Molecular and epidemiological investigations of lung involvement in very early Rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory joint disease with at least two distinct clinical phenotypes defined by the presence or absence of antibodies, i.e. rheumatoid factor (RF) and/or anti-­‐citrullinated protein antibodies (ACPAs). These two phenotypes differ both with respect to risk factors and disease outcome, with seropositive disease being more likely associated with extra-­‐articular manifestations, such as lung manifestations, and tobacco exposure. Both ACPA and RF can be detected in the blood years prior to the onset of joint inflammation suggesting that these antibodies are initially generated outside the joints. The current thesis investigates the pathogenic link between lungs and joints with a focus on the potential role of the lung as an initiating site for the RA-­‐associated autoimmunity. We investigated a cohort of patients with early, untreated RA, who underwent high resolution computed tomography and conducted lung function tests. A subgroup of these patients was subjected to bronchoscopy with retrieval of bronchoalveolar lavage (BAL) and bronchial biopsies. All investigations were repeated after six months of anti-­‐rheumatic treatment. We found more prevalent lung abnormalities, both parenchymal (54%) and airway (66%) in RA patients as compared to controls. The parenchymal abnormalities were significantly more frequent in the subgroup of ACPA-­‐positive RA patients compared to ACPA-­‐negative patients. The same was true after compensating for smoking. Signs of inflammation and immune activation with more lymphocytic infiltration and expression of citrullinated proteins were found in the lungs of ACPA-­‐positive as compared to ACPA-­‐negative patients. ACPAs were enriched in the BAL as compared to the blood compartment of ACPA-­‐positive patients. Using mass spectrometry we were able to identify two novel citrullinated vimentin peptides that were present in a majority of bronchial (n=6) and RA synovial biopsies (n=7) tested. Immune reactivity against these targets was specifically detected in the blood of RA patients. At 6 months follow-­‐up one third of patients with lung fibrosis (11%) at baseline had progressed and additionally 3 patients had developed new radiological changes suggestive of early interstitial lung disease. Moreover, there was an increase in airway obstruction, with a decline in forced expiratory volume in one second in all patients, more prominent in smokers. In conclusion, lung changes in early RA are prevalent and may be progressive despite anti-­‐ rheumatic treatment. Taken together our results support the hypothesis that the lung may be an early important player in the pathogenesis of RA in a subset of patients. These findings encourage new therapeutic strategies to target the local inflammation in the lungs, with the aim to prevent the progress of autoimmunity in ACPA-­‐positive healthy individuals

Willingness to pay entrance fees to natural attractions : an Icelandic case study

2008-2009 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishe

Immunopathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics

Differentiation at the MHCIIα and Cath2 Loci in Sympatric Salvelinus alpinus Resource Morphs in Lake Thingvallavatn

Publisher's versionNorthern freshwater fish may be suitable for the genetic dissection of ecological traits because they invaded new habitats after the last ice age (∼10.000 years ago). Arctic charr (Salvelinus alpinus) colonizing streams and lakes in Iceland gave rise to multiple populations of small benthic morphotypes, often in sympatry with a pelagic morphotype. Earlier studies have revealed significant, but subtle, genetic differentiation between the three most common morphs in Lake Thingvallavatn. We conducted a population genetic screen on four immunological candidate genes Cathelicidin 2 (Cath2), Hepcidin (Hamp), Liver expressed antimicrobial peptide 2a (Leap-2a), and Major Histocompatibility Complex IIα (MHCIIα) and a mitochondrial marker (D-loop) among the three most common Lake Thingvallavatn charr morphs. Significant differences in allele frequencies were found between morphs at the Cath2 and MHCIIα loci. No such signal was detected in the D-loop nor in the other two immunological genes. In Cath2 the small benthic morph deviated from the other two (FST = 0.13), one of the substitutions detected constituting an amino acid replacement polymorphism in the antimicrobial peptide. A more striking difference was found in the MHCIIα. Two haplotypes were very common in the lake, and their frequency differed greatly between the morphotypes (from 22% to 93.5%, FST = 0.67). We then expanded our study by surveying the variation in Cath2 and MHCIIα in 9 Arctic charr populations from around Iceland. The populations varied greatly in terms of allele frequencies at Cath2, but the variation did not correlate with morphotype. At the MHCIIα locus, the variation was nearly identical to the variation in the two benthic morphs of Lake Thingvallavatn. The results are consistent with a scenario where parts of the immune systems have diverged substantially among Arctic charr populations in Iceland, after colonizing the island ∼10.000 years ago.The Palsson laboratory is supported by Icelandic Research foundation and the University of Iceland research fund. Icelandic research foundation (grant of excellence: nr 100204011) to S.S. Sigurdsson, A. Palsson, B.K. Kristjansson, Zophonias O. Jonsson and Ian A. Johnston paid for part of this work. Kalina H. Kapralova and Johannes Gudbrandsson were supported by the University of Iceland doctoral fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer ReviewedRitrýnt tímari

High expression of ZNF703 independent of amplification indicates worse prognosis in patients with luminal B breast cancer

Peer reviewe

Mellom drøm og realitet - En kvalitativ studie om karriereveileders erfaring med å bidra til økt selvinnsikt for flerkulturelle veisøkere

Dagens arbeidsliv kjennetegnes av både kunnskapsintensivering, raske og dyptgående endringer og flerkulturalisme. Av både teoretikere, karriereveiledere og kunnskapsdepartementet etterspørres kompetanseheving for karriereveiledere knyttet til flerkulturalisme. Dette gjør at jeg betrakter selvinnsikt i inkluderende og kultursensitiv karriereveiledning som et viktig forskningstema, og har derfor valgt å gjennomføre en kvalitativ studie der jeg har undersøkt hvordan karriereveiledere opplever sitt arbeid med selvinnsikt i inkluderende karriereveiledning. Jeg har valgt meg følgende problemstilling: Hvordan erfarer karriereveiledere å bidra til økt selvinnsikt hos flerkulturelle veisøkere? For å besvare problemstillingen har jeg brukt kvalitativ tilnærming, siden den er velegnet til å fange opp nyanser i subjektive opplevelser og forståelsen av abstrakte begreper. Jeg har foretatt fire intervju med karriereveiledere og observert to av dem på sine arbeidsplasser. Ved å analysere forskningsmaterialet fra både intervjuer og observasjon kom jeg frem til tre hovedkategorier som kan belyse ulike aspekter ved temaet. Kategoriene er: 1) Ulikt fokus i rådgivningssamtalen, 2) Balansegang mellom drøm og realitet og 3) Ulik forståelse av kulturkompetanse. I lys av relevante teorier om helhetlig karriereveiledning, flerkulturalisme og selvinnsikt har jeg diskutert forskningens datamateriale. Jeg har drøftet de utfordringene og mulighetene informantene opplever i møte med dagens arbeidsliv når de arbeider med flerkulturelle veisøkere, hvilken temaer de retter sin oppmerksomhet mot og hvordan de påvirker den flerkulturelles forståelse av seg selv og sin karriere. Forskningens hovedfunn er at det fins mange måter å forstå selvinnsikt, og at det følgelig også er mange måter å arbeide med selvinnsikt. Selvinnsikt kan opparbeides gjennom økt forståelse av ens miljø, samt ved å utforske ens indre prosesser. For å bidra til økt selvinnsikt for flerkulturelle veisøkere må karriereveiledere arbeide mot en hensiktsmessig balanse mellom helhetlig perspektiv og informasjonsarbeid, samt mellom veisøkers drøm og realitet. Dette oppleves som utfordrende, og forskningens datamateriale viser et gap mellom karriereveiledernes intensjon og praksis, samt et gap mellom karriereveiledernes praksis og aktuelle kulturteorier

«Men vi er jo en klinikk for prevensjon, vi er jo ikke en skeiv organisasjon!»: Et studie av seksuell helsehjelp for lesbiske

Jeg er lesbisk og i mange år har jeg uten suksess lett etter prevensjonsmidler som jeg kan bruke for å ha sikker sex. Dette var inspirasjonen min til å skrive denne masteroppgaven med problemstillingen: «Hvordan forstår eksperter som rådgir unge om seksuell helse, spørsmålet: “Hvordan kan to lesbiske personer med vulva ha sex uten å få kjønnssykdommer?” Jeg har gjort kvalitative forskningsintervju med åtte informanter som er yrkesutøvere eller frivillige som jobber med å fremme god seksuell helse til ungdom, studenter eller unge voksne. Jeg bruker tematisk og affektdrevet analyse for å analysere innholdet fra intervjuene mine. I det teoretiske rammeverket presenterer jeg de viktigste begrepene jeg bruker i denne masteroppgaven: heteronormativitet, fallosentrisme, homotoleranse, homonormativitet og homofobi. I første analysekapittel undersøker jeg ressurser for sikker sex, og finner ut at alle prevensjonsmidler som informantenes arbeidsplasser tilbyr baser seg på en fallosentrisk forståelse av sex. I andre analysekapittel ser jeg på seksuell veiledning for lesbiske, og argumenterer for at veiledningen lesbiske får er performativ i kraft av å være homotolerant og heteronormativ. I det tredje analysekapittelet utforsker jeg informantenes forestillinger om lesbiskes behov. Flere av informantene uttrykker at de forstår lesbiske som annerledes og kompliserte, og det ligger også en cis- og heteronormativ forståelse til grunn for måten flere av dem forteller om møter med pasienter. I denne masteroppgaven kommer jeg frem til at ekspertene som rådgir unge om seksuell helse, misforstår spørsmålet mitt om hvordan to lesbiske personer med vulva kan ha sikker sex. Jeg tror det er fordi flere av ekspertenes definisjoner av sex er preget av fallosentrisme og heteronormativitet. Jeg konkluderer med at de ikke har god nok forståelse av hvordan sex mellom to personer med vulva foregår til å svare på hvordan denne gruppen kan ha sikker sex.I am a lesbian and for many years I have searched without success for contraceptives that I can use to have safe sex. This was my inspiration to write this master's thesis which attempts to answer the research question: "How do experts who advise young people about sexual health understand the question: "How can two lesbians with vulvas have sex without catching venereal diseases?" I have conducted qualitative research interviews with eight informants who are professionals or volunteers all of whom work to promote good sexual health for young people, students or young adults. I use thematic and affect-driven analysis to analyze the content from my interviews. In the theoretical framework, I present the most important theoretical concepts I use in this master's thesis: heteronormativity, phallocentrism, homotolerance, homonormativity and homophobia. In the first analysis chapter, I examine resources for safe sex, and find that all contraceptives offered by the informants' workplaces are based on a phallocentric understanding of sex. In the second analysis chapter, I look at sexual guidance for lesbians and argue that the guidance lesbians receive is performative by virtue of being homotolerant and heteronormative. In the third analysis chapter, I explore the informants' ideas about the needs of lesbians. Several of the informants express that they see lesbians as different and complicated, and there is also a cis- and heteronormative understanding at the basis of the way several of them talk about meetings with patients. In this master's thesis, I conclude that the experts who advise young people about sexual health misunderstand my question about how two lesbians with vulva can practice safe sex. I think it is because several of the experts' definitions of sex are characterized by phallocentrism and heteronormativity. I conclude that they do not have a good enough understanding of how sex between two people with a vulva takes place to answer how this group can have safe sex

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldWe recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism