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Blomgran Julinder, Robert
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Publications (10 of 18) Show all publications
Blomgran, P., Blomgran, R., Ernerudh, J. & Aspenberg, P. (2017). Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing. Muscles, ligaments and Tendons journal, 7(2), 223-229
Open this publication in new window or tab >>Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
2017 (English)In: Muscles, ligaments and Tendons journal, ISSN 2240-4554, Vol. 7, no 2, p. 223-229Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Rome, Italy: CIC Edizioni Internazionali, 2017
Keywords
tendon healing; NSAID; inflammation; rat model; flow cytometry
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-142352 (URN)10.11138/mltj/2017.7.2.223 (DOI)
Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2018-04-17
Blomgran, P., Blomgran, R., Ernerudh, J. & Aspenberg, P. (2016). A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat. Scientific Reports, 6(29824)
Open this publication in new window or tab >>A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 29824Article in journal (Refereed) Published
Abstract [en]

Loading influences tendon healing, and so does inflammation. We hypothesized that the two are connected. 48 rats underwent Achilles tendon transection. Half of the rats received Botox injections into calf muscles to reduce mechanical loading. Cells from the regenerating tissue were analyzed by flow cytometry. In the loaded group, the regenerating tissue contained 83% leukocytes (CD45(+)) day 1, and 23% day 10. The M1/M2 macrophage ratio (CCR7/CD206) peaked at day 3, while T helper (CD3(+)CD4(+)) and T-reg cells (CD25(+) Foxp3(+)) increased over time. With Botox, markers associated with down-regulation of inflammation were more common day 5 (CD163, CD206, CD25, Foxp3), and M1 or M2 macrophages and T-reg cells were virtually absent day 10, while still present with full loading. The primary variable, CCR7/CD206 ratio day 5, was higher with full loading (p = 0.001) and the T-reg cell fraction was lower (p amp;lt; 0.001). Free cage activity loading is known to increase size and strength of the tendon in this model compared to Botox. Loading now appeared to delay the switch to an M2 type of inflammation with more T-reg cells. It seems a prolonged M1 phase due to loading might make the tendon regenerate bigger.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-130383 (URN)10.1038/srep29824 (DOI)000379584000001 ()27405922 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; King Gustaf V and Queen Victoria Free Mason Foundation

Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2018-01-10
Gustafsson, M., Gawel, D., Alfredsson, L., Baranzini, S., Bjorkander, J., Blomgran, R., . . . Benson, M. (2015). A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases. Science Translational Medicine, 7(313), Article ID 313ra178.
Open this publication in new window or tab >>A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases
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2015 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 313, article id 313ra178Article in journal (Refereed) Published
Abstract [en]

Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2015
National Category
Biological Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-123522 (URN)10.1126/scitranslmed.aad2722 (DOI)000365237400003 ()26560356 (PubMedID)
Note

Funding Agencies|Cancer fund, Swedish Medical Research Council [K2013-61X-22310-01-04, 2012-3168]; Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research [250114]; Sigrid Juselius Foundation; Generalitat de Catalunya AGAUR [2014-SGR364]; Spanish Association Against Cancer; Spanish Ministry of Health ISCIII FIS [PI12/01528]; RTICC [RD12/0036/0008]

Available from: 2015-12-22 Created: 2015-12-21 Last updated: 2018-04-10Bibliographically approved
Andersson, H., Eklund, D., Ngoh, E., Persson, A., Andersson, B., Svensson, K., . . . Stendahl, O. (2014). Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages. PLoS ONE, 9(7), e101514
Open this publication in new window or tab >>Apoptotic neutrophils augment the inflammatory response to Mycobacterium tuberculosis infection in human macrophages
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e101514-Article in journal (Refereed) Published
Abstract [en]

Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during tuberculosis. Innate immune cells such as macrophages and neutrophils are first recruited to the site of infection, and mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Such anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens. We therefore investigated how uptake of apoptotic neutrophils by Mtb-activated human monocyte-derived macrophages modulates their function. We show that Mtb infection exerts a potent pro-inflammatory activation of human macrophages with enhanced gene activation and release of several cytokines (TNF, IL-1ß, IL-6, IL-18 and IL-10). This response was augmented by apoptotic neutrophils. Macrophages containing both Mtb and apoptotic cells showed a stronger cytokine expression than non-infected cells. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response, which can contribute to the early control of Mtb infection.

Place, publisher, year, edition, pages
PLoS, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100888 (URN)10.1371/journal.pone.0101514 (DOI)000338637300054 ()
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2017-12-06Bibliographically approved
Raffetseder, J., Pienaar, E., Blomgran, R., Eklund, D., Brodin Patcha, V., Andersson, H., . . . Lerm, M. (2014). Replication Rates of Mycobacterium tuberculosis in Human Macrophages Do Not Correlate with Mycobacterial Antibiotic Susceptibility. PLoS ONE, 9(11), e112426
Open this publication in new window or tab >>Replication Rates of Mycobacterium tuberculosis in Human Macrophages Do Not Correlate with Mycobacterial Antibiotic Susceptibility
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112426-Article in journal (Refereed) Published
Abstract [en]

The standard treatment of tuberculosis (TB) takes six to nine months to complete and this lengthy therapy contributes to the emergence of drug-resistant TB. TB is caused by Mycobacterium tuberculosis (Mtb) and the ability of this bacterium to switch to a dormant phenotype has been suggested to be responsible for the slow clearance during treatment. A recent study showed that the replication rate of a non-virulent mycobacterium, Mycobacterium smegmatis, did not correlate with antibiotic susceptibility. However, the question whether this observation also holds true for Mtb remains unanswered. Here, in order to mimic physiological conditions of TB infection, we established a protocol based on long-term infection of primary human macrophages, featuring Mtb replicating at different rates inside the cells. During conditions that restricted Mtb replication, the bacterial phenotype was associated with reduced acid-fastness. However, these phenotypically altered bacteria were as sensitive to isoniazid, pyrazinamide and ethambutol as intracellularly replicating Mtb. In support of the recent findings with M. smegmatis, we conclude that replication rates of Mtb do not correlate with antibiotic tolerance.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-113014 (URN)10.1371/journal.pone.0112426 (DOI)000345250400061 ()25386849 (PubMedID)
Note

Funding Agencies|Bill and Melinda Gates Foundation; Swedish Research Council [2009-3821, 2012-3349]; Swedish International Development Cooperation Agency; Swedish Heart-Lung Foundation; King Oscar II Foundation; Carl Trygger Foundation; Clas Groschinsky Foundation

Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2018-01-11
Blomgran, R., Brodin Patcha, V., Verma, D., Bergström, I., Söderkvist, P., Sjöwall, C., . . . Sarndahl, E. (2012). Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils. PLoS ONE, 7(3)
Open this publication in new window or tab >>Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3Article in journal (Refereed) Published
Abstract [en]

Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1 beta production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages. less thanbrgreater than less thanbrgreater thanMethods and Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response. less thanbrgreater than less thanbrgreater thanConclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.

Place, publisher, year, edition, pages
Public Library of Science, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77736 (URN)10.1371/journal.pone.0031326 (DOI)000303017700010 ()
Note
Funding Agencies|Swedish Research Council||Heart-Lung Foundation||King Gustaf V Memorial Foundation||County Council of Ostergotland||Soderberg Foundation||Available from: 2012-05-29 Created: 2012-05-28 Last updated: 2017-12-07
Blomgran, R., Desvignes, L., Briken, V. & Ernst, J. D. (2012). Mycobacterium tuberculosis inhibits neutrophil apoptosis, leading to delayed activation of naive CD4 T cells. Cell Host and Microbe, 11(1), 81-90
Open this publication in new window or tab >>Mycobacterium tuberculosis inhibits neutrophil apoptosis, leading to delayed activation of naive CD4 T cells
2012 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 11, no 1, p. 81-90Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis promotes its replication by inhibiting the apoptosis of infected macrophages. A proapoptotic M. tuberculosis mutant lacking nuoG, a subunit of the type I NADH dehydrogenase complex, exhibits attenuated growth in vivo, indicating that this virulence mechanism is essential. We show that M. tuberculosis also suppresses neutrophil apoptosis. Compared to wild-type, the nuoG mutant spread to a larger number of lung phagocytic cells. Consistent with the shorter lifespan of infected neutrophils, infection with the nuoG mutant resulted in fewer bacteria per infected neutrophil, accelerated bacterial acquisition by dendritic cells, earlier trafficking of these dendritic cells to lymph nodes, and faster CD4 T cell priming. Neutrophil depletion abrogated accelerated CD4 T cell priming by the nuoG mutant, suggesting that inhibiting neutrophil apoptosis delays adaptive immunity in tuberculosis. Thus, pathogen modulation of apoptosis is beneficial at multiple levels, and enhancing phagocyte apoptosis promotes CD4 as well as CD8 T cell responses.

Place, publisher, year, edition, pages
Elsevier, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-75365 (URN)10.1016/j.chom.2011.11.012 (DOI)22264515 (PubMedID)
Available from: 2012-02-28 Created: 2012-02-28 Last updated: 2017-12-07
Blomgran, R. & Ernst, J. D. (2011). Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection. Journal of Immunology, 186(12), 7110-7119
Open this publication in new window or tab >>Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection
2011 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, no 12, p. 7110-7119Article in journal (Refereed) Published
Abstract [en]

Initiation of the adaptive immune response to Mycobacterium tuberculosis occurs in the lung-draining mediastinal lymph node and requires transport of M. tuberculosis by migratory dendritic cells (DCs) to the local lymph node. The previously published observations that 1) neutrophils are a transiently prominent population of M. tuberculosis-infected cells in the lungs early in infection and 2) that the peak of infected neutrophils immediately precedes the peak of infected DCs in the lungs prompted us to characterize the role of neutrophils in the initiation of adaptive immune responses to M. tuberculosis. We found that, although depletion of neutrophils in vivo increased the frequency of M. tuberculosis-infected DCs in the lungs, it decreased trafficking of DCs to the mediastinal lymph node. This resulted in delayed activation (CD69 expression) and proliferation of naive M. tuberculosis Ag85B-specific CD4 T cells in the mediastinal lymph node. To further characterize the role of neutrophils in DC migration, we used a Transwell chemotaxis system and found that DCs that were directly infected by M. tuberculosis migrated poorly in response to CCL19, an agonist for the chemokine receptor CCR7. In contrast, DCs that had acquired M. tuberculosis through uptake of infected neutrophils exhibited unimpaired migration. These results revealed a mechanism wherein neutrophils promote adaptive immune responses to M. tuberculosis by delivering M. tuberculosis to DCs in a form that makes DCs more effective initiators of naive CD4 T cell activation. These observations provide insight into a mechanism for neutrophils to facilitate initiation of adaptive immune responses in tuberculosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-75364 (URN)10.4049/jimmunol.1100001 (DOI)21555529 (PubMedID)
Available from: 2012-02-28 Created: 2012-02-28 Last updated: 2017-12-07
Persson, A., Blomgran, R., Eklund, D., Lundstrom, C. & Stendahl, O. (2009). Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins. Microbial Pathogenesis, 47(3), 143-150
Open this publication in new window or tab >>Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins
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2009 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 47, no 3, p. 143-150Article in journal (Refereed) Published
Abstract [en]

Modulation of immune cell apoptosis is a key evasion strategy utilized by Mycobacterium tuberculosis (Mtb). To be able to multiply within macrophages, the bacterium delays apoptosis and down-regulates pro-inflammatory activation in these cells, whereas apoptosis is rapidly induced in the potently bactericidal neutrophils. Initial host-pathogen interactions between neutrophils and Mtb, subsequently leading to apoptosis, need to be investigated to understand the early features during Mtb infections. Opsonized Mtb were readily phagocytosed, and the immuno-mediated phagocytosis triggered early activation of anti-apoptotic Akt in the neutrophils but the bacteria still induced apoptosis to the same extent as non-phagocytosed Mtb. Mtb-induced apoptosis was strictly dependent on NADPH oxidase-generated reactive oxygen species, compounds shown to damage lysosomal granules. Despite this, we found no involvement of damaged azurophilic granules in Mtb-induced apoptosis in human neutrophils. Instead, the Mtb-induced apoptosis was p38 MAPK dependent and induced through the mitochondrial pathway. Moreover, Mtb deficient of mature lipoproteins lacked the determinants required for induction of neutrophil apoptosis. These results show that Mtb exert a strong intrinsic capacity to induce apoptosis in neutrophils that is capable of overcoming the anti-apoptotic signaling in the cell.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20401 (URN)10.1016/j.micpath.2009.05.006 (DOI)
Note
Original Publication: Alexander Persson, Robert Blomgran, Daniel Eklund, Charlotte Lundstrom and Olle Stendahl, Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins, 2009, MICROBIAL PATHOGENESIS, (47), 3, 143-150. http://dx.doi.org/10.1016/j.micpath.2009.05.006 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2009-09-08 Created: 2009-09-07 Last updated: 2017-12-13Bibliographically approved
Verma, D., Lerm, M., Blomgran Julinder, R., Eriksson, P., Söderkvist, P. & Särndahl, E. (2008). Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?. Arthritis and Rheumatism, 58(3), 888-894
Open this publication in new window or tab >>Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?
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2008 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 3, p. 888-894Article in journal (Refereed) Published
Abstract [en]

Objective: NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1β (IL-1β) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome.

Methods: Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1β production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects.

Results: Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1β measured in samples from the patient returned to normal levels after treatment with anakinra.

Conclusion: Our results indicate that the patient's symptoms were due to elevated levels of IL-1β, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1β levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19048 (URN)10.1002/art.23286 (DOI)
Available from: 2009-06-11 Created: 2009-06-09 Last updated: 2017-12-13Bibliographically approved
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