we aimed to assess dissemination of the bla(KPC) carbapenemase gene among humans and gulls in Alaska. Methods: We performed whole-genome sequencing to determine the genetic context of bla(KPC) in bacterial isolates from all four human carbapenemase-producing Enterobacteriaceae (CPE) infections reported in Alaska between 2013-2018 and to compare the sequences with seven previously reported CPE isolates from gull faeces within the same region and time period. Results: Genomic analysis of CPE isolates suggested independent acquisition events among humans with no evidence for direct transmission of bla(KPC) between people and gulls. However, some isolates shared conserved genetic elements surrounding bla(KPC), suggesting possible exchange between species. Conclusion: Our results highlight the genomic plasticity associated with bla(KPC) and demonstrate that sampling of wildlife may be useful for identifying clinically relevant antimicrobial resistance not observed through local passive surveillance in humans. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

    Download full text (pdf)
    fulltext
  • 3.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK USA; US Geol Survey, AK 99508 USA.
    Scott, Laura C.
    US Geol Survey, AK USA.
    Woksepp, Hanna
    Reg Kalmar Cty, Sweden; Linnaeus Univ, Sweden.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Reg Kalmar Cty, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK USA.
    Environmental antimicrobial resistance gene detection from wild bird habitats using two methods: A commercially available culture-independent qPCR assay and culture of indicator bacteria followed by whole-genome sequencing2023In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 33, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Objectives: A variety of methods have been developed to detect antimicrobial resistance (AMR) in differ-ent environments to better understand the evolution and dissemination of this public health threat. Com-parisons of results generated using different AMR detection methods, such as quantitative PCR (qPCR) and whole-genome sequencing (WGS), are often imperfect, and few studies have analysed samples in parallel to evaluate differences. In this study, we compared bacterial culture and WGS to a culture-independent commercially available qPCR assay to evaluate the concordance between methods and the utility of each in answering research questions regarding the presence and epidemiology of AMR in wild bird habitats.Methods: We first assessed AMR gene detection using qPCR in 45 bacterial isolates from which we had existing WGS data. We then analysed 52 wild bird faecal samples and 9 spatiotemporally collected water samples using culture-independent qPCR and WGS of phenotypically resistant indicator bacterial isolates.Results: Overall concordance was strong between qPCR and WGS of bacterial isolates, although concor-dance differed among antibiotic classes. Analysis of wild bird faecal and water samples revealed that more samples were determined to be positive for AMR via qPCR than via culture and WGS of bacterial isolates, although qPCR did not detect AMR genes in two samples from which phenotypically resistant isolates were found.Conclusions: Both qPCR and culture followed by sequencing may be effective approaches for characteris-ing AMR genes harboured by wild birds, although data streams produced using these different tools may have advantages and disadvantages that should be considered given the application and sample matrix.Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

    Download full text (pdf)
    fulltext
  • 4.
    Alehagen, Urban
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Alexander, Jan
    Norwegian Inst Publ Hlth, Norway.
    Aaseth, Jan
    Innlandet Hosp Trust, Norway; Inland Norway Univ Appl Sci, Norway.
    Larsson, Anders
    Uppsala Univ, Sweden.
    Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK2019In: Journal of Inflammation, E-ISSN 1476-9255, Vol. 16, article id 5Article in journal (Refereed)
    Abstract [en]

    Background: Inflammation is central to the pathogenesis of many diseases. Supplementation with selenium and coenzyme Q10 has been shown to reduce cardiovascular mortality, and increase cardiac function in elderly persons with a low intake of selenium. There are indications that one of the mechanisms of this positive effect is a decrease in inflammation. Methods: Osteopontin, osteoprotegerin, sTNF receptor 1, sTNF receptor 2 and the tumor necrosis factor-like weak inducer of apoptosis called TWEAK, were determined in plasma after 6 months and 42months in 219 community-living elderly persons, of whom 119 received supplements of selenium (200g/day) and coenzyme Q10 (200mg/day), and 101 received a placebo. Repeated measures of variance were used to evaluate the levels, and the results were validated through ANCOVA analyses with adjustments for important covariates. Results: Significantly lower concentrations of four of the five biomarkers for inflammation were observed as a result of the intervention with the supplements. Only TWEAK did not show significant differences. Conclusion: In this sub-analysis of the intervention with selenium and coenzyme Q10 or placebo in an elderly community-living population, biomarkers for inflammation were evaluated. A significantly lower concentration in four of the five biomarkers tested could be demonstrated as a result of the supplementation, indicating a robust effect on the inflammatory system. The decrease in inflammation could be one of the mechanisms behind the positive clinical results on reduced cardiovascular morbidity and mortality reported earlier as a result of the intervention. The study is small and should be regarded as hypothesis-generating, but nonetheless adds important data about mechanisms presently known to increase the risk of clinical effects such as reduced cardiovascular mortality, increased cardiac function and better health-related quality of life scoring, as previously demonstrated in the active treatment group.

    Download full text (pdf)
    fulltext
  • 5.
    Alfredsson, Joakim
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Duke University, NC 27710 USA.
    Alexander, Karen P.
    Duke University, NC 27710 USA.
    Multiple Chronic Conditions in Older Adults with Acute Coronary Syndromes2016In: Clinics in Geriatric Medicine, ISSN 0749-0690, E-ISSN 1879-8853, Vol. 32, no 2, p. 291-+Article in journal (Refereed)
    Abstract [en]

    Older adults presenting with acute coronary syndromes (ACSs) often have multiple chronic conditions (MCCs). In addition to traditional cardiovascular (CV) risk factors (ie, hypertension, hyperlipidemia, and diabetes), common CV comorbidities include heart failure, stroke, and atrial fibrillation, whereas prevalent non-CV comorbidities include chronic kidney disease, anemia, depression, and chronic obstructive pulmonary disease. The presence of MCCs affects the presentation (eg, increased frequency of type 2 myocardial infarctions [MIs]), clinical course, and prognosis of ACS in older adults. In general, higher comorbidity burden increases mortality following MI, reduces utilization of ACS treatments, and increases the importance of developing individualized treatment plans.

  • 6. Order onlineBuy this publication >>
    Ali, Zaheer
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Investigating mechanisms of angiogenesis in health and disease using zebrafish models2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Angiogenesis, the growth of blood vessels from an existing vasculature, can occur by sprouting from preexisting vessels or by vessel splitting (intussusception). Pathological angiogenesis drives choroidal neovascularization (CNV) in age related macular degeneration (AMD) which is commonly restricted under the retinal pigment epithelium (RPE), called occult CNV, but may also involve vessels penetrating through the RPE into the sub-retinal space. Pathological vessels are poorly developed, insufficiently perfused and highly leaky, phenotypes that are considered to drive disease progression and lead to poor prognosis. Currently, a number of anti-angiogenic drugs exists, the majority of which target vascular endothelial factor (VEGF), but although they often are highly beneficial for treating eye diseases in the short-term, they are generally of limited efficacy in other diseases such as cancer, and also have poorer efficacy when used for treatment of eye diseases in the long-term. A better understanding of the mechanisms underlying pathological angiogenesis can generate new targets for treatment leading to development of better drugs for cancer and retinopathies, but perhaps also other angiogenesis-dependent diseases, in the future. In this thesis mechanisms involved in developmental angiogenesis or pathological angiogenesis in the choroid, cornea or melanoma was identified. These findings highlight the need to further elaborate our knowledge related to angiogenesis in different tissues/conditions for a more targeted, and potentially effective treatment of diseases in the future.

    In paper I, we for the first time identified the choriocapillaries (CCs) in adult zebrafish and found that occult CNV could be induced by exposing the fish to severe hypoxia. Interestingly, we found that occult CNV relied on intussusception, involving not only de novo generation of intussusceptive pillars but also a previously poorly understood mechanism called pillar splitting. This involved HIF-VEGF-VEGFR2 signaling and evidence that this also occurred in both rats and humans suffering from AMD suggested that the mechanism was conserved and clinically relevant.

    In contrast, we found in paper II that the development of CCs in the zebrafish relies on sprouting angiogenesis, involve continuous remodeling, and delayed maturation of the vasculature in 2D. The initial development was found to occur by a unique process of tissuewide synchronized vasculogenesis. As expected, VEGFA via VEGFR2 was also critical for the development of these vessels in the zebrafish embryo, but surprisingly this was independent on hypoxia-inducible factor (HIF)-1.

    Inflammatory nuclear factor-kB (NF-kB) signaling is involved in the progression of angiogenesis, but this signaling pathway has mainly been studied in the inflammatory cells and the role of NF-kB in the endothelial cells during angiogenesis is poorly understood. In paper III, we found that blocking NF-kB signaling using a specific IKK2 blocker IMD0354, specifically blocks pathological as well as developmental angiogenesis by targeting endothelial cell NF-kB signaling in the endothelial cells. Using a rat model for suture-induced corneal neovascularization, IMD0354 treatment lead to reduced production of inflammatory C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 5 (CXCL5) and VEGF, and thereby reduced pathological corneal angiogenesis in this model.

    Using the zebrafish tumor xenograft model in paper IV, we found an association between Microphthalmia associated transcription factor (MITF) and pigment epithelium derived factor (PEDF), which was involved in pathological tumor angiogenesis and metastasis. Similarly, in paper V we used zebrafish transplantation models to study and investigate the use of biocompatible polymers for the delivery of pro-angiogenic FGF-2 as a potential treatment strategy for ischemic diseases such as myocardial infarction (MI). Conclusively, this thesis provides new insights into diverse fields of angiogenic assays using zebrafish, and reveals new mechanisms of angiogenesis in health and disease. This work will hopefully provide a foundation for further studies into occult CNV related to AMD, a process that has not been possible to study previously in pre-clinical models. In addition, zebrafish xenograft or other transplantation models used in this work will likely be important to study cancer biology and to develop more attractive pharmaceutical preparations based on biocompatible hydrogels formulated as microspheres in the future.

    List of papers
    1. Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis
    Open this publication in new window or tab >>Selective IKK2 inhibitor IMD0354 disrupts NF-kappa B signaling to suppress corneal inflammation and angiogenesis
    Show others...
    2018 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 21, no 2, p. 267-285Article in journal (Refereed) Published
    Abstract [en]

    Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-kappa B signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-kappa B activation through selective blockade of the IKK complex I kappa B kinase beta (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNF alpha-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-alpha expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-kappa B by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-kappa B signaling in the development of pathologic corneal neovascularization.

    Place, publisher, year, edition, pages
    Springer Netherlands, 2018
    Keywords
    Cornea; Neovascularization; NF-kappa B; IMD0354; IKK2; VEGF
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-147373 (URN)10.1007/s10456-018-9594-9 (DOI)000428924500007 ()29332242 (PubMedID)2-s2.0-85041334437 (Scopus ID)
    Note

    Funding Agencies|Swedish Research Council [2012-2472]; Swedish Foundation Stiftelsen Synframjandets Forskningsfond/Ogonfonden; Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Jeanssons Stiftelser

    Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2019-05-01Bibliographically approved
    2. Regulatory and Functional Connection of Microphthalmia-Associated Transcription Factor and Anti-Metastatic Pigment Epithelium Derived Factor in Melanoma
    Open this publication in new window or tab >>Regulatory and Functional Connection of Microphthalmia-Associated Transcription Factor and Anti-Metastatic Pigment Epithelium Derived Factor in Melanoma
    Show others...
    2014 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 6, p. 529-542Article in journal (Refereed) Published
    Abstract [en]

    Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor ( MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.

    Place, publisher, year, edition, pages
    Neoplasia, 2014
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-110497 (URN)10.1016/j.neo.2014.06.001 (DOI)000340553600007 ()25030625 (PubMedID)
    Note

    Funding Agencies|Ministerio de Ciencia y Competitividad of Spain [SAF-2010-19256, SAF-2011-24225, SAF-2012-32117, FIS 11/02568, RD09/0076/0101, PT13/0010/0012, PI12/01552]; LiU-Cancer; Svenska Sallskapet for Medicinsk Forskning; Ake Wibergs Stiftelse; Goesta Fraenkels Stifelse; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer

    Available from: 2014-09-15 Created: 2014-09-12 Last updated: 2018-12-07
    3. Adjustable delivery of pro-angiogenic FGF-2 by alginate: collagen microspheres
    Open this publication in new window or tab >>Adjustable delivery of pro-angiogenic FGF-2 by alginate: collagen microspheres
    Show others...
    2018 (English)In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 7, no 3, article id UNSP bio027060Article in journal (Refereed) Published
    Abstract [en]

    Therapeutic induction of blood vessel growth (angiogenesis) in ischemic tissues holds great potential for treatment of myocardial infarction and stroke. Achieving sustained angiogenesis and vascular maturation has, however, been highly challenging. Here, we demonstrate that alginate: collagen hydrogels containing therapeutic, pro-angiogenic FGF-2, and formulated as microspheres, is a promising and clinically relevant vehicle for therapeutic angiogenesis. By titrating the amount of readily dissolvable and degradable collagen with more slowly degradable alginate in the hydrogel mixture, the degradation rates of the biomaterial controlling the release kinetics of embedded proangiogenic FGF-2 can be adjusted. Furthermore, we elaborate a microsphere synthesis protocol allowing accurate control over sphere size, also a critical determinant of degradation/release rate. As expected, alginate: collagen microspheres were completely biocompatible and did not cause any adverse reactions when injected in mice. Importantly, the amount of pro-angiogenic FGF-2 released from such microspheres led to robust induction of angiogenesis in zebrafish embryos similar to that achieved by injecting FGF-2-releasing cells. These findings highlight the use of microspheres constructed from alginate: collagen hydrogels as a promising and clinically relevant delivery system for pro-angiogenic therapy.

    Place, publisher, year, edition, pages
    COMPANY OF BIOLOGISTS LTD, 2018
    Keywords
    Hydrogels; Microspheres; Angiogenesis; Vasculature; Zebrafish
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-147419 (URN)10.1242/bio.027060 (DOI)000429100500002 ()29449216 (PubMedID)
    Note

    Funding Agencies|Svenska Sallskapet for Medicinsk Forskning; Ake-Wiberg Foundation; Goesta Fraenkel Foundation; Ahrens Stiftelse; Ollie och Elof Ericssons Stiftelse; Carmen och Bertil Ragners Stiftelse; KI Stiftelser och fonder; Loo och Hans Ostermans Stiftelse for Medicinsk Forskning; Vetenskapsradet; Linkoping University

    Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-12-07
    Download full text (pdf)
    Investigating mechanisms of angiogenesis in health and disease using zebrafish models
    Download (pdf)
    omslag
    Download (png)
    presentationsbild
  • 7.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Vicente Carrillo, Alejandro
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Evidensia Valla Djursjukhus Linkoping, Linkoping, Sweden.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Hyaluronan improves neither the long-term storage nor the cryosurvival of liquid-stored CD44-bearing Al boar spermatozoa2018In: Journal of reproduction and development, ISSN 0916-8818, E-ISSN 1348-4400, Vol. 64, no 4, p. 351-360Article in journal (Refereed)
    Abstract [en]

    Hyaluronan (hyaluronic acid, HA) apparently improves sperm survival in vitro and in vivo (oviduct), maintaining sperm motility and inducing capacitation, but not acrosome exocytosis, either by direct action as a macromolecule or via CD44 membrane receptors. This study explored ejaculated, liquid-extended pig spermatozoa to ascertain (i) the presence (Western blotting) and specific location (immunocytochemistry) of the CD44 receptor, using a specific monoclonal commercial antibody; (ii) whether the CD44 receptor changed location when exposed to bicarbonate, a capacitating trigger, in vitro; and (iii) whether the addition of HA, of molecular size comparable to that produced in the oviduct sperm reservoir (0.0625 to 2.0 mg/ml; 0 HA: control), to semen extenders would improve sperm liquid storage in vitro or cryosurvival post freezing. Variables tested were sperm velocity and progressive motility (Qualisperm (TM)), sperm viability and acrosome status, membrane integrity and early destabilization, mitochondrial activation, and superoxide production (flow cytometry). The CD44 receptor presence in ejaculated, liquid-stored AI boar spermatozoa, as confirmed by a porcine-specific monoclonal antibody, maintained its membrane location under in vitro capacitation-inducing conditions. HA exposure to 24-, 48-, or 72-h liquid-stored (17-20 degrees C) spermatozoa lowered sperm velocity in membrane-intact spermatozoa, but increased mitochondrial superoxide production. Finally, HA addition during cooling did not improve cryosurvival but did increase mitochondrial activation and membrane destabilization in surviving cells. These results confirm the existence of a CD44 receptor in pig spermatozoa, but the usefulness of adding HA for long-term storage or cryopreservation of liquid-stored, extended boar semen remains in question, thereby warranting further non-empirical analyses of HA-sperm membrane interactions.

  • 8.
    Amirhosseini, Mehdi
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Alkaissi, Hammoudi
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Hultman, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Havarinasab, Said
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Autoantibodies in outbred Swiss Webster mice following exposure to gold and mercury2021In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 412, article id 115379Article in journal (Refereed)
    Abstract [en]

    Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored. Serum antinuclear antibodies (ANA), polyclonal B-cell activation, hypergammaglobulinemia and tissue immune complex deposition are the main features of metal-induced autoimmunity in inbred mice. However, inbred mouse strains do not represent the genetic heterogeneity in humans. In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl2) in drinking water, caused IgG antinucleolar antibodies (ANoA) after 5 weeks in SW mice accompanied by immune complex deposition in kidneys and spleen. Serum IgG antibodies corresponding to anti-fibrillarin, and anti-PM/Scl-100 antibodies, were observed in mercury-exposed SW mice. Gold and mercury trigger systemic autoimmune response in genetically heterogeneous outbred SW mice and suggest them as an appropriate model to study xenobiotic-induced autoimmunity.

    Download full text (pdf)
    fulltext
  • 9.
    Amirhosseini, Mehdi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Madsen, Rune V.
    Hosp Special Surg, NY 10021 USA.
    Escott, K. Jane
    AstraZeneca, England.
    Bostrom, Mathias P.
    Hosp Special Surg, NY 10021 USA.
    Ross, F. Patrick
    Hosp Special Surg, NY 10021 USA.
    Fahlgren, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    GSK-3 beta inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation2018In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 233, no 3, p. 2398-2408Article in journal (Refereed)
    Abstract [en]

    Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/beta-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/beta-catenin signaling by inhibiting glycogen synthase kinase-3 beta (GSK-3 beta) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3 beta inhibition on regulation of RANKL and OPG in a rat model of mechanical instability-induced peri-implant osteolysis. The rats were treated daily with a GSK-3 beta inhibitor, AR28 (20 mg/kg bw), for up to 5 days. Bone tissue and blood serum were assessed by qRT-PCR, immunohistochemistry, and ELISA on days 3 and 5, and by micro-CT on day 5. After 3 days of treatment with AR28, mRNA levels of beta-catenin, Runx2, Osterix, Col1 alpha 1, and ALP were increased leading to higher osteoblast numbers compared to vehicle-treated animals. BMP-2 and Wnt16 mRNA levels were downregulated by mechanical instability and this was rescued by GSK-3 beta inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3 beta inhibition, which correlated with enhanced OPG mRNA expression. This was accompanied by decreased serum levels of TRAP5b on days 3 and 5. Treatment with AR28 upregulated osteoblast differentiation, while osteoclastogenesis was blunted, leading to increased bone mass by day 5. These data suggest that GSK-3 beta inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability-induced osteolysis.

    Download full text (pdf)
    fulltext
  • 10.
    Andersson, Rolf G
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Bartonek, M
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lindström, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lindström, I M
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Toll, Johan B
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Studies of the mechanism of desensitization of anti-IgE-mediated histamine release from human basophils1989In: Agents and actions, ISSN 0065-4299, Vol. 27, no 1-2, p. 25-28Article in journal (Refereed)
    Abstract [en]

    Human basophils became hyporesponsive to anti-IgE when exposed to this agent in the absence of Ca2+ for more than 10 min. The desensitization process proceeded in parallel to the releasing-process. The mechanism of desensitization seems to involve a very early step in the release-reaction, since the response to phospholipase A2 and diolein, agents involved in the release-reaction, was not affected by the desensitization.

  • 11.
    Augier, Eric
    et al.
    Linköping University, Center for Social and Affective Neuroscience (CSAN). Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S.
    NIAAA, MD USA.
    Rauffenbart, Caroline
    NIAAA, MD USA.
    Augier, Gaelle
    Linköping University, Center for Social and Affective Neuroscience (CSAN). Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cross, Alan J.
    AstraZeneca Neurosci, MA USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats2016In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, no 12, p. 2932-2940Article in journal (Refereed)
    Abstract [en]

    Group II metabotropic glutamate receptors (mGluR2 and mGluR3) may control relapse of alcohol seeking, but previously available Group II agonists were unable to discriminate between mGluR2 and mGluR3. Here we use AZD8529, a novel positive allosteric mGluR2 modulator, to determine the role of this receptor for alcohol-related behaviors in rats. We assessed the effects of AZD8529 (20 and 40 mg/kg s.c.) on male Wistar rats trained to self-administer 20% alcohol and determined the effects of AZD8529 on self-administration, as well as stress-induced and cue-induced reinstatement of alcohol seeking. The on-target nature of findings was evaluated in Indiana P-rats, a line recently shown to carry a mutation that disrupts the gene encoding mGluR2. The behavioral specificity of AZD8529 was assessed using self-administration of 0.2% saccharin and locomotor activity tests. AZD8529 marginally decreased alcohol self-administration at doses that neither affected 0.2% saccharin self-administration nor locomotor activity. More importantly, cue- but not stress-induced alcohol seeking was blocked by the mGluR2 positive allosteric modulator. This effect of AZD8529 was completely absent in P rats lacking functional mGluR2s, demonstrating the receptor specificity of this effect. Our findings provide evidence fora causal role of mGluR2 in cue induced relapse to alcohol seeking. They contribute support for the notion that positive allosteric modulators of mGluR2 block relapse-like behavior across different drug categories.

  • 12.
    Augier, Eric
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Dulman, Russell S.
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training2017In: Journal of Visualized Experiments, E-ISSN 1940-087X, no 119, article id e53305Article in journal (Refereed)
    Abstract [en]

    Operant oral self-administration methods are commonly used to study the reinforcing properties of ethanol in animals. However, the standard methods require saccharin/sucrose fading, water deprivation and/or extended training to initiate operant responding in rats. This paper describes a novel and efficient method to quickly initiate operant responding for ethanol that is convenient for experimenters and does not require water deprivation or saccharin/sucrose fading, thus eliminating the potential confound of using sweeteners in ethanol operant self-administration studies. With this method, Wistar rats typically acquire and maintain self-administration of a 20% ethanol solution in less than two weeks of training. Furthermore, blood ethanol concentrations and rewards are positively correlated for a 30 min self-administration session. Moreover, naltrexone, an FDA-approved medication for alcohol dependence that has been shown to suppress ethanol self-administration in rodents, dose-dependently decreases alcohol intake and motivation to consume alcohol for rats self-administering 20% ethanol, thus validating the use of this new method to study the reinforcing properties of alcohol in rats.

  • 13.
    Augier, Gaëlle
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Schwabl, Veronika
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Lguensat, Asmae
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Atudorei, Mihai
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Iyere, Osamudiamen
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Eriksson Solander, Sandra
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Eric
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wistar rats choose alcohol over social interaction in a discrete-choice model2023In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 48, p. 1098-1107Article in journal (Refereed)
    Abstract [en]

    Animal models of substance use disorders have been criticized for their limited translation. One important factor behind seeking and taking that has so far been largely overlooked is the availability of alternative non-drug rewards. We recently reported that only about 15% of outbred Wistar rats will choose alcohol over a sweet solution of saccharin. It was also shown using a novel operant model of choice of drugs over social rewards that social interaction consistently attenuates self-administration and incubation of craving for stimulants and opioids. Whether this is also true for alcohol and choice of alcohol over a sweet reward translates to social rewards is currently unknown. We therefore evaluated choice between alcohol and a social reward in different experimental settings in both male and female Wistar rats. We found, in contrast to prior work that employed discrete choice of drugs vs. social reward, that rats almost exclusively prefer alcohol over social interaction, irrespective of the nature of the social partner (cagemate vs. novel rat), the length of interaction, housing conditions and sex. Alcohol choice was reduced when the response requirement for alcohol was increased. However, rats persisted in choosing alcohol, even when the effort required to obtain it was 10-16 times higher (for females and males respectively) than the one for the social reward. Altogether, these results indicate that the social choice model may not generalize to alcohol, pointing to the possibility that specific interactions between alcohol and social reward, not seen when a sweet solution is used as an alternative to the drug, may play a crucial role in alcohol vs. social choice experiments.

    Download full text (pdf)
    fulltext
  • 14.
    Azharuddin, Mohammad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology.
    Dhara, Ashis Kumar
    Natl Inst Technol Durgapur, India.
    Jain, Mayur Vilas
    Lund Univ, Sweden.
    D´arcy, Padraig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Slater, Nigel K. H.
    Univ Cambridge, England.
    Patra, Hirak Kumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Cambridge, England.
    Dissecting multi drug resistance in head and neck cancer cells using multicellular tumor spheroids2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 20066Article in journal (Refereed)
    Abstract [en]

    One of the hallmarks of cancers is their ability to develop resistance against therapeutic agents. Therefore, developing effective in vitro strategies to identify drug resistance remains of paramount importance for successful treatment. One of the ways cancer cells achieve drug resistance is through the expression of efflux pumps that actively pump drugs out of the cells. To date, several studies have investigated the potential of using 3-dimensional (3D) multicellular tumor spheroids (MCSs) to assess drug resistance; however, a unified system that uses MCSs to differentiate between multi drug resistance (MDR) and non-MDR cells does not yet exist. In the present report we describe MCSs obtained from post-diagnosed, pre-treated patient-derived (PTPD) cell lines from head and neck squamous cancer cells (HNSCC) that often develop resistance to therapy. We employed an integrated approach combining response to clinical drugs and screening cytotoxicity, monitoring real-time drug uptake, and assessing transporter activity using flow cytometry in the presence and absence of their respective specific inhibitors. The report shows a comparative response to MDR, drug efflux capability and reactive oxygen species (ROS) activity to assess the resistance profile of PTPD MCSs and two-imensional (2D) monolayer cultures of the same set of cell lines. We show that MCSs provide a robust and reliable in vitro model to evaluate clinical relevance. Our proposed strategy can also be clinically applicable for profiling drug resistance in cancers with unknown resistance profiles, which consequently can indicate benefit from downstream therapy.

    Download full text (pdf)
    fulltext
  • 15. Order onlineBuy this publication >>
    Aziz, Abdul Maruf Asif
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.

    The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.

    In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced “hangover” anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats.  Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.

    In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.

    In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for motivation to work for alcohol and reinstatement of alcohol-seeking behavior. Treatment with CYM-9840 (10 mg/kg) potently attenuated alcohol SA, progressive ratio responding and stress-induced reinstatement using yohimbine as the stressor, while alcohol cue-induced reinstatement was unaffected. Moreover, a range of control behaviors including taste sensitivity, locomotor and pharmacological sensitivity to the sedative effects of alcohol remained unaffected by CYM-9840 pretreatment, indicating that its effects are specific to the rewarding and motivational aspects of alcohol-intake and related behaviors. CYM-9840 also reversed acute alcohol withdrawal-induced “hangover” anxiety measured in the EPM and reduced alcohol-intake in the 4 hour limited access two-bottle free choice preference drinking model.

    Finally, in the fourth study (Paper IV), the selective MCH1-R antagonist GW803430 was tested in rat models of escalated alcohol-intake. Pretreatment with GW803430 (effective at 10 & 30 mg/kg) dose-dependently reduced alcohol and food-intake in rats that consumed high amounts of alcohol during IA, while it only decreased food-intake in rats that consumed low amounts of alcohol during IA, likely due to a floor effect. Upon protracted abstinence following IA, GW803430 significantly reduced operant alcohol SA and this was associated with adaptations in MCH and MCH1-R gene-expression. In contrast, GW803430 did not affect escalated alcohol SA induced by chronic alcohol vapor exposure and this was accompanied by no change in MCH or MCH1-R gene expression. Overall, these results suggest that the MCH1-R antagonist affects alcohol-intake through regulation of both motivation for caloric-intake and the rewarding properties of alcohol.

    In conclusion, our results suggest critical roles for these central neuropeptides in the regulation of anxiety and of alcohol reward, making them potential pharmacological targets in the treatment of AUD.

    List of papers
    1. The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Open this publication in new window or tab >>The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
    Show others...
    2016 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 19-20, p. 3553-3563Article in journal (Refereed) Published
    Abstract [en]

    RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

    OBJECTIVES: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

    RESULTS: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

    CONCLUSION: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

    Place, publisher, year, edition, pages
    Springer, 2016
    Keywords
    Nociception/orphanin FQ, Agonist, Wistar rat, Alcohol, Operant, Reinstatement, Elevated plus-maze
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-132347 (URN)10.1007/s00213-016-4385-8 (DOI)000383672500006 ()27515665 (PubMedID)
    Note

    Funding Agencies|National Institutes of Health [R01-DA035055]; Swedish Research Council [2010-3219]

    Available from: 2016-11-12 Created: 2016-11-01 Last updated: 2017-08-21Bibliographically approved
    2. Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Open this publication in new window or tab >>Melanin-Concentrating Hormone and Its MCH-1 Receptor: Relationship Between Effects on Alcohol and Caloric Intake
    Show others...
    2016 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, no 10, p. 2199-2207Article in journal (Refereed) Published
    Abstract [en]

    Background: Reward and energy homeostasis are both regulated by a network of hypothalamic neuropeptide systems. The melanin-concentrating hormone (MCH) and its MCH-1 receptor (MCH1-R) modulate alcohol intake, but it remains unknown to what extent this reflects actions on energy balance or reward. Here, we evaluated the MCH1-R in regulation of caloric intake and motivation to consume alcohol in states of escalated consumption.

    Methods: Rats had intermittent access (IA) to alcohol and were divided into high- and low-drinking groups. Food and alcohol consumption was assessed after administration of an MCH1-R antagonist, GW803430. Next, GW803430 was evaluated on alcohol self-administration in protracted abstinence induced by IA in high-drinking rats. Finally, the effect of GW803430 was assessed on alcohol self-administration in acute withdrawal in rats exposed to alcohol vapor. Gene expression of MCH and MCH1-R was measured in the hypothalamus and nucleus accumbens (NAc) in both acute and protracted abstinence.

    Results: High-drinking IA rats consumed more calories from alcohol than chow and GW803430 decreased both chow and alcohol intake. In low-drinking rats, only food intake was affected. In protracted abstinence from IA, alcohol self-administration was significantly reduced by pretreatment with GW803430 and gene expression of both MCH and the MCH1-R were dysregulated in hypothalamus and NAc. In contrast, during acute withdrawal from vapor exposure, treatment with GW803430 did not affect alcohol self-administration, and no changes in MCH or MCH1-R gene expression were observed.

    Conclusions: Our data suggest a dual role of MCH and the MCH1-R in regulation of alcohol intake, possibly through mechanisms involving caloric intake and reward motivation. A selective suppression of alcohol self-administration during protracted abstinence by GW803430 was observed and accompanied by adaptations in gene expression of MCH and MCH1-R. Selective suppression of escalated consumption renders the MCH1-R an attractive target for treatment of alcohol use disorders.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2016
    Keywords
    Alcohol Escalation, Reward, Motivation, Calorie Intake, Melanin-Concentrating Hormone Receptor-1
    National Category
    Substance Abuse
    Identifiers
    urn:nbn:se:liu:diva-132522 (URN)10.1111/acer.13181 (DOI)000385542900017 ()27579857 (PubMedID)
    Available from: 2016-11-14 Created: 2016-11-13 Last updated: 2018-03-19Bibliographically approved
    Download full text (pdf)
    Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders
    Download (pdf)
    omslag
    Download (jpg)
    presentationsbild
  • 16.
    Backberg, Matilda
    et al.
    RISE Res Inst Sweden, Sweden.
    Vikingsson, Svante
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, SE-58758 Linkoping, Sweden; RTI Int, NC 27709 USA.
    Strandberg, Joakim
    Publ Hlth Agcy Sweden, Sweden.
    Wall, Sara
    Publ Hlth Agcy Sweden, Sweden.
    Åstrand, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Hanna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Persson, Mattias
    Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, SE-58758 Linkoping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, SE-58758 Linkoping, Sweden.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, SE-58758 Linkoping, Sweden.
    Using in vitro receptor activity studies of synthetic cannabinoids to support the risk assessment of new psychoactive substances-A Swedish strategy to protect public health from harm2023In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 348, article id 111691Article in journal (Refereed)
    Abstract [en]

    In the past 15 years, close to 1000 of new psychoactive substances (NPS) have been reported in Europe and globally. At the time of identification, data on safety, toxicity and carcinogenic potential of many NPS are not available or very limited. To work more efficiently, a strategy and collaboration between the Public Health Agency of Sweden (PHAS) and the National Board of Forensic Medicine was established involving in vitro receptor activity assays to demonstrate neurological activity of NPS. This report summarizes the first results on the synthetic cannabinoid receptor agonists (SCRAs), and subsequent actions taken by PHAS. A total of 18 potential SCRAs were selected by PHAS for in vitro pharmacological characterization. 17 compounds could be acquired and investigated for their activity on the human cannabinoid-1 (CB1) receptors expressed together with the AequoScreen system in CHO-K1 cells. Dose-response curves were established using eight different concentrations in triplicates at three occasions with JWH-018 as reference. For the MDMB-4enPINACA, MMB-022, ACHMINACA, ADB-BUTINACA, 5F-CUMYL-PeGACLONE, 5C-AKB48, NM-2201, 5FCUMYL-PINACA, JWH-022, 5Cl-AB-PINACA, MPhP-2201, 5F-AKB57 the half maximal effective concentration values ranged from 2.2 nM (5F-CUMYL-PINACA) to 171 nM (MMB-022). EG-018 and 3,5-AB-CHMFUPPYCA were none-active. The results contributed to 14 of these compounds being scheduled as narcotics in Sweden. In conclusion, many of the emerging SCRAs are potent activators of the CB1 receptor in vitro, although some lack activity or are partial agonists. The new strategy proved useful when data on psychoactive effects of the SCRAs under investigation were not available or limited. (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

    Download full text (pdf)
    fulltext
  • 17.
    Baginski, Steven R.
    et al.
    Univ Dundee, Scotland.
    Rautio, Tobias
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nisbet, Lorna A.
    Univ Dundee, Scotland.
    Lindbom, Karin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Dahlén, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Mckenzie, Craig
    Univ Dundee, Scotland; Chiron AS, Norway.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    The metabolic profile of the synthetic cannabinoid receptor agonist ADB-HEXINACA using human hepatocytes, LC-QTOF-MS and synthesized reference standards2023In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403Article in journal (Refereed)
    Abstract [en]

    Synthetic cannabinoid receptor agonists (SCRAs) remain a major public health concern, with their use implicated in intoxications and drug-related deaths worldwide. Increasing our systematic understanding of SCRA metabolism supports clinical and forensic toxicology casework, facilitating the timely identification of analytical targets for toxicological screening procedures and confirmatory analysis. This is particularly important as new SCRAs continue to emerge on the illicit drug market. In this work, the metabolism of ADB-HEXINACA (ADB-HINACA, N-[1-amino-3,3-dimethyl-1-oxobutan-2-yl]-1-hexyl-1H-indazole-3-carboxamide), which has increased in prevalence in the United Kingdom and other jurisdictions, was investigated using in vitro techniques. The (S)-enantiomer of ADB-HEXINACA was incubated with pooled human hepatocytes over 3 hours to identify unique and abundant metabolites using liquid chromatography-quadrupole time-of-flight mass spectrometry. In total, 16 metabolites were identified, resulting from mono-hydroxylation, di-hydroxylation, ketone formation (mono-hydroxylation then dehydrogenation), carboxylic acid formation, terminal amide hydrolysis, dihydrodiol formation, glucuronidation and combinations thereof. The majority of metabolism took place on the hexyl tail, forming ketone and mono-hydroxylated products. The major metabolite was the 5-oxo-hexyl product (M9), while the most significant mono-hydroxylation product was the 4-hydroxy-hexyl product (M8), both of which were confirmed by comparison to in-house synthesized reference standards. The 5-hydroxy-hexyl (M6) and 6-hydroxy-hexyl (M7) metabolites were not chromatographically resolved, and the 5-hydroxy-hexyl product was the second largest mono-hydroxylated metabolite. The structures of the terminal amide hydrolysis products without (M16, third largest metabolite) and with the 5-positioned ketone (M13) were also confirmed by comparison to synthesized reference standards, along with the 4-oxo-hexyl metabolite (M11). The 5-oxo-hexyl and 4-hydroxy-hexyl metabolites are suggested as biomarkers for ADB-HEXINACA consumption.

  • 18.
    Bengtsson, Ulf
    et al.
    Linköping University, Department of Management and Engineering. Linköping University, Faculty of Science & Engineering.
    Hylander, Lars D.
    Swedish University of Agriculture Science, Sweden.
    Increased mercury emissions from modern dental amalgams2017In: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 30, no 2, p. 277-283Article in journal (Refereed)
    Abstract [en]

    All types of dental amalgams contain mercury, which partly is emitted as mercury vapor. All types of dental amalgams corrode after being placed in the oral cavity. Modern high copper amalgams exhibit two new traits of increased instability. Firstly, when subjected to wear/polishing, droplets rich in mercury are formed on the surface, showing that mercury is not being strongly bonded to the base or alloy metals. Secondly, high copper amalgams emit substantially larger amounts of mercury vapor than the low copper amalgams used before the 1970s. High copper amalgams has been developed with focus on mechanical strength and corrosion resistance, but has been sub-optimized in other aspects, resulting in increased instability and higher emission of mercury vapor. This has not been presented to policy makers and scientists. Both low and high copper amalgams undergo a transformation process for several years after placement, resulting in a substantial reduction in mercury content, but there exist no limit for maximum allowed emission of mercury from dental amalgams. These modern high copper amalgams are nowadays totally dominating the European, US and other markets, resulting in significant emissions of mercury, not considered when judging their suitability for dental restoration.

    Download full text (pdf)
    fulltext
  • 19.
    Bengtsson, Ulf
    et al.
    Linköping University, Department of Management and Engineering. Linköping University, Faculty of Science & Engineering.
    Hylander, Lars D
    Swedish University of Agriculture Science, Sweden..
    What happened in the dental offices in the 1970s and -80s?2017In: Atlas of ScienceArticle in journal (Other (popular science, discussion, etc.))
  • 20.
    Bilbao, Ainhoa
    et al.
    University of Heidelberg, Mannheim, Germany.
    Robinson, J Elliott
    Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Malanga, C J
    Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
    Spanagel, Rainer
    University of Heidelberg, Mannheim, Germany.
    Sommer, Wolfgang H
    University of Heidelberg, Mannheim, Germany.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice.2015In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, no 10, p. 850-858Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: It has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses.

    METHODS: Effects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free-choice drinking and operant alcohol self-administration paradigms.

    RESULTS: Alcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice.

    CONCLUSIONS: In a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype.

  • 21.
    Björn, Niclas
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Pharmacogenetic biomarkers for chemotherapy-induced adverse drug reactions2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancer is a serious disease expected to be the world-leading cause of death in the 21st century. The use of harsh chemotherapies is motivated and accepted but, unfortunately, is often accompanied by severe toxicity and adverse drug reactions (ADRs). These occur because the classical chemotherapies’ common modes of action effectively kill and/or reduce the growth rate not only of tumour cells, but also of many other rapidly dividing healthy cells in the body. There are also considerable interindividual differences in ADRs, even between patients with similar cancers and disease stage treated with equal doses; some experience severe to life-threatening ADRs after one dose, leading to treatment delays, adjustments, or even discontinuation resulting in suboptimal treatment, while others remain unaffected through all treatment cycles. Being able to predict which patients are at high or low risk of ADRs, and to adjust doses accordingly before treatment, would probably decrease toxicity and patient suffering while also increasing treatment tolerability and effects. In this thesis, we have used next-generation sequencing (NGS) and bioinformatics for the prediction of myelosuppressive ADRs in lung and ovarian cancer patients treated with gemcitabine/carboplatin and paclitaxel/carboplatin.

    Paper I shows that ABCB1 and CYP2C8 genotypes have small effects inadequate for stratification of paclitaxel/carboplatin toxicity. This supports the transition to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Papers II and IV, respectively, use WES and WGS, and demonstrate that genetic variation in or around genes involved in blood cell regulation and proliferation, or genes differentially expressed at chemotherapy exposure, can be used in polygenic prediction models for stratification of gemcitabine/carboplatininduced myelosuppression. Paper III reassuringly shows that WES and WGS are concordant and mostly yield comparable genotypes across the exome. Paper V proves that single-cell RNA sequencing of hematopoietic stem cells is a feasible method for elucidating differential transcriptional effects induced as a response to in vitro chemotherapy treatment.

    In conclusion, our results supports the transition to genome-wide approaches using WES, WGS, and RNA sequencing to establish polygenic models that combine effects of multiple pharmacogenetic biomarkers for predicting chemotherapy-induced ADRs. This approach could be applied to improve risk stratification and our understanding of toxicity and ADRs related to other drugs and diseases. We hope that our myelosuppression prediction models can be refined and validated to facilitate personalized treatments, leading to increased patient wellbeing and quality of life.

    List of papers
    1. ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
    Open this publication in new window or tab >>ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
    2018 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 3, p. 277-287Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    WILEY, 2018
    National Category
    Urology and Nephrology
    Identifiers
    urn:nbn:se:liu:diva-150852 (URN)10.1111/bcpt.12997 (DOI)000441237300009 ()29504705 (PubMedID)
    Note

    Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; ALF grants Region Ostergotland; Oasmia Pharmaceuticals AB, Uppsala, Sweden

    Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2020-08-18
    2. Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
    Open this publication in new window or tab >>Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
    Show others...
    2020 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, no 2, p. 179-191Article in journal (Refereed) Published
    Abstract [en]

    Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2020
    National Category
    Cancer and Oncology Medical Genetics Pharmacology and Toxicology Medicinal Chemistry
    Identifiers
    urn:nbn:se:liu:diva-162137 (URN)10.1038/s41397-019-0099-8 (DOI)000521728100003 ()
    Note

    Funding agencies:  Swedish Cancer SocietySwedish Cancer Society; Swedish Research CouncilSwedish Research Council; ALF grants Region ostergotland; Radiumhemmet; Marcus Borgstroms stiftelse; Spanish Ministry of Economy and Competitiveness [SAF2015-64850-R]; Science for Life 

    Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2024-01-26Bibliographically approved
    3. Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples
    Open this publication in new window or tab >>Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples
    Show others...
    2018 (English)In: Journal of Next Generation Sequencing & Applications, ISSN 2469-9853, Vol. 5, no 1, p. 1-8Article in journal (Refereed) Published
    Abstract [en]

    Whole exome sequencing (WES) has been extensively used in genomic research. As sequencing costs decline it is being replaced by whole genome sequencing (WGS) in large-scale genomic studies, but more comparative information on WES and WGS datasets would be valuable. Thus, we have extensively compared variant calls obtained from WGS and WES of matched germline DNA samples from 96 lung cancer patients. WGS provided more homogeneous coverage with higher genotyping quality, and identified more variants, than WES, regardless of exome coverage depth. It also called more reference variants, reflecting its power to call rare variants, and more heterozygous variants that met applied quality criteria, indicating that WGS is less prone to allelic drop outs. However, increasing WES coverage reduced the discrepancy between the WES and WGS results. We believe that as sequencing costs further decline WGS will become the method of choice even for research confined to the exome.

    Keywords
    Whole genome sequencing; Whole exome sequencing; Coverage; Depth; Genotyping quality; Discordant; Concordant; Variant calls; Single-nucleotide variants
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:liu:diva-155840 (URN)
    Note

    DOI not working/activated: https://doi.org/10.4172/2469-9853.1000154

    Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2020-08-18Bibliographically approved
    4. Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients
    Open this publication in new window or tab >>Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients
    Show others...
    2020 (English)In: npj Systems Biology and Applications, ISSN 2056-7189, Vol. 6, no 1, article id 25Article in journal (Refereed) Published
    Abstract [en]

    Gemcitabine/carboplatin chemotherapy commonly induces myelosuppression, including neutropenia, leukopenia, and thrombocytopenia. Predicting patients at risk of these adverse drug reactions (ADRs) and adjusting treatments accordingly is a long-term goal of personalized medicine. This study used whole-genome sequencing (WGS) of blood samples from 96 gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients and gene network modules for predicting myelosuppression. Association of genetic variants in PLINK found 4594, 5019, and 5066 autosomal SNVs/INDELs with p ≤ 1 × 10−3 for neutropenia, leukopenia, and thrombocytopenia, respectively. Based on the SNVs/INDELs we identified the toxicity module, consisting of 215 unique overlapping genes inferred from MCODE-generated gene network modules of 350, 345, and 313 genes, respectively. These module genes showed enrichment for differentially expressed genes in rat bone marrow, human bone marrow, and human cell lines exposed to carboplatin and gemcitabine (p < 0.05). Then using 80% of the patients as training data, random LASSO reduced the number of SNVs/INDELs in the toxicity module into a feasible prediction model consisting of 62 SNVs/INDELs that accurately predict both the training and the test (remaining 20%) data with high (CTCAE 3–4) and low (CTCAE 0–1) maximal myelosuppressive toxicity completely, with the receiver-operating characteristic (ROC) area under the curve (AUC) of 100%. The present study shows how WGS, gene network modules, and random LASSO can be used to develop a feasible and tested model for predicting myelosuppressive toxicity. Although the proposed model predicts myelosuppression in this study, further evaluation in other studies is required to determine its reproducibility, usability, and clinical effect.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2020
    Keywords
    Cancer, Genetic interaction, Systems analysis
    National Category
    Medical Genetics Bioinformatics and Systems Biology Cancer and Oncology
    Identifiers
    urn:nbn:se:liu:diva-168465 (URN)10.1038/s41540-020-00146-6 (DOI)000568927100001 ()32839457 (PubMedID)2-s2.0-85089776223 (Scopus ID)
    Note

    Funding agencies: Swedish Cancer Society, the Swedish Research Council, Linköping University, ALF grants Region Östergötland, the Funds of Radiumhemmet, Marcus Borgströms stiftelse, Stiftelsen Assar Gabrielssons Fond

    Available from: 2020-08-24 Created: 2020-08-24 Last updated: 2021-01-15Bibliographically approved
    5. Single-Cell RNA Sequencing of Hematopoietic Stem and Progenitor Cells Treated with Gemcitabine and Carboplatin.
    Open this publication in new window or tab >>Single-Cell RNA Sequencing of Hematopoietic Stem and Progenitor Cells Treated with Gemcitabine and Carboplatin.
    2020 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 11, no 5, article id E549Article in journal (Refereed) Published
    Abstract [en]

    Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The understanding of how human bone marrow is affected on a transcriptional level leading to the development of myelosuppression is required for the implementation of personalized treatments in the future. In this study, we treated human hematopoietic stem and progenitor cells (HSPCs) harvested from a patient with chronic myelogenous leukemia (CML) with gemcitabine/carboplatin. Thereafter, scRNA-seq was performed to distinguish transcriptional effects induced by gemcitabine/carboplatin. Gene expression was calculated and evaluated among cells within and between samples compared to untreated cells. Cell cycle analysis showed that the treatments effectively decrease cell proliferation, indicated by the proportion of cells in the G2M-phase dropping from 35% in untreated cells to 14.3% in treated cells. Clustering and t-SNE showed that cells within samples and between treated and untreated samples were affected differently. Enrichment analysis of differentially expressed genes showed that the treatments influence KEGG pathways and Gene Ontologies related to myeloid cell proliferation/differentiation, immune response, cancer, and the cell cycle. The present study shows the feasibility of using scRNA-seq and chemotherapy-treated HSPCs to find genes, pathways, and biological processes affected among and between treated and untreated cells. This indicates the possible gains of using single-cell toxicity studies for personalized medicine.

    Place, publisher, year, edition, pages
    MDPI, 2020
    Keywords
    adverse drug reactions, carboplatin, gemcitabine, hematopoietic stem and progenitor cells, myelosuppression, single-cell RNA sequencing, toxicity
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-165784 (URN)10.3390/genes11050549 (DOI)000542276700061 ()32422951 (PubMedID)2-s2.0-85085064537 (Scopus ID)
    Note

    Funding agencies:  Swedish Cancer SocietySwedish Cancer Society; Swedish Research CouncilSwedish Research Council; Linkoping University; ALF grants Region Ostergotland; Familjen Carl och Albert Molins i Motala minne

    Available from: 2020-05-25 Created: 2020-05-25 Last updated: 2020-08-18Bibliographically approved
    Download full text (pdf)
    Pharmacogenetic biomarkers for chemotherapy-induced adverse drug reactions
    Download (png)
    presentationsbild
  • 22.
    Björn, Niclas
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Sigurgeirsson, Benjamín
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
    Svedberg, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Pradhananga, Sailendra
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Lewensohn, Rolf
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    de Petris, Luigi
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Apellániz-Ruiz, Maria
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Rodríguez-Antona, Cristina
    Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Lundeberg, Joakim
    Science for Life Laboratory, Division of Gene Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden.
    Gréen, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia2020In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 20, no 2, p. 179-191Article in journal (Refereed)
    Abstract [en]

    Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

    Download full text (pdf)
    fulltext
  • 23.
    Björnsson, Bergthor
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Borrebaeck, Carl
    Lund Univ, Sweden.
    Elander, Nils
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Gasslander, Thomas
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Gawel, Danuta
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Jornsten, Rebecka
    Univ Gothenburg, Sweden; Chalmers Univ Technol, Sweden.
    Jung Lee, Eun Jung
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Yonsei Univ, South Korea.
    Li, Xinxiu
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health.
    Lilja, Sandra
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health.
    Martinez, David
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Matussek, Andreas
    Karolinska Univ Hosp, Sweden; Dept Lab Med, Sweden.
    Sandström, Per
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Schäfer, Samuel
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health.
    Stenmarker, Margaretha
    Futurum Acad Hlth and Care, Sweden; Inst Clin Sci, Sweden.
    Sun, Xiao-Feng
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Sysoev, Oleg
    Linköping University, Department of Computer and Information Science, The Division of Statistics and Machine Learning. Linköping University, Faculty of Arts and Sciences.
    Zhang, Huan
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health.
    Benson, Mikael
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health.
    Digital twins to personalize medicine2020In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 12, no 1, article id 4Article in journal (Other academic)
    Abstract [en]

    Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.

    Download full text (pdf)
    fulltext
  • 24.
    Blomgran, Parmis
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing2017In: Muscles, ligaments and Tendons journal, ISSN 2240-4554, Vol. 7, no 2, p. 223-229Article in journal (Refereed)
    Abstract [en]

    Background: During early tendon healing, the cells within the regenerating tissue are, to a large part, inflammatory leukocytes (CD45+). In a rat Achilles tendon healing model, the inflammation resolves between 5 and 10 days. In the same model, Cox inhibitors (NSAIDs) impair healing when given during the first 5 days, but have a positive effect if given later. We tested the hypothesis that a Cox inhibitor would exert these effects by influencing inflammation, and thereby the composition of the inflammatory cell subpopulations.Methods: Achilles tendon transection was performed in 44 animals. Animals were randomized to either parecoxib or saline injections. Healing was evaluated by mechanical testing day 7 after surgery and by flow cytometry day 3 and 10.Results: Cross-sectional area, peak force and stiffness were reduced by parecoxib 31, 33, and 25% respectively (p=0.005, p=0.002, and p=0.005). By flow cytometry, there was a strong effect of time (p<0.001) on virtually all inflammatory cell subpopulations (CD45, CD11b, CD68, CCR7, CD163, CD206, CD3, CD4), but no significant effect of parecoxib at any time point.Conclusion: The results suggest that the negative effects of Cox inhibitors on tendon healing might be exerted mainly via mechanisms not directly related to inflammatory cells.

    Download full text (pdf)
    fulltext
  • 25. Order onlineBuy this publication >>
    Boknäs, Niklas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Studies on interfaces between primary and secondary hemostasis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Our conceptual understanding of hemostasis is still heavily influenced by outdated experimental models wherein the hemostatic activity of platelets and coagulation factors are understood and studied in isolation. Although perhaps convenient for researchers and clinicians, this reductionist view is negated by an ever increasing body of evidence pointing towards an intimate relationship between the two phases of hemostasis, marked by strong interdependence. In this thesis, I have focused on factual and proposed interfaces between primary and secondary hemostasis, and on how these interfaces can be studied.

    In my first project, we zoomed in on the mechanisms behind the well-known phenomenon of thrombin-induced platelet activation, an important event linking secondary to primary hemostasis. In our study, we examined how thrombin makes use of certain domains for high-affinity binding to substrates, called exosite I and II, to activate platelets via PAR4. We show that thrombin-induced platelet activation via PAR4 is critically dependent on exosite II, and that blockage of exosite II with different substances virtually eliminates PAR4 activation. Apart from providing new insights into the mechanisms by which thrombin activates PAR4, these results expand our knowledge of the antithrombotic actions of various endogenous proteins such as members of the serpin superfamily, which inhibit interactions with exosite II. Additionally, we show that inhibition of exosite II could be a feasible pharmacological strategy for achieving selective blockade of PAR4.

    In my second project, we examined the controversial issue of whether platelets can initiate the coagulation cascade by means of contact activation, a hypothesis which, if true, could provide a direct link between primary and secondary hemostasis. In contrast to previous results, our findings falsify this hypothesis, and show that some of the erroneous conclusions drawn from earlier studies can be explained by inappropriate experimental models unsuitable for the study of plateletcoagulation interfaces.

    My third project comprised an assessment of the methodological difficulties encountered when trying to measure the ability of platelets to initiate secondary hemostasis by the release of microparticles expressing tissue factor. Our study shows that the functional assays available for this purpose are highly susceptible to error caused by artificial contact activation. These results could help to improve the methodology of future research and thus pave the way for new insights into the roles of tissue factor-bearing microparticles in the pathophysiology of various thrombotic disorders.

    From a personal perspective, my PhD project has been a fascinating scientific odyssey into the largely unexplored interfaces between primary and secondary hemostasis. Looking forward, my ambition is to continue our work exploring platelet-coagulation interactions and to translate these insights into clinically meaningful information, which may someday improve the treatment of patients with bleeding and/or thrombosis.

    List of papers
    1. Thrombin-induced platelet activation via PAR4: pivotal role for exosite II
    Open this publication in new window or tab >>Thrombin-induced platelet activation via PAR4: pivotal role for exosite II
    Show others...
    2014 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 112, no 3, p. 558-565Article in journal (Refereed) Published
    Abstract [en]

    Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with alpha- and gamma-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ib alpha.

    Place, publisher, year, edition, pages
    Schattauer Gmbh, 2014
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-111269 (URN)10.1160/TH13-12-1013 (DOI)000341547000015 ()24990072 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2010-65X-15060-07-3, K2013-65X-15060-10-3]; Swedish Heart and Lung Foundation [20100219, 20120263]

    Available from: 2014-10-15 Created: 2014-10-14 Last updated: 2023-08-28Bibliographically approved
    2. Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII
    Open this publication in new window or tab >>Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII
    Show others...
    2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 23, p. 3818-3824Article in journal (Refereed) Published
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Muller et al has been cited greater than100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of less than10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-104301 (URN)10.1182/blood-2013-05-499384 (DOI)000329735000021 ()
    Available from: 2014-02-17 Created: 2014-02-14 Last updated: 2020-01-23
    3. Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions
    Open this publication in new window or tab >>Response: platelets do not generate activated factor XII--how inappropriate experimental models have led to misleading conclusions
    Show others...
    2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 10, p. 1692-1694Article in journal, Letter (Other academic) Published
    Place, publisher, year, edition, pages
    American Society of Hematology, 2014
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-111531 (URN)10.1182/blood-2014-04-566067 (DOI)000342762300027 ()25190755 (PubMedID)
    Available from: 2014-10-22 Created: 2014-10-22 Last updated: 2020-01-23Bibliographically approved
    4. Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid-containing reagents
    Open this publication in new window or tab >>Contact activation: important to consider when measuring the contribution of tissue factor-bearing microparticles to thrombin generation using phospholipid-containing reagents
    2014 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 4, p. 515-518Article in journal (Refereed) Published
    Abstract [en]

    Background A commercial MP reagent containing phospholipids is used for thrombin generation (TG) measurements to estimate the procoagulant activity of microparticles (MPs). Previous reports have shown that contact activation affects TG when TF levels are low, and that addition of phospholipids might augment this effect. Objectives To quantify the impact of contact activation on TG in the presence of phospholipids and low/no TF, as is the case using a commercially available MP-reagent. Methods Thrombin generation was analyzed using MP- or platelet-rich plasma (PRP)-reagent in the presence and absence of corn trypsin inhibitor and anti-TF antibodies, respectively. To quantify the impact of different experimental parameters on contact activation, microparticle-depleted plasma was analyzed in the presence of different concentrations of phospholipids, TF and/or contact activating agents (kaolin). Results Even with low contact activating blood collection tubes, substantial thrombin generation was observed with the MP-reagent, but this was completely inhibited by addition of corn trypsin inhibitor. Control experiments illustrate that the phospholipids in the reagent play a major role in enhancing TG initiated by FXIIa. Even with the PRP-reagent, which is recommended for determining the content of phospholipids from MPs, TG was partly dependent on contact activation. Conclusions Contact activation plays a major role in TG when using reagents/samples containing phospholipids but little or no tissue factor. This needs to be considered and accounted for in future clinical studies using TG to assess the procoagulant activity of MPs.

    Place, publisher, year, edition, pages
    Wiley, 2014
    Keywords
    cell-derived microparticles; thromboplastin; blood coagulation; thrombin; factor XII
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-106682 (URN)10.1111/jth.12503 (DOI)000334157000012 ()
    Available from: 2014-05-21 Created: 2014-05-19 Last updated: 2020-01-23
    Download full text (pdf)
    Studies on interfaces between primary and secondary hemostasis
    Download (pdf)
    omslag
    Download (jpg)
    presentationsbild
  • 26.
    Bosagna, Carlos Guerrero
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Developmental and Epigenetic Origins of Male Reproductive Pathologies2015In: The Epigenome and Developmental Origins of Health and Disease / [ed] Cheryl Rosenfeld, Elsevier, 2015, 1, p. 171-189Chapter in book (Refereed)
    Abstract [en]

    Transgenerational epigenetic inheritance has gained increased attention due to the possibility that exposure to environmental toxicants or other stressors can induce long-lasting changes in lineages of organisms. The mechanism involves exposure of pregnant females and induction of germline epigenetic alterations in their developing embryos. This early developmental exposure generates phenotypic alterations in the adults. The germline epigenomic changes produced are then transmitted to future generations and associate with disease phenotypes in the unexposed individuals of subsequent generations. Exposures to environmental toxicants such as fungicides, pesticides, or plastic compounds have been shown in rodents to produce abnormal reproductive or metabolic phenotypes that are transgenerationally transmitted. These include transgenerational increases in the incidence of obesity, polycystic ovary syndrome (PCOS)-like symptoms, pregnancy defects, or germ cell apoptosis. Importantly, the increased incidence of these transgenerationally transmitted diseases in response to environmental exposures in animal models is sometimes drastic. The current evidence on transgenerational epigenetic inheritance observed in animal models allows predicting that environmental exposures of today's inhabitants of the world may affect the incidence of noninfectious diseases in future generations, which would be correlated with long-lasting alterations in the epigenome. The present chapter summarizes the evidence to date for transgenerational epigenetic inheritance, in both humans and animal models.

  • 27.
    Bouwman, Henk
    et al.
    North-Wast University, South Africa.
    Kylin, Henrik
    Linköping University, The Tema Institute, Department of Water and Environmental Studies. Linköping University, Faculty of Arts and Sciences.
    Sereda, Barbara
    Plant Protection Research Institute, South Africa.
    Bornman, Rianna
    University of Pretoria, South Africa.
    DDT IN BREAST MILK: INTAKE, GENDER, AND DURATION OF LACTATION2011Conference paper (Other academic)
    Download full text (pdf)
    fulltext
  • 28.
    Brito, Haissa Oliveira
    et al.
    Univ Fed Parana, Brazil.
    Radulski, Debora
    Univ Fed Parana, Brazil.
    Wilhelms, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine in Linköping.
    Stojakovic, Andrea
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Oliveira Brito, Luciane Maria
    Univ Fed Maranhao, Brazil.
    Gil da Costa, Rui Miguel
    Univ Fed Maranhao, Brazil.
    Trindade, Edvaldo
    Univ Fed Parana, Brazil.
    Engblom, David
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Cavichiolo Franco, Celia Regina
    Univ Fed Parana, Brazil.
    Zampronio, Aleksander Roberto
    Univ Fed Parana, Brazil.
    Immune-mediated febrile response in female rats: Role of central hypothalamic mediators2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 4073Article in journal (Refereed)
    Abstract [en]

    Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor kappa B ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 mu g/kg) intraperitoneally or CRF (2.5 mu g), ET-1 (1 pg), morphine (10 mu g) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 mu g, intracerebroventricularly). Expression of RANK, CRFI/II, ETB, mu-opioid (MOR) and NK1 receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.

    Download full text (pdf)
    fulltext
  • 29.
    Börjesson, Stefan
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Natl Vet Inst SVA, Sweden.
    Greko, Christina
    Natl Vet Inst SVA, Sweden.
    Myrenas, Mattias
    Natl Vet Inst SVA, Sweden.
    Landen, Annica
    Natl Vet Inst SVA, Sweden.
    Nilsson, Oskar
    Natl Vet Inst SVA, Sweden.
    Pedersen, Karl
    Natl Vet Inst SVA, Sweden.
    A link between the newly described colistin resistance gene mcr-9 and clinical Enterobacteriaceae isolates carrying bla(SHV-12) from horses in Sweden2020In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 20, p. 285-289Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to investigate the occurrence of the newly described transferable colistin resistance gene mcr-9 in extended-spectrum beta-lactamase (ESBL)-producing clinical Enterobacteriaceae isolates from horses in Sweden. Methods: A total of 56 whole-genome sequenced ESBL-producing Enterobacteriaceae isolates from horses were subjected to in silico detection of antimicrobial resistance genes and identification of plasmid replicons types. The colistin minimum inhibitory concentration (MIC) for mcr-positive isolates was determined by broth microdilution. Relatedness between Enterobacteriaceae carrying mcr genes was determined by multilocus sequence typing (MLST) and core genome MLST. Results: Thirty ESBL-producing Enterobacteriaceae isolates from horses were positive for the colistin resistance gene mcr-9. These isolates included Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca and Citrobacter freundii and belonged to diverse MLST sequence types within each species. Two of the mcr-9-containing isolates originated from the same horse. All mcr-9-positive isolates had colistin MICs below or equal to the EUCAST epidemiological cut-off value of 2 mg/L and were negative for the two potential regulatory genes qseB-like and qseC-like for mcr-9. Except for one isolate carrying only bla(TEM-1B), all of the isolates carried bla(SHV-12) and bla(TEM-1B), and were all considered multidrug-resistant as they harboured genes encoding resistance to aminoglycosides, chloramphenicol, fosfomycin, macrolides, quinolones, sulfonamides, trimethoprim and tetracyclines. Plasmid replicon types IncHI2 and IncHI2A were detected in all mcr-9-positive isolates. Conclusion: The occurrence of mcr-9 was common among clinical ESBL-producing Enterobacteriaceae isolates from horses in Sweden and was linked to the ESBL-encoding gene bla(SHV-12) and plasmid replicon types IncHI2 and IncHI2A. (C) 2019 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

    Download full text (pdf)
    fulltext
  • 30.
    Cambra, J. M.
    et al.
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Martinez Serrano, Cristina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Martinez, E. A.
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Cuello, C.
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Gil, M. A.
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    N-(2-mercaptopropionyl)-glycine enhances in vitro pig embryo production and reduces oxidative stress2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18632Article in journal (Refereed)
    Abstract [en]

    This study evaluated the effects of different concentrations (1, 10, 25, 50, and 100 mu M) of the antioxidant N-(2-mercaptopropionyl)-glycine (NMPG), during the culture of in vitro-fertilized porcine oocytes. While the highest concentrations of NMPG (50 and 100 mu M) were toxic to the developing embryos during the first two days of culture, 25 mu M NMPG achieved cleavage rates that were similar to those achieved by the control but did not sustain blastocyst production by Day 7 of culture. Compared to the control culture medium, the culture medium supplemented with 10 mu M NMPG increased (P&lt;0.05) the rates of blastocyst formation, decreased (P&lt;0.05) the intracellular levels of reactive oxygen substances, and downregulated (P&lt;0.05) the expression of the oxidative stress related gene GPX1. In conclusion, these results demonstrated that supplementation of porcine embryo culture medium with 10 &lt;mu&gt;M NMPG can attenuate oxidative stress and increase the yield of in vitro production of blastocysts.

    Download full text (pdf)
    fulltext
  • 31. Order onlineBuy this publication >>
    Chalise, Jaya Prakash
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Immune tolerance by interferon-alpha in experimental arthritis2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type I Interferons (mainly IFN-α & IFN-β) belong to a family of cytokines that possess strong antiviral and immunomodulatory properties. Pro- and/or anti-inflammatory effects of type I IFN have been observed in infectious diseases and several autoimmune diseases including SLE, MS, RA and experimental models thereof, but what defines either outcome is largely obscure. The main aim of this thesis is to understand how IFN-α may act anti-inflammatory in a model of antigen-induced arthritis (AIA). In this model, mice are sensitised with methylated-BSA (mBSA) emulsified in Freund’s adjuvant at day 1 and 7 followed by intra-articular injection of mBSA in the knee joint at day 21, which induces arthritis within 1 week.

    Administration of IFN-α at the time of mBSA sensitisations (day 1 and day 7) but not at induction of arthritis (day 21) clearly protected against arthritis in a type I IFN receptor dependent manner. Humoral immunity might not be involved in this protection as the levels of antigen-specific IgG (total, IgG1, IgG2a and IgG2b), IgA, IgE in serum were not altered in IFN-α treated mice. However, IFN-α-protection was accompanied by delayed and decreased antigen-specific proliferative responses in spleen and lymph node cells ex vivo, including impaired proliferative recall responses after intra-articular antigenic challenge.

    In the course of AIA, IFN-α inhibited the increase of circulatory IL-6, IL-10, IL-12, and TNF in the sensitisation phase (day 0-21) and also the re-call response of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 induced by intra-articular mBSA challenge in arthritis phase (day 21-28). This IFN-α-inhibition of cytokines was also apparent in mBSA-re-stimulated spleen and lymph node cell cultures ex vivo, including inhibited cytokine production in CD4+ T helper cells and macrophages. In contrast to the inhibition of pro-inflammatory cytokines, the levels of immunomodulatory TGF-β was clearly enhanced in IFN-α-treated mice, both in serum and in re-stimulated leucocytes cultures including both macrophages, especially in the sensitisation phase, and in CD4+ T cells in the arthritis phase. By  inhibiting TGF-β signalling in vivo, the protective effect of IFN-α was  shown to be dependent on TGF-β signalling in the sensitisation phase.

    The cytokine TGF-β is an activator of the indoleamine 2,3 dioxygnese (IDO1), a potent immuneregulatory component that acts via enzymatic production of kynurenine (Kyn) and signalling activity. The IFN-α-protective effect in AIA was associated with both increased expression and enzymatic activity of IDO1 and the IFN-α-protection was totally ablated in mice lacking IDO1 expression (IDO1 KO mice) and in mice treated with the inhibitor of the enzymatic activity of IDO1 (1-Methyl Tryptophan; 1-MT). Interestingly, administration of the IDO-metabolite Kyn protected mice from AIA in an IFNARindependent manner. These observations show that the IDO1 enzymatic activity is important for the protective effect of IFN-α. Using 1-MT, it was further shown that the enzymatic activity of IDO1 was, like TGF-β, crucial only at the sensitisation but not in the arthritis phase of AIA for IFN-α to protect against arthritis. Instead, IDO1’s non-enzymatic signalling activity, characterized by sustained expression of IDO1 and non-canonical NF-κB activation in pDCs, was observed in the arthritis phase in spleen cells from mice treated with IFN-α.

    Regulatory T cells (Treg cells) were also found to be important for IFN-α-protection in AIA. Transient depletion of Treg cells by diphtheria toxin in DEREG mice in the arthritis phase, but not during the sensitisation phase abolished IFN-α-protection. Treatment with IFN-α enhanced the numbers of Treg cells in the course of AIA and their function; compared to untreated mice, Treg cells isolated at day 10 and 20 of AIA from IFN-α- treated mice exhibited higher suppressive activity against mBSA-stimulated proliferation of responder T cells. The enhancing effect of IFN-α on Treg cell numbers was observed in blood, spleen, LNs and also in ex-vivo cultures of leucocytes re-stimulated with mBSA and IFN-α. Although IFN-α clearly increased the suppressive activity of Treg cells, adoptive transfer of Treg cells from mBSA immunized mice, regardless of IFN-α treatment, prevented the development of arthritis.

    Conclusion

    In the presence of IFN-α during antigen sensitisation, a state of tolerance is established, which is able to prevent joint inflammation induced by antigenic re-challenge. This immunological tolerance is created in the sensitisation phase of AIA and is characterized by inhibition of pro-inflammatory cytokines, increased TGF-β production and activity of the IDO1 enzyme, the latter two being indispensable for IFN-α-induced protection. Administration of Kyn, the metabolite of the enzymatic activity of IDO1, in the sensitisation phase also protected against AIA downstream of type I IFN signalling. In the arthritis phase regulatory T cells, whose numbers and suppressive capacity was clearly enhanced by IFN-α, mediate the actual prevention of arthritis development in IFN-α-treated animals. We have thus identified molecular and cellular components of the anti-inflammatory program elicited by IFN-α including Kyn that may not have the pro-inflammatory effects associated with IFN.

    List of papers
    1. Type I IFN protects against antigen-induced arthritis
    Open this publication in new window or tab >>Type I IFN protects against antigen-induced arthritis
    2011 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 6, p. 1687-1695Article in journal (Refereed) Published
    Abstract [en]

    Autoimmune diseases including rheumatoid arthritis (RA) involve immune reactions against specific antigens. The type I IFN system is suspected to promote autoimmunity in systemic lupus erythematosus, but may also dampen immune reactions in e. g. inflammatory bowel disease. This prompted us to investigate the role of type I IFN in antigen-induced arthritis (AIA). The importance of type I IFN in methylated (m) BSA-induced arthritis was studied by using mice deficient for the type I IFN receptor (IFNAR) and by administration of the IFN-alpha activator viral double-stranded (ds) RNA or recombinant IFN-alpha at antigen sensitization. In IFNAR knock-out mice, arthritis severity was significantly higher than in WT mice. Administration of dsRNA at antigen sensitization protected WT but not IFNAR KO mice from arthritis. Also, addition of recombinant IFN-alpha during the immunization, but not the induction phase of arthritis, almost abolished arthritis. Protection mediated by IFN-alpha was accompanied by delayed and decreased antigen-specific proliferative responses, including impaired lymph node recall responses after intra-articular antigenic challenge. In conclusion, we demonstrate that type I IFN can prevent joint inflammation by downregulating antigen-specific cellular immunity.

    Place, publisher, year, edition, pages
    John Wiley and Sons, Ltd, 2011
    Keywords
    Arthritis; Tolerance; Type I IFN
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-69898 (URN)10.1002/eji.201040956 (DOI)000291559700019 ()
    Available from: 2011-08-09 Created: 2011-08-08 Last updated: 2017-12-08
    2. Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis
    Open this publication in new window or tab >>Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis
    2013 (English)In: Arthritis Research and Therapy, ISSN 1478-6354, Vol. 15, no 5, p. R143-Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Interferon alpha (IFN-α) has a complex role in autoimmunity, in that it may both enhance and prevent inflammation. We have previously shown that the presence of IFN-α at sensitization protects against subsequent antigen-triggered arthritis. To understand this tolerogenic mechanism, we performed a descriptive, hypothesis-generating study of cellular and humoral responses associated with IFN-α-mediated protection against arthritis.Methods: Arthritis was evaluated at day 28 in mice given a subcutaneous injection of methylated bovine serum albumin (mBSA), together with Freund adjuvant and 0 to 5,000 U IFN-α at days 1 and 7, followed by intraarticular injection of mBSA alone at day 21. The effect of IFN-α on mBSA-specific IgG1, IgG2a, IgG2b, IgA, and IgE was evaluated by enzyme-linked immunosorbent assay (ELISA). Cytokines in circulation and in ex vivo cultures on mBSA restimulation was evaluated with ELISA and Luminex, and the identity of cytokine-producing cells by fluorescence-activated cell sorting (FACS) analysis.Results: Administration of IFN-α protected mice from arthritis in a dose-dependent manner but had no effect on antigen-specific antibody levels. However, IFN-α did inhibit the initial increase of IL-6, IL-10, IL-12, and TNF, and the recall response induced by intraarticular mBSA challenge of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 in serum. IFN-α decreased both macrophage and CD4+ T cell-derived IFN-γ production, whereas IL-17 was decreased only in CD4+ T cells. Ex vivo, in mBSA-restimulated spleen and lymph node cell cultures, the inhibitory effect of in vivo administration of IFN-α on proinflammatory cytokine production was clearly apparent, but had a time limit. An earlier macrophage-derived, and stronger activation of the antiinflammatory cytokine transforming growth factor beta (TGF-β) was observed in IFN-α-treated animals, combined with an increase in CD4+ T cells producing TGF-β when arthritis was triggered by mBSA (day 21). Presence of IFN-α at immunizations also prevented the reduction in TGF-β production, which was induced by the intraarticular mBSA injection triggering arthritis in control animals.Conclusions: Administration of IFN-α has a profound effect on the cellular response to mBSA plus adjuvant, but does not affect antigen-specific Ig production. By including IFN-α at immunizations, spleen and lymph node cells inhibit their repertoire of antigen-induced proinflammatory cytokines while enhancing antiinflammatory TGF-β production, first in macrophages, and later also in CD4+ T cells. On intraarticular antigen challenge, this antiinflammatory state is reenforced, manifested as inhibition of proinflammatory recall responses and preservation of TGF-β levels. This may explain why IFN-α protects against antigen-induced arthritis. © 2013 Chalise et al.; licensee BioMed Central Ltd.

    Place, publisher, year, edition, pages
    London, UK: BioMed Central, 2013
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102367 (URN)10.1186/ar4326 (DOI)000329737400043 ()
    Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2015-11-03Bibliographically approved
    3. IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritis
    Open this publication in new window or tab >>IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Interferon-α (IFN-α) prevents antigen-induced arthritis (AIA) in mice by an unknown mechanism. Indoleamine 2, 3 dioxygenase 1 (IDO1) is an immunoregulator via enzymatic as well as signalling activity, which can be activated by TGF-β and further mediated via non canonical NF-κB signalling. We here investigated whether IDO1 and TGF-β are involved in IFN-α protective effects in AIA. Arthritis was induced in wt, Ido1-/- or Ifnar-/- mice, treated or not with IFN-α or kynurenine, the main IDO1 product, and antibodies neutralizing TGF-β or 1-methyltryptophan (1-MT), an inhibitor of IDO1 catalytic activity. IDO1 expression and enzymatic activity were determined by RT-PCR and HPLC, respectively. Proliferation was measured by 3H-Thymidine incorporation. Non-canonical NF-κB signalling was evaluated by ELISA and Western blot in plasmacytoid DCs (pDCs) from treated mice. Protective effects of IFN-α in AIA were associated with increased IDO1 expression and kynurenine production in spleen cells, particularly at the time of mBSA sensitization. Lack of IDO1 ablated IFN-α protection and kynurenine prevented AIA in an IFNAR-independent manner. The IDO1 catalytic activity was crucial for IFN-α effects at the sensitization but not effector phase of AIA. The disease effector phase in mice treated with IFN-α was instead characterized by sustained IDO1 and TGF-β expression and activation of the noncanonical NF-κB pathway in pDCs. IFN-α protective effects in AIA involves IDO1 enzymatic and signalling activity in the disease sensitization and effector phase, respectively. Kynurenine, the main IDO1 metabolite, can be used as an alternative treatment to IFN-α in protecting mice from AIA.

    National Category
    Pharmacology and Toxicology Rheumatology and Autoimmunity Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-122461 (URN)
    Funder
    Swedish Research CouncilSwedish Rheumatism AssociationLinköpings universitet
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-01-10Bibliographically approved
    4. Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritis
    Open this publication in new window or tab >>Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction

    Type I interferon induces tolerance against arthritogenic antigen and protects against antigen induced arthritis (AIA). Regulatory T cells (Treg cells) resolve aberrant immune reaction, maintain self-tolerance and prevent the development of autoimmune diseases. We here investigated the impact of Interferon alpha (IFN-α) on Treg cells development and function during antigen induced arthritis.

    Methods

    For AIA, mice were immunized with methylated bovine serum albumin (mBSA) at day 1 and 7 in presence or absence of IFN-α. At day 21, arthritis was induced by intra-articular injection of mBSA and arthritis was evaluated at day 28. At various days of AIA, CD4, CD25, Foxp3 and CTLA-4 expression was quantified by FACS in blood cells, splenocytes, lymph nodes cells and in ex vivo re-stimulated leucocytes (pooled splenocytes and lymph nodes cells) isolated at same days. To investigate the importance of Treg cells in IFN-α protection in AIA, Foxp3DTReGFP+mice were used, where Treg cells can be depleted transiently by administration of diptherin toxin. CFSE based suppression assay was used to assess the suppression by Treg cells isolated day 4, 10, 20 of AIA against proliferation of mBSA or anti-CD3 stimulated responder T cells (Tresp cells) isolated at same days. For adoptive transfer experiments, 250,000 Treg cells from IFN-α treated or untreated mice day 20 of AIA were intravenously injected to recipient pre-immunized mice without IFN-α treatment during the induction of arthritis. The importance of IFN-α signalling on T cells for the IFN-α protection was evaluated by using CD4-Cre+/- IFNAR flox/flox mice.

    Results

    Protective effects of IFN-α in AIA were associated with significant TGF-β dependent increase in Foxp3+ T cells in blood at day 4 and minor increase of Foxp3+T cells in spleen and lymph node cells. However IFN-α signalling in T cells is not required for IFN-α-protection. Upon ex vivo re-stimulation in presence of IFN-α with mBSA but not anti-CD3, the Treg cells numbers were increased in leucocytes isolated from day 4 and day 10 of AIA. Transient depletion of Treg cells during induction of arthritis (day 21) abolished IFN-α-protection however the protection was not affected when Treg cells are depleted during immunization phase (day 1 and day 7). Against mBSA-stimulated proliferation of Tresp cells, suppression by Treg cells isolated from day 10 and day 20 from IFN-α treated mice are significantly higher than Treg cells from untreated mice. Treg cells isolated from IFN-α or untreated mice at day 20 of AIA when transferred to pre-immunized untreated mice prevent the development of arthritis.

    Conclusion

    Treg cells are critically associated with IFN-α protective effects in AIA. IFN-α enhances TGF-β dependent early development of Treg cells and later IFN-α enhances their suppressive capacity against T cells proliferation in antigen specific manner during AIA.

    Keywords
    Interferon alpha, regulatory T cells, antigen induced arthritis, TGF-beta
    National Category
    Pharmacology and Toxicology Rheumatology and Autoimmunity Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-122462 (URN)
    Funder
    Swedish Research CouncilSwedish Rheumatism AssociationLinköpings universitet
    Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2018-01-10Bibliographically approved
    Download full text (pdf)
    fulltext
    Download (pdf)
    omslag
    Download (jpg)
    presentationsbild
  • 32.
    Chalise, Jaya Prakash
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Chenna Narendra, Sudeep
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Biggs, Sophie
    Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kalinke, Ulrich
    Twincore, Germany.
    Iacono, Alberta
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Boon, Louis
    EPIRUS Biopharmaceuticals, Utrecht, Netherlands.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritisManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction

    Type I interferon induces tolerance against arthritogenic antigen and protects against antigen induced arthritis (AIA). Regulatory T cells (Treg cells) resolve aberrant immune reaction, maintain self-tolerance and prevent the development of autoimmune diseases. We here investigated the impact of Interferon alpha (IFN-α) on Treg cells development and function during antigen induced arthritis.

    Methods

    For AIA, mice were immunized with methylated bovine serum albumin (mBSA) at day 1 and 7 in presence or absence of IFN-α. At day 21, arthritis was induced by intra-articular injection of mBSA and arthritis was evaluated at day 28. At various days of AIA, CD4, CD25, Foxp3 and CTLA-4 expression was quantified by FACS in blood cells, splenocytes, lymph nodes cells and in ex vivo re-stimulated leucocytes (pooled splenocytes and lymph nodes cells) isolated at same days. To investigate the importance of Treg cells in IFN-α protection in AIA, Foxp3DTReGFP+mice were used, where Treg cells can be depleted transiently by administration of diptherin toxin. CFSE based suppression assay was used to assess the suppression by Treg cells isolated day 4, 10, 20 of AIA against proliferation of mBSA or anti-CD3 stimulated responder T cells (Tresp cells) isolated at same days. For adoptive transfer experiments, 250,000 Treg cells from IFN-α treated or untreated mice day 20 of AIA were intravenously injected to recipient pre-immunized mice without IFN-α treatment during the induction of arthritis. The importance of IFN-α signalling on T cells for the IFN-α protection was evaluated by using CD4-Cre+/- IFNAR flox/flox mice.

    Results

    Protective effects of IFN-α in AIA were associated with significant TGF-β dependent increase in Foxp3+ T cells in blood at day 4 and minor increase of Foxp3+T cells in spleen and lymph node cells. However IFN-α signalling in T cells is not required for IFN-α-protection. Upon ex vivo re-stimulation in presence of IFN-α with mBSA but not anti-CD3, the Treg cells numbers were increased in leucocytes isolated from day 4 and day 10 of AIA. Transient depletion of Treg cells during induction of arthritis (day 21) abolished IFN-α-protection however the protection was not affected when Treg cells are depleted during immunization phase (day 1 and day 7). Against mBSA-stimulated proliferation of Tresp cells, suppression by Treg cells isolated from day 10 and day 20 from IFN-α treated mice are significantly higher than Treg cells from untreated mice. Treg cells isolated from IFN-α or untreated mice at day 20 of AIA when transferred to pre-immunized untreated mice prevent the development of arthritis.

    Conclusion

    Treg cells are critically associated with IFN-α protective effects in AIA. IFN-α enhances TGF-β dependent early development of Treg cells and later IFN-α enhances their suppressive capacity against T cells proliferation in antigen specific manner during AIA.

  • 33.
    Chalise, Jaya Prakash
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Pallotta, Maria Teresa
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Chenna Narendra, Sudeep
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Iacono, Alberta
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Boon, Louis
    EPIRUS Biopharmaceuticals, Utrecht, Netherlands.
    Grohmann, Ursula
    Department of Experimental Medicine, University of Perugia, Perugia, Italy.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    IDO1 and TGF- 1 β mediate protective effects of IFN-α in antigen-induced arthritisManuscript (preprint) (Other academic)
    Abstract [en]

    Interferon-α (IFN-α) prevents antigen-induced arthritis (AIA) in mice by an unknown mechanism. Indoleamine 2, 3 dioxygenase 1 (IDO1) is an immunoregulator via enzymatic as well as signalling activity, which can be activated by TGF-β and further mediated via non canonical NF-κB signalling. We here investigated whether IDO1 and TGF-β are involved in IFN-α protective effects in AIA. Arthritis was induced in wt, Ido1-/- or Ifnar-/- mice, treated or not with IFN-α or kynurenine, the main IDO1 product, and antibodies neutralizing TGF-β or 1-methyltryptophan (1-MT), an inhibitor of IDO1 catalytic activity. IDO1 expression and enzymatic activity were determined by RT-PCR and HPLC, respectively. Proliferation was measured by 3H-Thymidine incorporation. Non-canonical NF-κB signalling was evaluated by ELISA and Western blot in plasmacytoid DCs (pDCs) from treated mice. Protective effects of IFN-α in AIA were associated with increased IDO1 expression and kynurenine production in spleen cells, particularly at the time of mBSA sensitization. Lack of IDO1 ablated IFN-α protection and kynurenine prevented AIA in an IFNAR-independent manner. The IDO1 catalytic activity was crucial for IFN-α effects at the sensitization but not effector phase of AIA. The disease effector phase in mice treated with IFN-α was instead characterized by sustained IDO1 and TGF-β expression and activation of the noncanonical NF-κB pathway in pDCs. IFN-α protective effects in AIA involves IDO1 enzymatic and signalling activity in the disease sensitization and effector phase, respectively. Kynurenine, the main IDO1 metabolite, can be used as an alternative treatment to IFN-α in protecting mice from AIA.

  • 34.
    Chen, Ricky Hao
    et al.
    Univ Sydney, Australia.
    Michael, Toni
    Univ Sydney, Australia.
    Kuhlin, Johanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Schön, Thomas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Infectious Diseases.
    Stocker, Sophie
    Univ Sydney, Australia; St Vincents Hosp, Australia; Univ New South Wales, Australia.
    Alffenaar, Jan-Willem C.
    Univ Sydney, Australia; Westmead Hosp, Australia.
    Is there a need to optimise pyrazinamide doses in patients with tuberculosis? A systematic review2023In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 62, no 3, article id 106914Article, review/survey (Refereed)
    Abstract [en]

    Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment responses. This systematic review, conducted according to PRISMA guidelines, aimed to evaluate the concentration-effect relationship. In vitro/in vivo studies had to contain information on the infection model, PZA dose and concentration, and microbiological outcome. Human studies had to present information on PZA dose, measures of drug exposure and maximum concentration, and microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed, including in vitro (n = 2), in vivo (n = 3) and clinical studies (n = 29). Intracellular and extracellular models demonstrated a direct correlation between PZA dose of 15-50 mg/kg/day and reduction in bacterial count between 0.50-27.7 log(10) CFU/mL. Consistent with this, higher PZA doses (&gt;150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between PZA dose (i.e. 21.4-35.7 mg/kg/day) and drug exposure (AUC range 220.6-514.5 mg center dot h/L). Additionally, human studies confirmed a dose-effect relationship, with an increased 2-month sputum culture conversion rate at AUC/MIC targets of 8.4-11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at PZA dose of 25 mg/kg. A direct concentration-effect relationship and increased treatment efficacy with higher PZA exposure to susceptibility ratios was observed. Taking into account variability in drug exposure and treatment response, further studies on dose optimisation are justified.

  • 35. Order onlineBuy this publication >>
    Chenna Narendra, Sudeep
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future.

    Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis.

    Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.

    List of papers
    1. Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
    Open this publication in new window or tab >>Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
    2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 10, p. e0141863-Article in journal (Refereed) Published
    Abstract [en]

    Objective Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis. Methods Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice preimmunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint. Results Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium. Conclusion Local, but not systemic administration of uridine efficiently prevented development of antigen- induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2015
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-123070 (URN)10.1371/journal.pone.0141863 (DOI)000363920300089 ()26512984 (PubMedID)
    Note

    Funding Agencies|Vetenskapsradet-Grant [521-2011-3095]; Reumatikerforbundet Grant [155261]; County Council of Ostergotland, Sweden; Linkoping University

    Available from: 2015-12-04 Created: 2015-12-03 Last updated: 2021-06-14
    2. IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
    Open this publication in new window or tab >>IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
    Show others...
    2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 197, no 8, p. 3142-3151Article in journal (Refereed) Published
    Abstract [en]

    IFN-alpha prevents Ag-induced arthritis (AIA), and in this study we investigated the role of IDO1 and TGF-beta signaling for this anti-inflammatory property of IFN-alpha. Arthritis was induced by methylated BSA (mBSA) in mBSA-sensitized wild-type (WT), Ido1(-/-), or Ifnar(-/-) mice, treated or not with IFN-alpha or the IDO1 product kynurenine (Kyn). Enzymatic IDO1 activity, TGF-beta, and plasmacytoid dendritic cells (pDC) were neutralized by 1-methyltryptophan and Abs against TGF-beta and pDC, respectively. IDO1 expression was determined by RT-PCR, Western blot, and FACS, and enzymatic activity by HPLC. Proliferation was measured by H-3-thymidine incorporation and TGF-beta by RT-PCR and ELISA. WT but not Ido1(-/-) mice were protected from AIA by IFN-alpha, and Kyn, the main IDO1 product, also prevented AIA, both in WTand Ifnar(-/-) mice. Protective treatment with IFN-alpha increased the expression of IDO1 in pDC during AIA, and Ab-mediated depletion of pDC, either during mBSA sensitization or after triggering of arthritis, completely abrogated the protective effect of IFN-alpha. IFN-alpha treatment also increased the enzymatic IDO1 activity (Kyn/tryptophan ratio), which in turn activated production of TGF-beta. Neutralization of enzymatic IDO1 activity or TGF-beta signaling blocked the protective effect of IFN-alpha against AIA, but only during sensitization and not after triggering of arthritis. Likewise, inhibition of the IDO1 enzymatic activity in the sensitization phase, but not after triggering of arthritis, subdued the IFN-alpha-induced inhibition of mBSA-induced proliferation. In conclusion, presence of IFN-alpha at Ag sensitization activates an IDO1/TGF-beta-dependent anti-inflammatory program that upon antigenic rechallenge prevents inflammation via pDC.

    Place, publisher, year, edition, pages
    AMER ASSOC IMMUNOLOGISTS, 2016
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-133121 (URN)10.4049/jimmunol.1502125 (DOI)000387965100018 ()27647832 (PubMedID)
    Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2019-02-11
    3. Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
    Open this publication in new window or tab >>Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
    2014 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 95, no 4, p. 661-666Article in journal (Refereed) Published
    Abstract [en]

    Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis. Here, we show, by immunohistochemistry, that cells expressing the pan-DC marker CD11c and the pDC marker 120G8 are present in the inflamed synovium in dsRNA-induced arthritis. Flt3L-generated and splenic DCs preactivated with dsRNA before intra-articular injection, but not mock-stimulated cells, clearly induced arthritis. Induction of arthritis was dependent on type I IFN signaling in the donor DCs, whereas IFNAR expression in the recipient was not required. Sorting of the Flt3L-DC population into cDCs (CD11c(+), PDCA-1(-)) and pDCs (CD11c(+), PDCA-1(+)) revealed that both subtypes were arthritogenic and produced type I IFN if treated with dsRNA. Taken together, these results demonstrate that viral nucleic acids can elicit arthritis by activating type I IFN signaling in DCs. Once triggered, autocrine type I IFN signaling in dsRNA-activated DCs is sufficient to propagate arthritis.

    Place, publisher, year, edition, pages
    Society for Leukocyte Biology, 2014
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102370 (URN)10.1189/jlb.0613320 (DOI)000335346300011 ()24304616 (PubMedID)
    Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2017-12-06
    Download full text (pdf)
    fulltext
    Download (pdf)
    omslag
    Download (jpg)
    presentationsbild
  • 36. Order onlineBuy this publication >>
    Chermá Yeste, Maria Dolores
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Therapeutic Drug Monitoring in Psychiatry: Some aspects of utility in clinical practice and research2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described.

    Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study.

    The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype.

    The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug.

    Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.

    List of papers
    1. Therapeutic Drug Monitoring of Escitalopram in an outpatient setting
    Open this publication in new window or tab >>Therapeutic Drug Monitoring of Escitalopram in an outpatient setting
    2007 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 29, no 6, p. 758-766Article in journal (Refereed) Published
    Abstract [en]

    The main objectives of this study were to outline the inter- and intraindividual and overall pharmacokinetic variability of S-citalopram, S-desmethylcitalopram, and S-didesmethylcitalopram in serum by means of therapeutic drug monitoring, and to investigate potential correlations between the serum concentration and simultaneously collected clinical data. The study was conducted on outpatients in Sweden in 2002 to 2005. Included in the pharmacokinetic evaluation were 155 patients (68% women and 32% men) aged 17 to 95 years (average, 51 years). One serum sample per patient, taken as a trough value in steady state, was assessed. For the inter- and intraindividual variation calculation, 16 patients were included with two eligible samples each. The median daily dose was 20 mg/day (range, 5-40 mg). Extensive overall serum concentration variability was seen for all dose levels. The interindividual coefficient of variation for dose-normalized concentrations was 71% for S-citalopram, 36% for S-desmethylcitalopram, and 50% for S- didesmethylcitalopram. The intraindividual variations over time for the same parameters were approximately 30%, except for the ratio S-desmethylcitalopram/S- citalopram, which was 23%. The median S-desmethylcitalopram level was approximately 60% of the parent substance and the S-didesmethylcitalopram level approximately 9%. Higher age was correlated with higher serum concentrations, but no gender-related concentration differences were found. A majority (76%) of the patients took one or more drugs in addition to escitalopram, but concomitant medication did not seem to interact with escitalopram. However, women taking oral contraceptives showed a lower metabolic ratio compared with age-matched women. As a result of the wide range of the ratio in this population, these findings are not considered of clinical relevance.

    Keywords
    Escitalopram, Serum concentration, SSRI, Therapeutic drug monitoring
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-41188 (URN)10.1097/FTD.0b013e31815b3f62 (DOI)55316 (Local ID)55316 (Archive number)55316 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    2. Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
    Open this publication in new window or tab >>Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
    Show others...
    2008 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, no 6, p. 682-688Article in journal (Refereed) Published
    Abstract [en]

    There is limited information on the pharmacokinetics of ziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linkoping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20-320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L-1 mg(-1) d(-1)) for ZIP and SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively, with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for close-normalized scruin concentrations of ZIP, SMDZ, and SMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIP concentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.

    Keywords
    Antipsychotic agents, ziprasidone, therapeutic drug monitoring, serum concentration, naturalistic setting
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16195 (URN)10.1097/FTD.0b013e31818ac8ba (DOI)
    Available from: 2009-01-09 Created: 2009-01-09 Last updated: 2017-12-14Bibliographically approved
    3. Assessment of the prescription of antidepressant drugs in elderly nursing home patients
    Open this publication in new window or tab >>Assessment of the prescription of antidepressant drugs in elderly nursing home patients
    Show others...
    2008 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, no 4, p. 424-431Article in journal (Refereed) Published
    Abstract [en]

    The aim of the study was to investigate the use of antidepressant drugs among elderly people in nursing homes. Elderly residents who where found to have been prescribed at least one antidepressant drug according to the specific medication dispensing system were identified in 8 nursing homes in the county of Östergötland, Sweden. Data were collected from the medical record forms at the nursing home. Blood samples were drawn for the assessment of drug concentration, blood chemistry parameters and cytochrome P450 expression. At least one antidepressant drug was prescribed to 38% of elderly people in the nursing home studied. A total of 71 patients were evaluated, 80% women and 20% men. The median age was 84 years (range, 71-100 years). Indications for antidepressant drug treatment were found on 96% of medical record forms (depression, 60%); however, information relating to when treatment was initiated could not be found on 34% of medical record forms and a clear time schedule for how long this drug treatment was planned to continue could not be found either. A possible adverse effect of antidepressant drug treatment was retrieved in at least 77% of patients. Polypharmacotherapy was common; median number of drugs per patient was 11. Concentrations of drugs were higher than expected in 73%. Most patients were medicated with citalopram (n = 44). A clear interindividual variability of concentrations at each dose level was found for citalopram and for the metabolites desmethylcitalopram and didesmethylcitalopram. A significant correlation was found between the estimation of creatinine clearance and concentration-dose ratio of citalopram. Poor metabolizers, who had been prescribed an antidepressant drug that are substrate for the cytochrome P450 isoenzyme examined, have higher concentrations of prescribed antidepressant drug than do non-poor metabolizers in relation to dose. An increase in quality contribution to follow-up at antidepressant medications is needed. A more frequent clinical use of therapeutic drug monitoring and pharmacogenetic tests in addition to therapeutic drug monitoring may be one important tool in this process.

    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-20985 (URN)10.1097/JCP.0b013e31817d79eb (DOI)
    Available from: 2009-09-27 Created: 2009-09-27 Last updated: 2018-01-13Bibliographically approved
    4. Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
    Open this publication in new window or tab >>Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Objective: The aims of this study were to evaluate the pharmacokinetics (PKs) of antidepressant agents, in terms of steady-state and trough values, in a heterogeneous cohort of patients and to describe the utilisation of antidepressant drugs (ATDs) in Child and Adolescent Psychiatry in the south- east of Sweden.

    Method: Patients from Child and Adolescent Psychiatry centres in the counties of Östergötland, Jönköping and Kalmar (Sweden) to be prescribed an antidepressant drug, were studied between 2002 and 2004. The blood concentration of ATDs and, in some cases, also CYP2D6 were determined and relevant clinical information provided.

    Results: Two hundred and eleven children: 64 % girls and 36 % boys, between the ages of 8 and 20 were evaluated. The concentrations of drugs in the patient evaluated (PE) population were as expected from the dose administered in 63 % of this population, higher than expected in 26 % and lower than expected in 11 %.

    Dose-concentration relationships for sertraline (rs=0.48, p<0.001) and metabolite desmethylsertraline (rs=0.5, p<0.001) were seen. No relationship was found between dose and ratio desmethylsertraline-to-sertraline. CYP2D6*4 was the most common poor metabolizer (PM) allele. The primary indication for the antidepressant treatment was depression in 69 % of subjects. Suspected adverse drug reactions were spontaneously reported in 31 %. Monotherapy was indicated in 49 % of request forms. The most common drug combinations with the antidepressant drug were oral anticontraceptives and anxiolytics/sedatives/hypnotic drugs.

    Conclusion: the most prescribed antidepressant drug in children and adolescents in the present study was sertraline. The pharmacokinetic outcomes of serum concentration of sertraline, as well as daily doses administered were similar to the referenced data for adults. Antidepressant drug monotherapy was most common. No serious adverse side effects were spontaneously reported. TDM may provide support to the prescribing physicians to individual dose optimising and to assess drug compliance, above all when the antidepressant drugs are not well studied in pediatric patients before approval for general prescription. Further clinical trials, as well as naturalistic studies are necessary to ensure that children are not exposed to unnecessary risk and to determine the most appropriate dose in children of different ages.

    Keywords
    antidepressants, therapeutic drug monitoring, dosage, serum concentration, pediatrics
    National Category
    Pharmacology and Toxicology Psychiatry
    Identifiers
    urn:nbn:se:liu:diva-52106 (URN)
    Available from: 2009-12-04 Created: 2009-12-04 Last updated: 2018-01-12Bibliographically approved
    Download full text (pdf)
    Therapeutic Drug Monitoring in Psychiatry : Some aspects of utility in clinical practice and research
  • 37.
    Chermá Yeste, Maria Dolores
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Gustafsson, Per A.
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry . Linköping University, Faculty of Health Sciences.
    Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical studyManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: The aims of this study were to evaluate the pharmacokinetics (PKs) of antidepressant agents, in terms of steady-state and trough values, in a heterogeneous cohort of patients and to describe the utilisation of antidepressant drugs (ATDs) in Child and Adolescent Psychiatry in the south- east of Sweden.

    Method: Patients from Child and Adolescent Psychiatry centres in the counties of Östergötland, Jönköping and Kalmar (Sweden) to be prescribed an antidepressant drug, were studied between 2002 and 2004. The blood concentration of ATDs and, in some cases, also CYP2D6 were determined and relevant clinical information provided.

    Results: Two hundred and eleven children: 64 % girls and 36 % boys, between the ages of 8 and 20 were evaluated. The concentrations of drugs in the patient evaluated (PE) population were as expected from the dose administered in 63 % of this population, higher than expected in 26 % and lower than expected in 11 %.

    Dose-concentration relationships for sertraline (rs=0.48, p<0.001) and metabolite desmethylsertraline (rs=0.5, p<0.001) were seen. No relationship was found between dose and ratio desmethylsertraline-to-sertraline. CYP2D6*4 was the most common poor metabolizer (PM) allele. The primary indication for the antidepressant treatment was depression in 69 % of subjects. Suspected adverse drug reactions were spontaneously reported in 31 %. Monotherapy was indicated in 49 % of request forms. The most common drug combinations with the antidepressant drug were oral anticontraceptives and anxiolytics/sedatives/hypnotic drugs.

    Conclusion: the most prescribed antidepressant drug in children and adolescents in the present study was sertraline. The pharmacokinetic outcomes of serum concentration of sertraline, as well as daily doses administered were similar to the referenced data for adults. Antidepressant drug monotherapy was most common. No serious adverse side effects were spontaneously reported. TDM may provide support to the prescribing physicians to individual dose optimising and to assess drug compliance, above all when the antidepressant drugs are not well studied in pediatric patients before approval for general prescription. Further clinical trials, as well as naturalistic studies are necessary to ensure that children are not exposed to unnecessary risk and to determine the most appropriate dose in children of different ages.

  • 38.
    Chermá Yeste, Maria Dolores
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Löfgren, Ulla-Britt
    n/a.
    Almkvist, Göran
    n/a.
    Hallert, Claes
    Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland. Linköping University, Department of Social and Welfare Studies, Health, Activity, Care. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Assessment of the prescription of antidepressant drugs in elderly nursing home patients2008In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, no 4, p. 424-431Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate the use of antidepressant drugs among elderly people in nursing homes. Elderly residents who where found to have been prescribed at least one antidepressant drug according to the specific medication dispensing system were identified in 8 nursing homes in the county of Östergötland, Sweden. Data were collected from the medical record forms at the nursing home. Blood samples were drawn for the assessment of drug concentration, blood chemistry parameters and cytochrome P450 expression. At least one antidepressant drug was prescribed to 38% of elderly people in the nursing home studied. A total of 71 patients were evaluated, 80% women and 20% men. The median age was 84 years (range, 71-100 years). Indications for antidepressant drug treatment were found on 96% of medical record forms (depression, 60%); however, information relating to when treatment was initiated could not be found on 34% of medical record forms and a clear time schedule for how long this drug treatment was planned to continue could not be found either. A possible adverse effect of antidepressant drug treatment was retrieved in at least 77% of patients. Polypharmacotherapy was common; median number of drugs per patient was 11. Concentrations of drugs were higher than expected in 73%. Most patients were medicated with citalopram (n = 44). A clear interindividual variability of concentrations at each dose level was found for citalopram and for the metabolites desmethylcitalopram and didesmethylcitalopram. A significant correlation was found between the estimation of creatinine clearance and concentration-dose ratio of citalopram. Poor metabolizers, who had been prescribed an antidepressant drug that are substrate for the cytochrome P450 isoenzyme examined, have higher concentrations of prescribed antidepressant drug than do non-poor metabolizers in relation to dose. An increase in quality contribution to follow-up at antidepressant medications is needed. A more frequent clinical use of therapeutic drug monitoring and pharmacogenetic tests in addition to therapeutic drug monitoring may be one important tool in this process.

  • 39.
    de Wit, H.
    et al.
    Univ Chicago, IL 60637 USA.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Bershad, A. K.
    Univ Calif Los Angeles, CA USA.
    Does acute stress play a role in the lasting therapeutic effects of psychedelic drugs?2023In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634XArticle in journal (Refereed)
    Abstract [en]

    Psychedelic drugs, when used in the context of psychotherapy, can produce significant and long-lasting memories with enduring beneficial effects. Yet, the behavioral and neurobiological mechanisms that underlie these beneficial effects remain a mystery. Here, we suggest that both the quality and durability of memories of the drug-facilitated therapeutic experience may be mediated, in part, by the acute stress responses induced by the drugs. It is known that high doses of psychedelic drugs activate autonomic and hormonal stress responses. For evolutionarily adaptive reasons, acute stress is known to i) instill meaning to the immediate context in which it is experienced, and ii) lead to the formation of salient and lasting memories of the events surrounding the stress. Thus, the stress-inducing effect of psychedelic drugs may contribute to the reported sense of meaning, as well as the durability of the memory of the drug experience. When used in a therapeutic context these actions may i) enhance the salience of insights gained during the experience and ii) strengthen the memories formed by these experiences. Future empirical studies will help to determine whether acute stress contributes to the emotional significance and lasting effects of psychedelic-assisted psychotherapy.

  • 40.
    Deventer, Marie H.
    et al.
    Univ Ghent, Belgium.
    Persson, Mattias
    Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Laus, Antonio
    Univ Cagliari, Italy.
    Pottie, Eline
    Univ Ghent, Belgium.
    Cannaert, Annelies
    Univ Ghent, Belgium.
    Tocco, Graziella
    Univ Cagliari, Italy.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linkoping, Sweden.
    Stove, Christophe P.
    Univ Ghent, Belgium.
    Off-target activity of NBOMes and NBOMe analogs at the mu opioid receptor2023In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738Article in journal (Refereed)
    Abstract [en]

    New psychoactive substances (NPS) are introduced on the illicit drug market at a rapid pace. Their molecular targets are often inadequately elucidated, which contributes to the delayed characterization of their pharmacological effects. Inspired by earlier findings, this study set out to investigate the mu opioid receptor (MOR) activation potential of a large set of psychedelics, substances which typically activate the serotonin (5-HT2A) receptor as their target receptor. We observed that some substances carrying the N-benzyl phenethylamine (NBOMe) structure activated MOR, as confirmed by both the NanoBiT (R) beta arr2 recruitment assay and the G protein-based AequoScreen (R) Ca2+ release assay. The use of two orthogonal systems proved beneficial as some aspecific, receptor independent effects were found for various analogs when using the Ca2+ release assay. The specific off-target effects at MOR could be blocked by the opioid antagonist naloxone, suggesting that these NBOMes occupy the same common opioid binding pocket as conventional opioids. This was corroborated by molecular docking, which revealed the plausibility of multiple interactions of 25I-NBOMe with MOR, similar to those observed for opioids. Additionally, structure-activity relationship findings seen in vitro were rationalized in silico for two 25I-NBOMe isomers. Overall, as MOR activity of these psychedelics was only noticed at high concentrations, we consider it unlikely that for the tested compounds there will be a relevant opioid toxicity in vivo at physiologically relevant concentrations. However, small modifications to the original NBOMe structure may result in a panel of more efficacious and potent MOR agonists, potentially exhibiting a dual MOR/5-HT2A activation potential.

  • 41.
    Di Gennaro, Antonio
    et al.
    Karolinska Inst, Sweden.
    Araujo, Ana Carolina
    Karolinska Inst, Sweden.
    Busch, Albert
    Karolinska Inst, Sweden; Tech Univ Munich, Germany.
    Jin, Hong
    Karolinska Inst, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Caidahl, Kenneth
    Karolinska Inst, Sweden; Gothenburg Univ, Sweden.
    Eriksson, Per
    Karolinska Inst, Sweden.
    Samuelsson, Bengt
    Karolinska Inst, Sweden.
    Maegdefessel, Lars
    Karolinska Inst, Sweden; Tech Univ Munich, Germany.
    Haeggstrom, Jesper Z.
    Karolinska Inst, Sweden.
    Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 8, p. 1907-1912Article in journal (Refereed)
    Abstract [en]

    Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (amp;gt;50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.

    Download full text (pdf)
    fulltext
  • 42.
    Domi, Ana
    et al.
    Univ Camerino, Italy.
    Lunerti, Veronica
    Univ Camerino, Italy.
    Petrella, Michele
    Univ Camerino, Italy.
    Domi, Esi
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Borruto, Anna Maria
    Univ Camerino, Italy.
    Ubaldi, Massimo
    Univ Camerino, Italy.
    Weiss, Friedbert
    Scripps Res Inst, CA USA.
    Ciccocioppo, Roberto
    Univ Camerino, Italy.
    Genetic deletion or pharmacological blockade of nociceptin/orphanin FQ receptors in the ventral tegmental area attenuates nicotine-motivated behaviour2022In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 179, no 11, p. 2647-2658Article in journal (Refereed)
    Abstract [en]

    Background and Purpose The nociceptin/orphanin FQ (N/OFQ)-nociceptin opioid-like peptide (NOP) receptor system is widely distributed in the brain and pharmacological activation of this system revealed therapeutic potential in animal models of substance use disorder. Studies also showed that genetic deletion or pharmacological blockade of NOP receptors confer resistance to the development of alcohol abuse. Here, we have used a genetic and pharmacological approach to evaluate the therapeutic potential of NOP antagonism in smoking cessation. Experimental Approach Constitutive NOP receptor knockout rats (NOP-/-) and their wild-type counterparts (NOP+/+) were tested over a range of behaviours to characterize their motivation for nicotine. We next explored the effects of systemic administration of the NOP receptor antagonist LY2817412 (1.0 & 3.0 mg center dot kg(-1)) on nicotine self-administration. NOP receptor blockade was further evaluated at the brain circuitry level, by microinjecting LY2817412 (3.0 & 6.0 mu g center dot mu l(-1)) into the ventral tegmental area (VTA), nucleus accumbens (NAc) and central amygdala (CeA). Key Results Genetic NOP receptor deletion resulted in decreased nicotine intake, decreased motivation to self-administer and attenuation of cue-induced nicotine reinstatement. LY2817412 reduced nicotine intake in NOP+/+ but not in NOP-/- rats, confirming that its effect is mediated by inhibition of NOP transmission. Finally, injection of LY2817412 into the VTA but not into the NAc or CeA decreased nicotine self-administration. Conclusions and Implications These findings indicate that inhibition of NOP transmission attenuates the motivation for nicotine through mechanisms involving the VTA and suggest that NOP receptor antagonism may represent a potential treatment for smoking cessation.

  • 43.
    Domi, Esi
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Xu, Li
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Sichuan Prov Peoples Hosp, Peoples R China.
    Paetz, Marvin
    Heidelberg Univ, Germany.
    Nordeman, Anton
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Holm, Lovisa
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Toivainen, Sanne
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Eric
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Hansson, Anita C.
    Heidelberg Univ, Germany.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Nicotine increases alcohol self-administration in male rats via a mu-opioid mechanism within the mesolimbic pathway2020In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 177, no 19, p. 4516-4531Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: Alcohol and nicotine use disorders are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of mu and kappa-opioid receptors to nicotine-induced escalation of alcohol self-administration in rats. Experimental Approach: Chronic nicotine was tested on alcohol self-administration and motivation to obtain alcohol. We then tested the effect of the kappa antagonist CERC-501 and the preferential mu receptor antagonist naltrexone on basal and nicotine-escalated alcohol self-administration. To probe mu or kappa receptor adaptations, receptor binding and G-protein coupling assays were performed in reward-related brain regions. Finally, dopaminergic activity in response to alcohol was examined, using phosphorylation of DARPP-32 in nucleus accumbens as a biomarker. Key Results: Nicotine robustly induced escalation of alcohol self-administration and motivation to obtain alcohol. This was blocked by naltrexone but not by CERC-501. Escalation of alcohol self-administration was associated with decreased DAMGO-stimulated mu receptor signalling in the ventral tegmental area (VTA) and decreased pDARPP-32 in the nucleus accumbens shell in response to alcohol. Conclusions and Implications: Collectively, these results suggest that nicotine contributes to escalate alcohol self-administration through a dysregulation of mu receptor activity in the VTA. These data imply that targeting mu rather than kappa receptors may be the preferred pharmacotherapeutic approach for the treatment of alcohol use disorder when nicotine use contributes to alcohol consumption.

    Download full text (pdf)
    fulltext
  • 44.
    Eliasson, Pernilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Svensson, Rene B.
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Giannopoulos, Antonis
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Eismark, Christian
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Kjaer, Michael
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Schjerling, Peter
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Heinemeier, Katja M.
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Simvastatin and atorvastatin reduce the mechanical properties of tendon constructs in vitro and introduce catabolic changes in the gene expression pattern2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 3, article id e0172797Article in journal (Refereed)
    Abstract [en]

    Treatment with lipid-lowering drugs, statins, is common all over the world. Lately, the occurrence of spontaneous tendon ruptures or tendinosis have suggested a negative influence of statins upon tendon tissue. But how statins might influence tendons is not clear. In the present study, we investigated the effect of statin treatment on mechanical strength, cell proliferation, collagen content and gene expression pattern in a tendon-like tissue made from human tenocytes in vitro. Human tendon fibroblasts were grown in a 3D tissue culture model (tendon constructs), and treated with either simvastatin or atorvastatin, low or high dose, respectively, for up to seven days. After seven days of treatment, mechanical testing of the constructs was performed. Collagen content and cell proliferation were also determined. mRNA levels of several target genes were measured after one or seven days. The maximum force and stiffness were reduced by both statins after 7 days (pamp;lt;0.05), while the cross sectional area was unaffected. Further, the collagen content was reduced by atorvastatin (p = 0.01) and the cell proliferation rate was decreased by both types of statins (pamp;lt;0.05). Statin treatment also introduced increased mRNA levels of MMP-1, MMP-3, MMP-13, TIMP-1 and decreased levels of collagen type 1 and 3. In conclusion, statin treatment appears to have a negative effect on tendon matrix quality as seen by a reduced strength of the tendon constructs. Further, activated catabolic changes in the gene expression pattern and a reduced collagen content indicated a disturbed balance in matrix production of tendon due to statin administration.

    Download full text (pdf)
    fulltext
  • 45.
    El-Serafi, Ibrahim
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.
    Loy, Orlaith
    Karolinska Inst, Sweden.
    Zhao, Ying
    Karolinska Inst, Sweden.
    Oerther, Sandra
    Karolinska Inst, Sweden.
    Mattsson, Jonas
    Karolinska Inst, Sweden; Oslo Univ Hosp, Norway.
    Pre-formulation investigations for establishing a protocol for treosulfan handling and activation2019In: Pharmaceutical development and technology (Print), ISSN 1083-7450, E-ISSN 1097-9867, Vol. 24, no 5, p. 639-648Article in journal (Refereed)
    Abstract [en]

    Introduction: Treosulfan is an alkylating agent that is used for the treatment of ovarian cancer and for conditioning prior to stem cell transplantation. It is a prodrug that is activated non-enzymatically to two active epoxides. Objectives: To optimize a protocol for both in vivo samples handling and in vitro drug preparation. Treosulfan stability was tested in biological fluids at different conditions as well as for its cytotoxicity on cell lines. Results: Plasma samples can be safely frozen for a short period up to 8 h, however; for longer periods, samples should be acidified. Urine samples and cell culture media can be safely frozen regardless their pH. For in vitro investigations, incubation of treosulfan at 37 degrees C for 24 h activated 100% of the drug. Whole blood acidification should be avoided for the risk of hemolysis. Finally; treosulfan cytotoxicity on HL-60 cells has increased following pre-incubation for 24 h at 37 degrees C compared to K562 cell line. Conclusion: The stability profiling of treosulfan provided a valuable reference for handling of biological samples for both in vivo and in vitro studies. These results can be utilized for further investigations concerning the drug kinetics and dynamics in addition to the development of new pharmaceutical formulations.

    Download full text (pdf)
    fulltext
  • 46. Order onlineBuy this publication >>
    Eriksson, Andreas
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet Adhesion to Proteins in Microplates: Applications in Experimental and Clinical Research2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Platelets are crucial for prevention of blood loss after vessel injury. Platelet adhesion to disrupted vessel walls is mediated by receptors such as the GPIb-IX-V complex that binds von Willebrand factor and the collagen-binding integrin α2β1. Also cross-linking of platelets, mediated by αIIbβ3 that binds to fibrinogen, results in platelet aggregation that further contributes to hemostasis. Platelets are also important pathophysiologically because of their role in thrombus formation following atherosclerotic plaque rupture. Pharmacological treatments aimed to prevent such events include use of platelet inhibitors such as acetylsalicylic acid (ASA) and clopidogrel. Despite the presence of several different platelet function assays, no one has so far been considered useful for clinical evaluation of the effect of anti-platelet treatment. The aim of this thesis was to evaluate possible applications in experimental as well as in clinical research for a platelet adhesion assay performed during static conditions. In principle, platelets in plasma are allowed to attach to protein coated microplates. Adhered platelets are then detected by induction of an enzymatic reaction followed by spectrophotometric measurements of the developed product. Our results show that the platelet adhesion assay is able to detect experimentally induced activation as well as inhibition of platelets. The assay also seems useful for investigation of synergistically induced platelet activation, especially when the coated surface consists of albumin. This is exemplified by the combination of lysophosphatidic acid and adrenaline, which induced a synergistically increased platelet adhesion to albumin that was dependent on αIIbβ3-receptors and on the secretion of ADP. Furthermore, secretion of ADP as well as TXA2 seems to contribute to several adhesive reactions investigated with this assay. The dependence on secretion, together with results showing that adhesion to collagen and fibrinogen is dependent on α2β1- and αIIbβ3-receptors respectively, indicate that the adhesive interactions occurring in the assay is in accordance with the general knowledge about platelet function. Regarding clinical applications, we found that platelet adhesion was increased for patients with essential thrombocythemia (ET) compared to controls. This is in line with the in vivo function of ET-platelets since a common complication for ET-patients is thrombosis. Furthermore, the assay was able to detect effects of treatment with clopidogrel in patients with unstable angina. To some extent it also measured the effects of ASA-treatment. In conclusion, our results suggest that the assay is suitable for experimental research and that further studies should be performed aimed at developing the assay into a clinically useful device.

    List of papers
    1. Measurement of adhesion of human platelets in plasma to protein surfaces in microplates
    Open this publication in new window or tab >>Measurement of adhesion of human platelets in plasma to protein surfaces in microplates
    2005 (English)In: Journal of Pharmacological and Toxicological Methods, ISSN 1056-8719, Vol. 52, no 3, p. 356-365Article in journal (Refereed) Published
    Abstract [en]

    Introduction

    Platelet adhesion is an initial, crucial and complex event for inhibiting blood loss upon vascular injury. Activation and adhesion of platelets also play a fundamental role in the development of thrombosis. A combination of exposed extracellular matrix proteins in the vascular wall and release of activating compounds from the participating cells activate the platelets. New potent anti-platelet agents are in progress but there is a shortage of methods that measure the concerted action of adhesive surfaces and soluble compounds upon platelet adhesion in vitro. The aim of this work was to develop a method to measure adhesion of platelets in plasma with standard laboratory equipment.

    Methods

    Platelet-rich plasma from healthy humans was used in studies to optimise the conditions of the present assay. Different proteins were coated in microplate wells and various soluble platelet activators and inhibitors were added to establish the ability of the current method to detect increased as well as decreased platelet adhesion. The amount of platelet adhesion was measured by the reaction between p-nitrophenyl phosphate and the intracellular enzyme acid phosphatase.

    Results

    Adhesion of platelets in plasma to microplate wells coated with albumin, collagen, fibrinogen and activated plasma showed significant surface dependency. The known soluble platelet activators adenosine diphosphate, adrenaline and ristocetin enhanced the levels of adhesion. Available anti-platelet agents such as prostacyclin, forskolin, acetylsalicylic acid and RGD containing peptides caused dose-dependent inhibition of platelet adhesion.

    Discussion

    This report describes a further development of a previously described method and offers the advantage to use platelets in plasma to measure platelet adhesion to protein surfaces. The assay is simple and flexible and is suitable in basic research for screening and characterisation of platelet adhesion responsiveness.

    Keywords
    Antiplatelet agents; Collagen; Fibrinogen; Human; Methods; Platelet activation; Platelet adhesion; Platelet assay
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13246 (URN)10.1016/j.vascn.2005.06.002 (DOI)
    Available from: 2008-05-21 Created: 2008-05-21 Last updated: 2013-09-03
    2. Adhesion of human platelets to albumin is synergistically increased by lysophosphatidic acid and adrenaline in a donor-dependent fashion
    Open this publication in new window or tab >>Adhesion of human platelets to albumin is synergistically increased by lysophosphatidic acid and adrenaline in a donor-dependent fashion
    2006 (English)In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, Vol. 17, no 5, p. 359-368Article in journal (Refereed) Published
    Abstract [en]

    Lysophosphatidic acid (LPA) and adrenaline are weak platelet activators considered important for thrombus formation, and were previously shown to synergistically increase platelet aggregation. Here we investigate synergistic activation by LPA and adrenaline when measuring platelet adhesion. Platelet-rich plasma from healthy blood donors together with adrenaline and/or LPA were added to protein-coated microplates. Platelets were allowed to adhere and the amount of adhesion detected enzymatically. The LPA and adrenaline combination induced a synergistic increase of platelet adhesion to a normally non-adhesive albumin surface. The degree of synergy varied markedly between individuals; these variations could not be explained by age, gender, blood type or different amounts of platelets, oxidized low-density lipoprotein, insulin or glucose in plasma. There was a trend indicating increased synergistic effect for platelets sensitive to adrenaline stimulation. The synergistic effect was blocked by the α2-adrenoceptor antagonist yohimbine and inhibited by the ADP scavenger system creatine phosphate/creatine phosphokinase and antibodies against αIIbβ3. Furthermore, platelets adhering to albumin after adrenaline and LPA treatment expressed P-selectin. In conclusion, LPA and adrenaline act synergistically to increase αIIbβ3-mediated platelet adhesion to albumin, dependent on α2-adrenoceptor signalling and platelet secretion. We also confirm that synergistic platelet activation achieved with LPA and adrenaline is highly donor dependent.

    Keywords
    adrenaline, albumin, lysophosphatidic acid, platelet adhesion, synergism
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13247 (URN)10.1097/01.mbc.0000233366.18605.b2 (DOI)
    Available from: 2008-05-21 Created: 2008-05-21 Last updated: 2018-02-20
    3. Characterization of static adhesion of human platelets in plasma to protein surfaces in microplates
    Open this publication in new window or tab >>Characterization of static adhesion of human platelets in plasma to protein surfaces in microplates
    2009 (English)In: BLOOD COAGULATION and FIBRINOLYSIS, ISSN 0957-5235 , Vol. 20, no 3, p. 197-206Article in journal (Refereed) Published
    Abstract [en]

    Platelet adhesion is a complex and important event for prevention of blood loss after vessel injury. This study investigated fundamental adhesive mechanisms occurring in an in-vitro assay developed for the measurement of static adhesion of human platelets in plasma. The aim was to gain methodological knowledge that could be used for interpretations of results from other studies using this specific assay. Involvement of adhesive receptors was investigated by the use of various antibodies as well as therapeutic drugs (abciximab, eptifibatide and tirofiban). Inhibitors of adenosine 5-diphosphate receptors (cangrelor, MRS2179) and of thromboxane A(2) signalling (BM-531) were used to estimate the role of autocrine activation. Adhesion to collagen was found to be mainly mediated by alpha(2)beta(1) and to some extent by alpha(IIb)beta(3) Adhesion to fibrinogen was mediated by alpha IIb beta 3. In addition, adenosine 5-diphosphate-induced adhesion to albumin was dependent on alpha(IIb)beta(3). Furthermore, experiments with cangrelor and BM-531 showed that the majority of the adhesive interactions tested were dependent on adenosine 5-diphosphate or thromboxane A(2). We conclude that the mechanisms of adhesion measured by the static platelet adhesion assay are in accordance with the current knowledge regarding platelet activation and adhesion. Despite its simplicity, we suggest that this adhesion assay could be used as a screening device for the study of the influence of various surfaces and soluble substances on platelet adhesion.

    Keywords
    adhesion receptor, antiplatelet agents, autocrine signalling, platelet adhesion, platelet assay
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-18037 (URN)10.1097/MBC.0b013e328327353d (DOI)
    Note
    This is a non-final version of an article published in final form: Andreas Eriksson and Per Whiss , Characterization of static adhesion of human platelets in plasma to protein surfaces in microplates, 2009, BLOOD COAGULATION and FIBRINOLYSIS, (20), 3, 197-206. http://dx.doi.org/10.1097/MBC.0b013e328327353d Copyright: Lippincott Williams and Wilkins; 1999 http://www.lww.com/ Available from: 2009-05-14 Created: 2009-05-04 Last updated: 2013-09-03Bibliographically approved
    4. Enhanced platelet adhesion in essential thrombocythemia after in vitro activation
    Open this publication in new window or tab >>Enhanced platelet adhesion in essential thrombocythemia after in vitro activation
    2010 (English)In: TURKISH JOURNAL OF HEMATOLOGY, ISSN 1300-7777, Vol. 27, no 2, p. 82-90Article in journal (Refereed) Published
    Abstract [en]

    Objective: Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by elevated platelet counts and increased risk of thrombosis. Ex vivo data suggest increased platelet reactivity in agreement with the increased thrombosis risk, while in vitro tests often detect decreased platelet activity. The present study aimed to investigate adhesion of ET-platelets in vitro, which is an aspect of platelet function that has been addressed in only a few studies on ET patients. Material and Methods: The study included 30 Er patients and 14 healthy controls. Platelet adhesion was measured with a static platelet adhesion assay. Results: The main finding was that ET-platelets were more readily activated by adhesion-inducing stimuli in vitro than control platelets. This was particularly evident in elderly patients and when using multiple stimuli, such as surfaces of collagen or fibrinogen combined with addition of adenosine 5-diphosphate or ristocetin. Such multiple stimuli resulted in adhesion above the control mean +2 standard deviations for approximately 50% of the patients. Conclusion: The results are in accordance with the concept of increased platelet activity in ET, but opposite to most other in vitro studies. We suggest that the conditions in the adhesion assay might mimic the in vivo situation regarding the presence of chronic platelet activation. (Turk J Hematol 2010; 27: 82-90)

    Place, publisher, year, edition, pages
    Aves Yayincilik, 2010
    Keywords
    Essential thrombocythemia; platelet activation; adhesion; thrombosis; platelet assay
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13249 (URN)10.5152/tjh.2010.05 (DOI)000278947500005 ()
    Available from: 2008-05-21 Created: 2008-05-21 Last updated: 2013-09-03
    5. Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study
    Open this publication in new window or tab >>Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study
    Show others...
    2009 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 7, no 42Article in journal (Refereed) Published
    Abstract [en]

    Background: Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA) and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment. Methods: With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B-2 (TXB2)-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis. Results: The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r(2) = 0.49). In opposite, TXB2-levels decreased with ASA compared to clopidogrel. Serum TXB2 and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow cytometry were lower for clopidogrel compared to ASA. Furthermore, adhesion to collagen was lower for ASA and clopidogrel combined compared with either drug alone. Conclusion: The indirect pharmacodynamic measures of the effects of ASA and clopidogrel might be used together with ADP-induced activation and serum TXB2 for evaluation of anti-platelet treatment. This should be further evaluated in future clinical studies where screening opportunities with the adhesion assay will be optimised towards increased sensitivity to anti-platelet treatment.

    Place, publisher, year, edition, pages
    BioMed Central, 2009
    National Category
    Microbiology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-19665 (URN)10.1186/1479-5876-7-42 (DOI)000267242100001 ()19508722 (PubMedID)
    Note

    Original Publication: Andreas Eriksson, Lena Jonasson, Tomas Lindahl, Bo Hedbäck and Per Whiss, Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study, 2009, JOURNAL OF TRANSLATIONAL MEDICINE, (7), 42. http://dx.doi.org/10.1186/1479-5876-7-42 Licensee: BioMed Central http://www.biomedcentral.com/

    Available from: 2009-08-28 Created: 2009-07-10 Last updated: 2018-01-13Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
    Download (pdf)
    COVER01
    Download (pdf)
    POPULARSUMMARY01
  • 47.
    Eriksson, Irene
    et al.
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Wettermark, Bjorn
    Stockholm County Council, Sweden; Karolinska Institute, Sweden.
    Persson, Marie
    Stockholm County Council, Sweden.
    Edström, Morgan
    Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Godman, Brian
    University of Liverpool, England; Karolinska University Hospital, Sweden; University of Strathclyde, Scotland.
    Lindhe, Anna
    Regional Vastra Gotaland, Sweden.
    Malmstrom, Rickard E.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Ramstrom, Helena
    Stockholm County Council, Sweden.
    von Eulerz, Mia
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bergkvist Christensen, Anna
    Regional Skåne, Sweden.
    The Early Awareness and Alert System in Sweden: History and Current Status2017In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 8, article id 674Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Over the past decades, early awareness and alert (FAA) activities and systems have gained importance and become a key early health technology assessment (HTA) tool. While a pioneer in HTA, Sweden had no national level EAA activities until 2010. We describe the evolution and current status of the Swedish EAA System. Methods: This was a historical analysis based on the knowledge and experience of the authors supplemented by a targeted review of published and gray literature as well as documents relating to EM activities in Sweden. Key milestones and a description of the current state of the Swedish FAA System is presented. Results: Initiatives to establish a system for the identification and assessment of emerging health technologies in Sweden date back to the 1980s. In the 1990s, the Swedish Agency for HTA and Assessment of Social Services (SBU) supported the development of EuroScan as one of its founder members. In the mid-2000s, an independent regional initiative, driven by the Stockholm County Drug and Therapeutics Committee, resulted in the establishment of a regional horizon scanning function. By 2009, this work had expanded to a collaboration between the four biggest counties in Sweden. The following year it was further expanded to the national level and since then the Swedish EAA System has been carrying out identification, filtration and prioritization of new medicines, early assessment of the prioritized medicines, and dissemination of information. In 2015, the EAA System was incorporated into the Swedish national process for managed introduction and follow-up of new medicines. Outputs from the EAA System are now used to select new medicines for inclusion in this process. Conclusions: The Swedish FAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the system today is its complete integration into the national process for managed introduction and follow-up of new medicines. The system will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international level.

    Download full text (pdf)
    fulltext
  • 48. Order onlineBuy this publication >>
    Evaldsson, Chamilly
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Uridine, 4-thiouridine and isomaltitol in an asthma-like model: Anti-inflammatory and modulating effects2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In chronic inflammatory diseases like asthma or rheumatoid arthritis, erroneous and exaggerated accumulation of leukocytes in a tissue inadvertently causes the body harm. Several efficient anti-inflammatory drugs exist, for example corticosteroids and cyclo-oxygenase inhibitors. However, these drugs have potent and diverse effects and often act by inhibiting events subsequent to initiation of the inflammatory response, leading to more or less severe side-effects, especially when used in high doses for long periods of time. For this reason, strategies aimed at early inhibition of recruitment and activation of leukocytes have been suggested as safer and more specific approaches to reduce inflammation.

    Leukocyte adhesion to activated endothelium is a prerequisite to the following activation and extravasation, and takes place in the initial phase of inflammation. By using a model that allows leukocytes to adhere to tumour necrosis factor (TNF)-activated endothelial cells, thus mimicking aspects of an inflammatory reaction, we found that uridine, 4-thiouridine and isomaltitol could all reduce adhesion. This suggested that they may have anti-inflammatory potential.

    We therefore tried the three substances in a Sephadex-induced lung inflammation model and found that uridine and 4-thiouridine have several anti-inflammatory effects, such as being able to reduce leukocyte accumulation, decrease TNF protein levels and partly inhibit the oedema induced by Sephadex. Isomaltitol turned out to have immunomodulating, rather than anti-inflammatory, effects, which could be of interest in diseases where inadequate inflammatory responses are a problem.

    List of papers
    1. Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model.
    Open this publication in new window or tab >>Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model.
    2004 (English)In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 4, no 9, p. 1241-1248Article in journal (Refereed) Published
    Abstract [en]

    Since leukocyte adhesion to endothelial cells is crucial for extravasation of leukocytes to sites of inflammation, inhibition of cell-cell adhesion has been suggested as a means to achieve selective modulation of the immune system. We have, using a static in vitro adhesion assay involving adhesion of granulocytes to tumor necrosis factor alpha (TNFalpha)-stimulated human umbilical vein endothelial cells (HUVEC), found three substances--uridine, isomaltitol and 4-thiouridine-that, independently and significantly, reduced leukocyte adhesion by approximately 30-65%. 4-Thiouridine was also tested in an in vivo model of Sephadex (SDX)-induced lung inflammation with Sprague-Dawley rats. Intratracheal instillation of Sephadex (5 mg/kg) alone resulted in a dramatic increase in lung edema and total leukocyte count after 24 h. A differential count of bronchoalveolar lavage (BAL) cells indicated an increased influx of macrophages, eosinophils and neutrophils. Co-administration of 4-thiouridine significantly reduced lung edema by 38%. There was also a significant reduction of the total leukocyte count by 58%. The differential leukocyte count indicated that eosinophil influx alone was reduced by 70%. After Sephadex challenge, we found elevated levels of TNFalpha--an important inflammatory mediator--in the bronchoalveolar lavage fluid (BALF). TNFalpha levels were significantly reduced by more than 80% by co-administration of 4-thoiuridine. These results suggest that uridine, isomaltitol and, especially, 4-thiouridine affect adhesion between leukocytes and activated endothelium, and warrant further in vitro and in vivo studies.

    Keywords
    Inflammation; Adhesion; TNFa; Uridine; Isomaltitol; 4-thiouridine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19093 (URN)10.1016/j.intimp.2004.04.016 (DOI)15251120 (PubMedID)