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Koordinerings- og støtteaktivitet

Hovedmålet med kreftbehandling er å eliminere kreftceller og dette er tradisjonelt oppnådd ved kirurgi, bruk av giftige medikamenter (cellegift) og stråling. En ny og betydningsfull tilnærming til kreftbehandling kalt immunterapi, har derimot fått mye oppmerksomhet det siste tiåret; Her forsøker leger og forskere å utnytte immunsystemet vårt for å målrettet  ødelegge kreftceller. En nøkkelaktør i denne banebrytende tilnærmingen er en gruppe «drapsmenn» i immunsystemet kjent som cytotoxiske T-lymfocytter (CTL-er). Disse cellene har en bemerkelsesverdig evne til å oppdage kreftceller ved å gjenkjenne unormale molekyler på overflaten av kreftcellene - molekyler som friske celler ikke har. Når CTL-er gjenkjenner kreftcellene ødelegger de dem ved å frigjøre giftige molekyler som initierer kreftcellenes selvdestruksjon. 
 
Selv om betydelige innsats har blitt dedikert til å forstå hvordan CTL-er aktiveres og hvordan de gjenkjenner kreftceller, vet vi mindre om de påfølgende hendelsene inne i kreftcellene som fører til deres død. Fra før vet vi at CTL-er kan initiere to forskjellige typer celledød i kreft: den første, kalt apoptose, er en stille og ordnet prosess der kreftcellene krymper og brytes opp uten å varsle immunsystemet; den andre, kalt pyroptose, er en mer dramatisk prosess som involverer dannelse av åpninger i cellemembranen, noe som fører til at cellene svulmer opp og sprekker. Under denne cellebristen blir innholdet inne i cellene frigitt i omgivelsene, og dette kan fungere som 'faretegn' som kan stimulere en sterkere immunrespons mot kreftcellene. Betydningen av denne cellebristen for å forsterke anti-tumorresponsene vil bli undersøkt i dette prosjektet. 
 
Videre er vi fascinert av muligheten for å avdekke ytterligere, ennå ukjente, former for celledød indusert av CTL-er. Utforsking av disse dødsrelaterte prosessene i kreftcellene kan potensielt øke effektiviteten av immunterapi og bidra betydelig i den pågående kampen mot kreft.

The primary goal of most cancer therapies is to induce cancer cell death. Immunotherapy relies on the cytotoxic activity of lymphocytes such as natural killer cells (NKs) and cytotoxic T lymphocytes (CTLs) to achieve this. While a significant amount of research in immunotherapy focuses on the events within cytotoxic lymphocytes or at the interface between cytotoxic lymphocytes and cancer cells, less is known about the molecular mechanisms that orchestrate cancer cell death, particularly in the case of CTL-mediated death.
CTLs are known to induce two types of cell death in cancer: non-inflammatory apoptosis and proinflammatory pyroptosis. Pyroptotic cancer cells release proinflammatory signals that attract immune cells to the tumor site, thereby enhancing the anti-tumor response. Cell lysis is a common outcome of pyroptotic cell death. It is unclear whether lysis can be decoupled from pyroptosis in cancer cells and whether the proinflammatory properties of pyroptotic cancer cell death depend on lysis. Moreover, it remains unknown whether CTLs can induce other forms of cell death in cancer, apart from apoptosis and pyroptosis.
Studying the mechanisms of CTL-mediated cancer cell death is challenging because CTLs selectively target cells expressing specific antigens. However, given the critical role of CTLs in immunotherapy, it is essential to deepen our understanding of CTL-induced cancer cell death.
This project aims to develop novel methodologies to investigate the death mechanisms that are initiated by CTLs. In addition, we will identify new pathways and mediators involved in CTL-induced cancer cell death. Furthermore, we will assess the contribution of proinflammatory cell death and lysis in promoting anti-tumor responses in vivo. Overall, this research will improve our knowledge of the molecular mechanisms of CTL-mediated cancer cell death and potentially reveal novel targets to enhance the efficacy of cancer immunotherapy.

T-cell-mediated proinflammatory cell death and lysis in cancer

En av de vanligste, men minst studerte, utfordringene med å bli eldre er problemer med å kommunisere. Mange eldre sliter spesielt med pragmatiske ferdigheter, som å forstå undertekst, eller tilpasse det de sier til personen de snakker med. 

La oss si at en lege må gi en alvorlig beskjed til en pasient. For å gjøre det litt lettere å takle, bruker legen vagere språk, som "kanskje" i stedet for "sannsynligvis". Mens yngre voksne ofte tar hensyn til høflighetsstrategier i måten de tolker det som blir sagt på, har eldre ofte vanskelig for å forstå når noen snakker indirekte. Mange eldre voksne har vanskelig for å forstå ikke-bokstavelig språk og kan misforstå alvorlighetsgraden av diagnosen. Dette kan påvirke beslutningen deres om behandling, noe som kan føre til utilsiktede konsekvenser. 

Siden god kommunikasjon er viktig både i viktige medisinske samtaler og i hverdagen, er det viktig at vi finner ut hva som gjør at eldre kan ha vansker med å forstå og bli forstått. RESILIENCE skal hjelpe til med denne utfordringen ved å samle data om praktiske, kognitive og språklige ferdigheter hos voksne i alderen 18-90 år over tid. Dette vil gi oss en stor mengde data om pragmatiske, kognitive og språk ferdigheter og gjøre det tilgjengelig for forskning. Med denne dataen som grunnlag har vi følgende mål: 

• Forstå hvordan praktiske evner endrer seg generelt gjennom voksenlivet. 
• Finne ut hvilke mekanismer som påvirker pragmatiske evner på forskjellige tidspunkter i livet.
 • Utvikle en teoretisk modell som forklarer hvordan pragmatiske ferdigheter endrer seg med alderen.
 • Lage algoritmer som kan forutsi hvordan pragmatiske evner vil utvikle seg for enkeltpersoner i årene som kommer. 
• Utvikle og teste et verktøy som kan måle pragmatisk helse (både pragmatiske ferdigheter og deres underliggende mekanismer), noe som kan åpne  for å iverksette tiltak. 

Dette vil gi oss muligheten til å forstå bedre hvordan folk kan utvikle pragmatisk resiliens gjennom livsløpet.

A cornerstone of human communication is our reliance on pragmatic skills to guide linguistic interactions (e.g., reasoning about others' mental states to bridge the gap between what is said and intended in conversation). However these skills are highly sensitive to age-related decline, leading to miscommunication and uninformed decision making in the older adult population. This raises an important question, one which has puzzled linguistics and psychologists for decades: if pragmatic competence is fundamental to communication, why do individuals vary so much in this capacity? 

Traditionally, psychologists have approached pragmatic competence from a cognitive angle, reasoning that individual differences in executive functions (i.e., the cognitive skills associated with goal-directed actions) are what underlie effective pragmatic behavior. In a similar vein, language scientists have taken a linguistic approach, reasoning that one’s language background (e.g., the frequency with which individuals shift between languages) shapes pragmatic skills by enhancing sensitivity to the communicative context. This focus on either cognitive or linguistic influences has resulted in two expansive yet disparate areas of research.

RESILIENCE will unite these disciplines to pursue a longstanding debate on what underlies pragmatic resilience and decline using a large-scale, interdisciplinary and longitudinal approach. By gathering data on adults' (ages 18-90) pragmatic, cognitive and language skills over multiple time points, we will develop a comprehensive theoretical model that explains how cognitive and linguistic systems interact to shape pragmatic competence as we age, and create algorithms that predict the trajectory of an individual’s pragmatic abilities in upcoming years. Based on these results we will design a multidimensional tool that detects the earliest signs of pragmatic deficits, leading to future interventions, allowing us to uncover the paths to pragmatic resilience.

Uncovering the paths to pragmatic resilience

Noen av oss tåler stressende livshendelser godt. Andre derimot utvikler vedvarende fysiske og psykiske plager som følger av stress. Hvor godt vi håndterer stress avhenger av et komplekst samspill mellom miljøfaktorer, sosiale forhold, biologisk sårbarhet og indre motstandskraft. Forskning på stressreaksjonene til dyr og pasientgrupper som til vanlig lever under mye stress viser at en gruppe signalstoffer i kroppen som aktiverer det samme hjernesystemet som cannabis – endocannabinoidene – kan begrense styrken på stressreaksjoner og bidra til at man raskere kommer seg til hektene. I dette prosjektet skal vi undersøke hvordan mestring av stress på kort og lang sikt henger sammen med nivåer av endocannabinoider i kroppen for å forstå hvorfor noen personer er mer motstandsdyktige mot stress enn andre. I den ene studien følger vi pasienter som skal gjennomgå en stressende, men veldig vanlig, situasjon: kirurgi. Her måler vi pasientenes opplevelse av stress, samt mentale og fysiske helse, fra tiden før til to år etter operasjonen og undersøker hvordan dette henger sammen med nivåene deres av endocannabinoider og andre stresshormoner. I den andre studien bruker vi data fra et eksperiment hvor deltakerne har blitt utsatt for psykososialt stress til å undersøke om endocannabinoidnivået deres påvirker hvordan de reagerer på stress, og om stresset i seg selv kan påvirke kroppens produksjon av endocannabinoider. Til syvende og sist er målet med studien å vurdere hvorvidt målinger av endocannabinoidnivåer kan brukes til å forebygge helseplager og til å evaluere behovet for økt oppfølging etter alvorlig stressende påkjenninger i livet.

In the face of major life stressors, some individuals cope well whereas others develop ill health and long-term adverse outcomes. Predicting who needs additional support in response to major life stressors is essential for targeted prevention and more efficient allocation of resources. The endocannabinoid system is emerging as a promising target for understanding vulnerability and resilience to stress. This system appears to buffer stress in two ways: by limiting the magnitude of the stress response, and by facilitating recovery after a stressful event. While the early findings are intriguing, they mainly stem from studies in rodents and small clinical groups with high stress burden. What role endocannabinoids have more globally for human resilience, health and well-being remains elusive. 

In this project we address this gap by leveraging comprehensive experimental and clinical data on two potent stress models: psychosocial stress and surgery. Drawing on these unique datasets, which combine experimental control with ecological validity, we will decipher how endocannabinoid levels influence people’s stress response and recovery across minutes, days, weeks and years. The project represents a novel directional shift for endocannabinoid research and will (i) determine the value of endocannabinoid levels as a biomarker to predict outcomes after surgery, (ii) quantify sex differences, (iii) assess endocannabinoid interplay with opioid analgesics, sex hormones and other stress markers (iv) spearhead open and reproducible science practices in endocannabinoid research, and (v) make this fine-grained and novel data available through an interactive web application. 

This project represents an ambitious effort to understand endocannabinoids’ role in stress resilience and will determine the value of endocannabinoids as a predictive biomarker and potential target for individualized treatment.

Deciphering endocannabinoid stress buffering in humans: 
Mechanistic and clinical investigations

WHeelchair Activity Monitoring project (WHAM)

Wheelchair users (WCU) are three to five times more inactive than the general population, leading to a high risk of developing preventable secondary conditions. Although physical activity (PA) guidelines have been specifically developed for WCU, we lack systematic approaches to implement them in practice, as well as valid algorithms to monitor PA change in WCU through sensor-based solutions. Accordingly, the overall scientific aim of the WHeelchair Activity Monitoring project (WHAM) is to advance PA research and practice in WCU by developing valid digital markers for monitoring of and providing feedback on PA, paving the way for implementation and intervention. I will accomplish this through combining the complementary research fields of 1) behavioural intervention studies focusing on increasing PA in WCU (core competence University of British Columbia, UBC; outgoing phase) and 2) sensor-based PA monitoring (core competence Norwegian University of Science and Technology, NTNU; returning phase – consolidated by non-academic placement at Maastricht Instruments, which develop research prototypes including PA monitors). WHAM’s scientific aim is achieved through three objectives: 1) Measure the effect of a pragmatic exercise intervention trial on self-reported physical activity levels and cardio-respiratory fitness, 2) Develop valid algorithms for tracking PA markers in WCU, and 3) Co-create a framework that outlines how PA can be conjointly monitored and provided feedback on in WCU. This fellowship will enable me to become established as an internationally recognized researcher in the field of “physical activity and disability”, while bringing together ongoing national disjointed research activities in this field. Altogether, my overall ambition is to contribute to reducing inequalities in daily-life participation among WCU compared to the rest of the population.

The goal of the Bilingual Experiences, Cognitive Ageing and underlying Mechanisms (BECAME) project is to examine the functional neuroplastic mechanisms underlying mitigatory effects of bilingual experience on age-related cognitive decline. While evidence is available for structural brain changes supporting bilingualism-induced effects on cognitive aging (CA), functional mechanisms underlying such effects are not yet well understood. BECAME aims to fill this gap by investigating the trajectory of bilingualism-induced functional neuroplasticity across the adult lifespan (ages 18-85), crucially adopting an individual differences approach related to measurable degree of bilingual engagement. Importantly, although such benefits are thought to be rooted early in the lifespan, evidence for the timeframe and conditions of their early emergence is scarce. The choice of including the whole adult lifespan allows us to investigate these mechanisms and their emergence more directly from a lifespan perspective. I combine behavioral testing with brain recordings via electroencephalography (EEG). EEG is widely used in cognitive neuroscience to assess brain activity and the degree of communication between brain regions (functional connectivity) in response to stimuli and at rest. Combining behavioral and EEG modalities will allow me to test bilingualism’s effect on functional connectivity, as well as its consequences for functional efficiency, the minimum required neural activation to successfully perform a task. This will enable a detailed, evidence-based account of the protective effects observed in older-aged bilinguals, and how they are built from earlier life stages. By illuminating the relationship between multilingualism and resulting neurocognitive adaptations, BECAME will enable to capitalize on it as a health initiative, with manifold societal implications and the potential to be translated into actionable policies exploiting multilingualism to ameliorate effects of CA.

Bilingual Experiences, Cognitive Ageing and underlying Mechanisms

Per- og polyfluorerte stoffer (PFAS) er en stor gruppe menneskeskapte kjemikalier med høyt fluorinnhold som antas å ha negative helseeffekter. Kilder til PFAS kan være produksjon av vann-, varme- og flekkbestandige produkter og disse kjemikaliene er en del av hverdagen vår. PFAS påvirkning av biologiske systemer er ikke fullstendig forstått. Noen PFAS er antatt å øke risikoen for å utvikling av ikke-alkoholisk fettleversykdom (NAFLD) og øke risikoen for diabetes. 

For å forstå hvordan PFAS påvirker organene våre ønsker vi å bruke små laboratoriedyrkede organmodeller, kalt organoider. Disse miniatyrorganene kan dyrkes fra menneskelige stamceller og tilbyr et kontrollert miljø for å studere hvordan PFAS påvirker f.eks lever og bukspyttkjertelen vår, uten bruk av dyreforsøk.

For å studere helseeffekter må vi kunne måle nivået av biomolekyler som fettstoffer i leveren og hormoner i bukspyttkjertelen. Til dette trenger vi å utvikle analytiske verktøy for å måle effektene. Først vil vi bekrefte at når leverorganoidene eksponeres for enkelte PFAS-forbindelser utvikles det NAFLD-lignende sykdom ved å sammenligne den biokjemiske profilen (proteiner og metabolitter) til organoider av lever med PFAS-eksponerte organoider. Deretter vil vi utvide den analytiske verktøykassen for å undersøke hvilke metabolske veier som påvirkes, og om effekten er den samme i NAFLD-induserte og PFAS-eksponerte organoider. Vi vil også eksponere insulinproduserende bukspyttkjertelorganoider for PFAS for å undersøke effekten av PFAS på hormonproduksjon. Når effektene av PFAS-eksponering på lever- og bukspyttkjertel-organoider er etablert, vil organoidene bli samkultivert i en chip, og effektene av PFAS-eksponering vil bli undersøkt og sammenlignet med individuelle organoider.

Persistent organic pollutants (POPs) are believed to contribute to metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and type 1 diabetes. HE-POP aims to investigate the effects of per- and polyfluoroalkyl compounds (PFAS), a type of POPs), on organ function in a controlled environment.

Organoids are multicellular laboratory-grown miniature organs, that are grown from stem cells. HE-POP will use organoids to examine how PFAS affects our organs and develop cutting-edge bioanalytical tools and methodology to measure these effects using liquid chromatography-mass spectrometry. HE-POP hypothesizes that PFAS negatively affects organ function, as evidenced by changes in hormone and lipid levels characteristic of NAFLD and type 1 diabetes. 

Organoids offer a controlled environment to study the effects of PFAS on the liver and pancreas, without the use of animal models. HE-POP aims to gain evidence of the negative effects of PFAS on organ function through controlled experiments on organoids and aid in understanding the biological mechanisms underlying NAFLD and type 1 diabetes.

HE-POP has fundaments in UN sustainable development goals, specifically #3, #12, and #14/15, seeking an understanding of diseases with worldwide prevalence, and understanding how POPs affect our life and surroundings and help enable the right regulatory actions and replacement chemicals.

HE-POP: Studying the Health Effects of Persistent Organic Pollutants, Using Mass Spectrometry, Organoids, and Organ-On-A-Chip

Rundt 7% av norske 4-åringer har så store psykiske vansker at de kvalifiserer for en diagnose, men det tar ofte lang tid fra vanskene oppstår, til de blir oppdaget og barna får rett hjelp. Myndighetene har derfor lagt tydelige føringer for at de som jobber med barn, må vite hva de skal se etter og hvordan de skal gå frem for at barna skal få den hjelpen de trenger. I Norge går over 95% av barna i barnehage hvor pedagogene blir godt kjent med barna over tid i deres naturlige miljø og har utviklingssamtaler med de foresatte 1-2 ganger i året. Barnehagen skulle derfor være en ideell arena for tidlig oppdagelse av psykiske vansker. Det har imidlertid ikke vært tilgjengelig noen tilpasset metode for de arbeidsformene og terminologi som er vanlig i barnehagene. Vi har derfor utviklet metoden Dialogbasert tidlig oppdagelse (DBTO) i nært samarbeid med pedagoger og foreldre i 8 ulike barnehager. Metoden går ut på å bruke utviklingssamtalen mer systematisk ved at både foreldre og barnehagelærer på forhånd fyller ut et spørreskjema om mulige bekymringer de har hatt for barnets utvikling og trivsel de siste månedene. I samtalen kan de så utforske og forsøke å enes om forståelsen av barnet og om det er behov for ytterligere vurdering eller andre tiltak. Tilbakemeldingene under utviklingen og tidlig utprøving tyder på at metoden fungerer godt og oppleves som et nyttig verktøy i foreldresamarbeidet. For å få tydeligere dokumentert kunnskap om hvordan DBTO fungerer i barnehagene, har vi utviklet forskningsprosjektet PRO-DIALOG. Vi ønsker med det å få kunnskap om (1) hvordan DBTO fungerer som et screening-instrument, (2) hvor brukervennlig den er, (3) hvordan den påvirker tidspunkt for igangsetting av tiltak og (4) hvordan den påvirker utviklingen av den psykiske helsen til barna over tid. 12 barnehager er plukket tilfeldig ut til å gjennomføre metoden, mens 11 skal fungere som kontroller. Foresatte til rundt 300 barn som har tre år igjen av barnehagen, vil bli spurt om å delta.

There is an unambiguous call for early interventions at the municipal level for children at risk of developing mental health problems. However, there is a surprisingly absence of socially valid methods for detecting children in need of early support.
        The aim of the project is to establish the properties of such a novel method; Dialogue Based Early Detection (DBED). We will study its properties as a mental health screener, how well it is adapted in an ordinary kindergarten context, and whether it affects activation of interventions for mental health concerns and children’s future mental health.
        The novel aspect of DBED is the systematic assessment of the child’s development and well-being by the kindergarten teacher and his/her parents, and the subsequent dialogue that aims to explore and converge their understanding of the child and conclude whether there is a need for further assessment or supportive actions.
        Parents of approximately 300 children in 23 different kindergartens aged 2-3 years will be invited to participate for the three last years before school start and follow-up the next two years. The kindergartens will be randomized to an implementation group or a control group. Parents’ socio-demographic characteristics and data from parent-teacher meetings, initiated interventions, user satisfaction, parental stress, and child mental health will be collected biannually, as well as tape recordings from interviews about user experiences of parents and teachers.
        The most critical challenges of the project will be participation rate of the invited parents in addition to attrition due to the time pressures in a busy workday in the kindergartens, and willingness of the control parents to complete the repeated questionnaires. Appropriate measures are made to take those risks into account.

Promoting mental health in young children – a sustainable dialogue based approach in kindergartens (PRO-DIALOG)

InterNASH - An intercellular-pathway therapeutic for non-alcoholic steatohepatitis

Demografiske endringer fører til at andelen av befolkningen som er arbeidsfør er fallende. I tillegg til teknologisk utvikling og import av arbeidskraft vil det å beholde unge voksne i arbeidsstyrken i flere tiår være viktig for å kunne opprettholde en sterk velferdsstat. Samtidig viser studier en økende forekomst av psykiske plager blant unge vokse – spesielt depresjon og angst. Denne utviklingen gir grunn til bekymring, både for de unges helsetilstand og deres evne til å stå i arbeidsstyrken over tid.
Det finnes mange ulike forklaringer på økningen i rapporterte psykiske plager blant unge, som for eksempel bruk av sosiale medier, økt skolepress og et mer krevende arbeidsmarked. Samtidig har det blitt hevdet at økningen også kan reflektere et redusert stigma knyttet til psykiske helseproblemer, bedre behandlingstilbud og en økende tilbøyelighet til å søke medisinsk hjelp for psykisk ubehag som tidligere ble ansett som «normalt» , såkalt medikalisering.
YoungPsych-prosjektet vil undersøke om samfunnet har blitt mer eller mindre inkluderende for unge med psykiske helseproblemer, samt om unge voksne med psykiske problemer i dag har større (eller mindre) sannsynlighet for å fullføre utdanning og være aktive i arbeidsstyrken. Videre vil prosjektet belyse i hvilken grad skolepress, stressende arbeidsforhold og bruk av sosiale medier bidrar til økningene i psykiske helseproblemer blant unge. Ikke minst vil prosjektet undersøke i hvilken grad mer åpenhet om psykiske problemer og en økende tilbøyelighet til å søke medisinsk hjelp bidrar til den observerte økning i psykiske diagnoser.
For å besvare disse spørsmålene vil prosjektet benytte seg av norske registerdata og store befolkningsundersøkelser. Resultatene fra prosjektet vil kunne hjelpe beslutningstakere, forskere og den interesserte offentligheten til å bedre forstå de nylige økningene i psykiske helseproblemer hos ungdom og unge voksne, samt i hvilken grad dette kan forventes å påvirke arbeidsmarkedene i fremtiden.

A high rate of labor force participation is an important foundation of the Norwegian welfare state. At the same time, an increasing share of young adults is not participating in the labor market due to mental health problems. Moreover, the share of young adults seeking help for mental health problems is strongly increasing. Together with a demographic shift towards an older population during the next decades, these developments have stirred concerns regarding future cohorts' ability to participate in the workforce. Work force participation is both important for the welfare state and for an individual’s social and economic integration into society. 

Against that background, the YoungPsych-project will provide the best to-date knowledge about (i) the relationship between early-life mental health problems, educational attainment and labor market attachment; (ii) the impact of academic pressure and job characteristics on the likelihood of developing mental health problems; (iii) the extent to which a lower threshold for seeking help and a more widespread use of social media can explain the increase in mental health diagnoses.

With a highly competent interdisciplinary project team, the project will produce new knowledge that is highly likely to move the field forward. The empirical foundation of the project is a uniquely comprehensive register linkage, linked to population wide survey data from the Armed Forces' selection process, and large register-linked longitudinal population-based surveys. These data sources allow for examining changes during the past two decades and to take into account different aspects of mental health, including self-perceived mental health, help-seeking behavior and doctors’ diagnoses. The strength of the project lies in the combination of exceptionally rich longitudinal data, creative research designs, modern data analysis, and important and timely research questions.

Young adults’ mental health and labor market exclusion - causes, consequences, and trends

I denne randomiserte kontrollerte studien har vi som mål å optimalisere behandlingen av pasienter med juvenil idiopatisk artritt (JIA) som er i stabil remisjon. Å finne riktig behandlingsnivå hvor risikoen for sykdomsoppbluss er balansert med byrden av å ta medisiner og deres bivirkninger er svært viktig for pasienter, foreldre og helsepersonell.

JIA er den vanligste kroniske revmatiske sykdommen hos barn og ungdom, og rammer flest jenter. Sykdommen er karakterisert av leddbetennelser, og kan føre til leddskader og funksjonstap. Heldigvis, takket være moderne medisiner og behandlingsstrategier, kan mange JIA-pasienter oppnå "vedvarende remisjon" - uten symptomer på sykdommen.

Men fortsatt vet vi ikke: hvordan bør JIA-pasienter som er i remisjon best behandles? Det finnes ikke kontrollerte studier som veileder oss, og det foreligger ingen anbefalinger om hvorvidt behandlingen bør trappes ned eller avsluttes.

Derfor introduserer vi "MOVE-JIA": en nasjonal studie som vil inkludere JIA-pasienter i vedvarende remisjon behandlet med tumor nekrosefaktor-hemmere (TNFi) og metotreksat. De vil bli tilfeldig delt i tre grupper: A) Gradvis seponering av TNFi, B) Gradvis seponering av metotreksat, eller C) Fortsatt stabil behandling med både TNFi og metotreksat. Studiens hovedmål er å måle hvor mange pasienter i hver gruppe som opplever sykdomsoppbluss i løpet av et år.

MOVE-JIA studien vil bli den første studien som undersøker om å redusere metotreksat fører til færre sykdomsoppbluss sammenlignet med å redusere TNFi hos JIA-pasienter i remisjon. Studien vil også vurdere om behandling med kun TNFi eller kun metotreksat er like effektivt som kombinasjonsbehandling.

MOVE-JIA studien er et nasjonalt samarbeid som inkluderer alle barnerevmatologiske avdelinger i Norge og aktiv deltakelse fra pasientene. Dette sikrer rask overføring av resultater til klinisk praksis. Funnene vil gi etterlengtet kunnskap om hvordan vi best skal håndtere barn og ungdommer med JIA i remisjon.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and adolescents and occurs 3-6 times more often in girls. It is characterized by joint inflammation with a potential for joint destruction and disability if not treated. Sustained remission (no sign of active disease) is an achievable goal in JIA after the introduction of biological agents such as inhibitors of tumor necrosis factor (TNFi) and treat-to-target strategies. However, strategies to best treat JIA patients in remission remains unclear. No controlled studies have addressed the effect of tapering strategies for JIA in remission, and there are no current recommendations for stepdown or optimizing maintenance treatment. Given the risks, side effects and costs of JIA medications, treatment withdrawal can give patients and families relief and improve their quality of life. 
The MyJIA-Ahead trial is a national, investigator initiated, multicenter, 36 months, RCT of JIA patients in sustained remission on TNF-inhibitor and methotrexate. 150 JIA patients will be randomized 1:1:1 at baseline to A) Stepwise withdrawal of TNFi, B) Stepwise withdrawal of MTX, or C) Continued stable treatment with TNFi and MTX. The primary endpoint is proportion of patients with disease flare within 12 months. Key secondary endpoints are time to flare and time to regain remission after flare. If a disease flare occurs, the patient will return to the full dose study medication (the treatment the patient was receiving at baseline). Exploration of risk factors for disease flare includes patients reported health status and preferences, clinical characteristics, immunogenicity, molecular signalling (transcriptional, cellular and genetic risk) and ultrasound assessment of synovitis.

While evidence-based advice for starting therapies in active disease is available, The MyJIA-Ahead will provide much needed knowledge about treatment continuation in children and young adults with JIA in remission.

Moving towards evidence-based treatment strategies for children with juvenile idiopathic arthritis in sustained remission: The MOVE-JIAtrial

Midlene fra ISPHUM-ISP - Humaniora fordelt på år

Midlene fra ISPHUM-ISP - Humaniora fordelt på fylker

Midlene fra ISPHUM-ISP - Humaniora fordelt på fagområde

Rektor

Forskningssabbat ved VID Vitenskapelige høgskole (tidligere Misjonshøgskolen)

Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD). Surgical treatment (total repair) has been available for 50 years, with favorable outcome in most patients. We are now, however, faced with an increasing number of patients presenting with right ventricular (RV) failure. Furthermore, because of geometric limitations, there is currently no generally accepted echocardiographic standard for assessment of right ventricular function.
Speckle tracking echocardiography (STE) is a new method for angle-independent assessment of regional myocardial deformation properties (strain rate, strain and torsion).

To test the hypothesis that right ventricular function can be assessed by speckle tracking echocardiography in patient s after repair of tetralogy of Fallot, we will perform two studies:

Study 1: Correlation between RV function by STE and physical exercise capacity.

50 patients followed at the Toronto Congenital Cardiac Center for Adults previously undergoing repair for  TOF, will be recruited for echocardiography and cardiopulmonary exercise test. This population will invariably have a wide range of RV dysfunction and we will correlate RV function by STE to physical exercise capacity. We will use magnetic resonance imag ing (MRI) tagging as reference method. 


Study 2: Alteration in RV function during surgical interventions.

It is well known that extensive cardiac surgery reduces myocardial function temporarily (stunning). To investigate if STE can identify changes in RV-function over time, we will perform per- and postoperative STE in 30 TOF patients admitted for surgical intervention. MRI tagging will be performed preoperatively and 2 months postoperatively. Per- and postoperative central venous oxygen saturation wil l be recorded to assess cardiac output.

Non-invasive Assessment of Right Ventricular Function in Patients With Tetralogy of Fallot

Therapeutic alliance is considered to be one of the central aspects of the relationship between therapists and patients in psychotherapy, as well as therapy process and outcome. Therapeutic alliance includes three central aspects: the goals of therapy, ho w to proceed to reach the goals, and the bond between therapist and patient. The project will analyze personal characteristics in therapists and patients that may influence the psychotherapy relationship in favourable versus unfavourable directions. A suf ficient strength of the alliance is important from early on in therapy. The study uses data from Norwegian Multicenter Study on Process and Outcome of Psychotherapy, an internationally well known study of psychotherapy, which now has complete data from ne arly 400 patients, ready for analyses. 

Analysis of the impact of therapists' interventions, i.e. what the therapists actually say to the patients, particularly their use of interpretation, is another research question. Different patients within the same  therapist respond differently; some obtain a high change, while others obtain only low change. This investigation will clarify the associations between therapist interventions and patients? development during therapy. Sequences of the dialogue between th erapist and patient will be explored in detail. Several variables that measure change over the course of therapy will be analyzed, e.g. the change of patients? defensive functioning, whether it becomes more mature during therapy. 

Therapists' and patient s' evaluation of the outcome usually overlap to some degree, but a certain discrepancy is expected. How their evaluations overlap and how they differ, will be examined, in order to clarify the therapists' and patients' different perspective on the psychot herapy results. The analyses will bring about information regarding what is a positive outcome, from the patients' perspective, and what are important results, from the therapists' perspective

The significance of therapist and patient characteristics in psychotherapy

Chronic heart failure (HF) is an important and increasing cause of cardiovascular morbidity and mortality. Several lines of clinical and experimental evidence indicate that inflammation may play an important role in the development of HF, a notion that ha s opened up for new treatment principles in this disorder. 
	The aim of the project is to characterize the potential pathogenic effects of new inflammatory mediators in HF. We will especially focus on immunopathogenic mechanisms related to regulatory chem okines and ligands in the TNF superfamily. Furthermore, we will through interventional studies in patients with HF, investigate how immunomodulating therapy affects these and other immunopathogenic mechanisms in this patient group. Such "in-depth" studies  will represent an important step towards new therapeutic modalities.
	Central in the project is plasma/serum and isolated monocytes and lymphocyte subpopulations from HF patients. An important supplement to clinical studies will be animal models for HF a nd transgenic mouse models, as well as studies of cardiomyocytes, endothelial cells and macrophages in vitro. Important laboratory methods will be ELISA, western blots, flow cytometry and real-time RT-PCR.
The current project attempts to study inflammator y mechanisms in HF and approaches unresolved issues in the intersection between cardiology, immunology and molecular biology. and represent a unique opportunity to establish a bridge between bench and bedside, which is of the outmost importance in order t o exploit in clinical medicine the recent development in immunology and molecular biology. With respect to the important health problem HF represents both in Norway and in other countries, such new therapeutic options may have important consequences. The current project will also be relevant for other disorders in which chronic inflammation is involved as an important pathogenic factor such as autoimmune diseases, chronic infectious disorders and cancer.

Pathophysiological role of inflammatory mechanisms in heart failure

In this project we plan to continue our long term studies regarding basic mechanisms of brain injury in newborn infants. We have previously  shown that oxidative stress both in preterm and  term infants induces long term potential harmful effects that may   affect growth and development. As the first we have shown that a brief exposure of oxygen at birth may increase neonatal mortality and increase the time to first cry and breath. Further, heart rate at 90 sec and Apgar score at 5 min are  significantly l ower in newborns exposed to pure oxygen at birth. These data that recently have been summarized in a Cocrhane review and a meta-analysis and an editorial in The Lancet indicate that ten thousands of newborn infants worldwide may be  rescued  each year by avoiding the use of pure oxygen for newborn resuscitation. Thus this finding may represent one of the most successful breakthroughs in neonatal medicine as well as in Norwegian medical research.

We also have  gained new insight into basic mechanisms of b ilirubin toxicity on the human brain. 

By using human neuron cells in culture, animal models as  well as participating in international randomized clinical trials we will contribute to new knowledge and probably in the development of new therapeutic guid elines for newborn infants. Through an extensive national and international collaboration we have access to the most sophisticated methods to assess cell affection and injury even at the molecular level.

Injury in newborn infants. Basic mechanisms related to oxidative stress and bilirubin encephalopathy

Regulatory T cells (Treg) represent 5-10% of the CD4 T cells and are identified by constitutively expressing CD25. Treg are subdivided into naturally occuring Treg devolped in the thymus, and adaptive Treg that are induced in the periphery from naïve CD4 T cells. Naturally occuring Treg are intstrumental in suppressing autoreactive T cells and thereby prevent autoimmune diseases. Adaptive Treg that are induced in the periphery, suppress immune responses to exogenous antigens and tumor antigens. We have re cently demonstrated that regulatory T cells inhibit virus-specific immune responses in chronic viral infections. The molecular mechanism of the suppressive function of regulatory T cells is not yet elucidated. Based on our unpublished observations, the hy pothesis of the present application is that adaptive regulatory T cells develop from naïve T cells as a result of
continuous antigen stimulation by HIV antigens in the vicinity of antigen presenting cells. Adaptive regulatory T cells express COX-2 that le ad to production of prostaglandins, including PGE2 that binds to G-protein coupled receptors on normal T cells engaged in the immune response against the virus.
PGE2 leads to production of cAMP that activates an inhbitory signal pathway that involves prot ein kinase A (PKA) in the T cells which suppress the anti-viral immune response. Therapeutic strategies devised to target the COX-2 - PGE2 - cAMP - PKA - inhibitory pathway may have application as immunomodulatory treatment for HIV. Disrupting the pathway  may enhance the immune response against the virus, reduce the need for antiviral treatment, reduce the incidence of opportunistic infections and potentially enable the immune system to eradicate the virus.

Novel therapeutic strategies for immunostimulation in HIV targeting CD25+ T-regulatory cells.

The project is aimed at developing male contraceptives on a collaborative basis between the Institute of Basic Medical Sciences (project leader Bjørn Steen Skålhegg) and the Department of Andrology, The National University Hospital of Norway (research lea der Dr. Peter Fedorcsak and head of department Dr. Tom Tanbo). We have made a unique discovery in that we have identified and characterized the function of the gene and  the protein for CaS. CaS is a catalytic subunit of the protein kinase A (PKA) family of serine (Ser) and threonine (Thr) protein kinases and is only expressed (identified) one place in the body, namely the sperm cell. We and others have shown using knock-out (KO) mice that CaS regulates sperm cell forward velocity and male fertility. This  conclusion is based on to experiments performed on sperm cells isolated from CaS KO mice which are unable to penetrate the egg due to abrogated swimming capability. Moreover, breeding experiments with such mice demonstrate that 100 % of the male mice KO for CaS are infertile. Our experiments demonstrate target validation of CaS as a unique molecule that can be manipulated by substances (leads) that can be used to develop male contraceptives. Due to the  unique location of CaS and its function (one target , one place, one function) our discovery is rare both in a national and international perspective. Substances that can target CaS? function are expected to be used pharmacologically to regulate sperm movement without side effects.

Development of male contraceptive through manipulation of CaS

The complement system is an essential part of innate immunity protecting the host against infection. However, it is a double-edged sward in the sense that inappropriate activation may damage host tissue. Uncontrolled systemic activation of complement, as seen in sepsis, may contribute to the breakdown of homeostatic mechanisms leading to the irreversible state of septic shock. Sepsis is a major health problem with high morbidity and the mortality is in the range of 30-70%. The pathopysiology is complex. T here are more than 200 putative mediators of sepsis and there have been more than 70 well designed clinical trials to test the effect of manipulation of a number of these mediators. The results in large have been disappointing. Endotoxin (LPS) has been im plicated in the pathogenesis of gram-negative sepsis by inducing synthesis of proinflammatory cytokines through binding to CD14 and the toll-like receptor 4 (TLR4)/MD-2 complex. Neutralisation of LPS or blocking of CD14 has been effective in preventing le thal shock in animal studies, but results from clinical studies have been disappointing as for most other therapeutic strategies. Based on pilot data recently obtained in vitro, we hypothesise that inhibition of complement using specific antibodies and pe ptides combined with neutralisation of LPS-induced effects by blocking CD14/TLRs may attenuate the uncontrolled inflammatory reaction which leads to breakdown of homeostasis during sepsis. This combined approach may be a therapeutic strategy in the treatm ent of sepsis. To test this hypothesis a number of candidate antibodies and peptides for complement inhibition and antibodies to block CD14/TLRs in pigs will be tested in vitro and the best candidates will be selected for the a combined therapeutic strate gy in a pig model of gram-negative sepsis.

The relative role of complement and LPS in sepsis/SIRS: a rational for combined treatment with complement- and CD14/TLRs inhibitors.

Preterm birth (PTB) is the main cause of perinatal mortality and short- and long-term morbidity. The pathophysiology of spontaneous PTB remains poorly understood. Infection and inflammation, fetal growth, uterine distention and decidual haemorrhage are be lieved to be part of the mechanisms resulting in preterm delivery.

The genetic aspects of the mechanisms of spontaneous PTB will be the main focus of this research project, and it will be conducted as part of the Norwegian Mother and Child cohort study. Biological material, in the form of maternal serum, has been sampled at 18th gestational week and at delivery. Paternal serum has also been sampled. Umbilical cord blood (fetal blood) has been sampled at delivery. At present more than 50 000 deliveries ar e included. DNA is extracted and stored. The Norwegian Mother and Child cohort study has prospectively stored a huge amount of epidemiological data from questionnaires regarding the included deliveries. These data can be linked to the Norwegian Medical Bi rth Register as well.     

The study will be conducted using a triad-design with contol trios. We will use a candidate gene approach defined from a thoroughly review of the literature with regard to plausible pathways and available data on the protein le vel from women with threatening PTB. New high throughput technologies within the genetic field will be used. A new analytical model developed at Vanderbilt University, Nashville Tenessee will be used in the analyses after genotyping. Other analytical tool s applicable in trios will also be used.

The significance of the project will be an increased understanding of PTB and its mechanisms at the genetic level. Furthermore, it will contribute to our growing knowledge of the preterm low-risk population. This will make it possible to find strategies for treatment and prevention of PTB. An intermediate aim will be development of biomarkers for PTB in women without symptoms of threatening preterm delivery.

Spontaneous preterm birth and genetics

The purpose of this project is to characterize mechanisms for bone regeneration and healing and to use this knowledge to develop new strategies for improving the performance of loaded metal implants used to restore function in compromised skeletal structu res. From the clinical perspective skeletal implants, including dental and orthopaedic devices should be able to withstand loading as soon as possible after placing. A shortened postoperative period is important to avoid serious complications and to resto re skeletal function before irreversible physiological, pathological and morphological changes are manifest. For the community a shortened "time to load" also is synonymous with reduced recovery costs and improved health care services. Moreover, if metal implant surfaces can be modified to allow an optimal and stable integration into boney tissues, the need for revisions of failing implants will be reduced with accordingly positive outcomes for patients and community alike.
Thus, to achieve an optimal bio logical reaction in the bone following replacing of an implant, and to develop new biomimetic strategies for improved implant performance in bone, 3 major factors must be optimized and carefully controlled. These are: 1) The surface structure and surface chemistry of the implanted device, 2) The nature and quality of the tissue-implant interface and the peri-implant environment, 3) The physiology and biology of the healing process in the compromised bone. 
Each of these topics will be studied in 3 collabo rating sub-projects addressing several research areas including material science, biofilm aggregation, extra-cellular matrix biology and bone biology. By taking full advantage of the multidiciplinary research environment, the highly experienced researcher s behind this application aims at establishing a problem oriented, innovative project team with high productivity and a high change for success in this brave project at the forefront of biomaterial research.

NOVEL BIOTHERAPEUTIC STRATEGIES FOR IMPROVING IMPLANT PERFORMANCE IN BONE

The aim of this project is to identify factors contributing to development of multiple sclerosis (MS) in a PhD project. MS is a debilitating inflammatory disease of the central nervous system. The etiology is unknown, but both genetic and environmental fa ctors are involved. Identification of these factors can allow development of effective therapies, and could enable prevention of the disease in genetically susceptible individuals.
The sub-aims of this project exploit the results obtained through previous  collaborative efforts within the Oslo MS group, the Nordic Group of MS genetics and the GAMES (Genetic Analysis of Multiple Sclerosis in EuropeanS) collaborative. In particular we will correlate HLA class I and II, KIR and SH2D2A genotypes with MS diseas e expression. Since Norway is a high prevalence region for MS, we will also exploit the possibility of searching for susceptibility factors in MS patients having migrated to Oslo from low prevalence geographic regions. Furthermore, since activated T cells  are supposed to play an important role in the etiology of MS, we will perform a systematic search for candidate genes involved in signal transduction pathways leading to T cell activation. Also, there is an agreement that the PhD student will work for a period in Cambridge, UK, to perform a candidate gene study in one of the gene regions identified through the GAMES project. The PhD student will also take part in the work with establishment of a national MS DNA biobank. This will be done in collaboration  with the National MS competence centre and the National Institute of Public Health. 


Identification of genetic and environmental factors contributing to disease susceptibility and clinical presentation of multiple sclerosis

Hyperemesis gravidarum (HG) is defined as severe, intractable nausea and vomiting in early pregnancy. The HG-patient suffers from dehydration, weight loss, ketonuri and a nutritional deficiency. HG affects 0,5-2,0% of pregnant women, and the etiology is u nknown. Until recently HG was believed to have a psychological cause, but is now considered to have a biological explanation. As yet, few studies on risk factors of HG have been published. There is evidence that HG is associated with young age, immigratio n from non-western countries, intake of saturated fat before pregnancy and female gender of the fetus. We want to estimate the association between HG and pre-pregnant fat intake in a subcohort of 8000 women who are participating in The Norwegian Mother an d Child Cohort Study (MoBa). Another part of this project is a population based cross-sectional study of registry data of The Medical Birth Registry of Norway (MFR) and Statistics Norway. We will focus on the prevalence of HG according to time trends, liv ing area, ethnic group, parity and age. In addition we want to estimate familial correlations in the registry. This study may provide knowledge that will elucidate the etiology of HG. This project can also contribute to prevent the disease or lead to an e arly, targeted treatment.

Infections, prepregnant diet and other environmental factors as possible causes of hyperemesis gravidarum (HG).

Rheumatoid arthritis (RA) is a common multifactorial inflammatory disorder. It is characterised by a chronic synovial inflammation that destroys the affected joints and causes disability. The molecular basis of RA is largely unknown, but it is clear that the main genetic contribution to RA is by certain DR4 genes in the HLA complex. No environmental factor has been identified. These observations, and the presence of antibodies that target self proteins, indicate that RA may be a “truly” autoimmune disorde r driven by T cells specific for self-peptide-DR4 complexes. The problem with this hypothesis is that self-reactive T cells mostly become tolerant during maturation in the thymus. An intriguing alternative is that rheumatoid joint T cells, rather than nat ive self, recognise modified self-peptides that are not expressed in the thymus and thus not established tolerance to. Strong arguments in favour of this possibility come from recent data on the disease-specific serum autoantibodies in RA. It appears that  most of these antibodies, whose production by B cells require specific T cell help, target modified proteins in which post-translational deimination of arginine residues to yield citrulline have occurred. Our ultimate aim it to find out whether the synov ial T cells that provide help to the citrulline-specific B cells also recognise deiminated peptides. To this end we will search for citrullinated peptides in vivo and establish systems for deiminating candidate proteins in vitro using the only human enzym e that can deiminate protein bound arginine; peptidyl arginine deimnase. Identified peptides will ultimately be tested with synovial T cells. This approach should allow better insight into the pathogenesis of RA and contribute to the development of a more  specific and safer therapy for the disease. The latter is critically needed as the currently available drugs for RA are non-specific immune suppressors with serious systemic side effects.

The role of Peptidyl Arginine Deiminase and protein citrullination in the pathogenesis of rheumatoid arthritis

Colorectal cancer (CRSC) is one of the leading cancers and the mortality is high and hardly has changed over the past decades. It is believed that most CRCs are preceded by a pre-invasive phase, called colorectal adenoma (CRA). 
About 2-5% of all CRAs pro gress to cancer. It is therefore important to have accurate identifiers of metachronous cancer risk in CRAs, but current methods (number of polyps, polyp size, dysplasia grade and histologic type) are inaccurate. 
The number of studies targeting CRAs for the analysis of metachronous risk factors is limited, due to the fact that follow-up time must be long and the number of patients large (due to the relative low frequency of cancers in CRAs). 
We have collected before nearly 8000 polyps, and unpublished r esults have shown that a morphometrically defined Monotonous Population of Elongated Cells (MPECS) in ColoRectal Adenomas (CRAs) is much stronger predictive of metachronous cancer (Hazard ratio=HR=54, positive predictive value 20%, sensitivity 100%, negat ive predictive value 100%) than classical features (HR1.5-3). 
The current research project aims to analyze a series of routinely diagnosed 21000 biopsies of CRAs, to validate these potentially important results. If confirmed, this may drastically prevent  under-and overtreatment of CRA patients, and save large amounts for the national health care system. MPECS may then be used as surrogate intermediate endpoint biomarkers (SEBS) for detecting a specific protein profile using proteomics. Soluble proteins a lso may be detected in blood and sputum, thereby opening the possibility for population screening and perhaps even vaccination to prevent CRAs and perhaps also CRCs.

Possible implications of the research results are:
1. Implementation in diagnostic patho logy routine and
2. Possibly in clinical gastro-enterologic decision making.
3. Early etection of CRAs by proteomics.

Dr. Baak is professor-2 of pathology, Univ. of Bergen, position accepted 16-06-2004.

MPECS to detect high risk colorectal adenomas

Meconiumstained amniotic fluid is present in approximately 10-12% of all deliveries. Out of these approximately 5% develop respiratory problems called Meconium Aspiration Syndrom (MAS). This is caused by aspiration of fetal stools (meconium into the lungs ) and occur mainly in term or postterm infants. In severe cases this leads to pulmonary insufficiency with high morbidity and a mortality of 5-10%. Many need long time intensive high technology care for instance inhaled NO gas or extracorporeal membrane o xygenation.

The group has for the first time shown that some of the toxic effects of meconium can be inhibited by adding albumin. We have for the first time shown a massive activation of the complementsystem in experimental MAS. These findings elevate ou r understanding and insight of the patophysiological mechanisms in MAS and might lead to new therapies for this feared condition.

The following study is planned as two main parts constituting a doctoral thesis:. 

A) The effect of intrathracheally instil led albumin as rescue therapy on the course of experimental MAS 
                                                                                                        
B) The effect of complementinhibition on the pathophysiology of experimental MAS.                                     

To study the effect of complement inhibition by diluting meconium in dextran sulphate or nafamostate mesilate which both are known to inhibit complement, before instillation into the lungs. A subproject will be includ ed where inhibition of the meconiuminduced  inflammatory reaction  in vitro will be tested  using both complement inhibitors and CD 14 blockers

Pathophysiological and Immunological Aspects of Meconium Aspiration Syndrom
A search for new understanding and therapy

Finegrained methods are needed to assess postural stability during standing and walking. Such measures must be reliable, valid and easy to use under real life conditions. The Balance and Gait Unit, University of Bergen is a member of the EC thematic netwo rk Prevention of Falls Network Europe (PROFANE) and is engaged in developing and applying bodyworn sensors and other ambulatory methods for assessing balance and gait. Section of Geriatric Medicine, St. Olavs Hospital/NTNU and Rikshospitalet University Ho spital are engaged in projects utilising similar methodological approach. Based on previous and ongoing research by the cooperating groups in collaboration with SINTEF, Department of Applied Cybernetics, the principal objective is to objectively assess lo comotor control in clinical populations, by adapting and applying commercially available state-of-the-art technology developed for governing movement of aerial and nautical objects. The project is aimed at updating and further develop measures currently u sed by the groups to assess postural stability by combining the methodological expertise of PROFANE and the Bergen group with the clinical expertise of the Trondheim and Oslo groups, in a collaborating network. The network will expand ongoing engagement w ith SINTEF-Dept. of Applied Cybernetics to improve user interface and data logging solutions by also including the application of new technology. Funding from NFR is applied for to cover R&D services from SINTEF and necessary networking to fulfil the obje ctives. Combined with measures from other ambulatory instruments used by the networking groups, the results from this project may improve and expand the applicability of present methodology significantly. Thus the ground may be prepared for further Norweg ian participation in a future pan-European intervention study planned by PROFANE, where state-of-the-art ambulatory methodologies are needed.

Development of methodology and equipment for assessing postural stability during standing and walking

PE is regarded as a two-step disease, with poor placentation and placental hypoperfusion as the first step in pathogenesis. The recognition of fetal trophoblasts by maternal uterine (uNK) cells is fundamental in placental development. Observations suggest  that the superficial trophoblast invasion in PE may be due to  reduced/aberrant trophoblast expression of HLA-G and FasL (both inhibiting NK cell cytotoxicity). In contrast, other data suggest that PE is due to increased uNK cell cytotoxicity. In this pr oject, trophoblast,  uNK cells and apoptosis in decidual tissues from pregnancies with poor placentation and controls will be studied (using immunohistochemical methods with mabs against relevant markers). In vitro NK cells cultures will be established fr om decidual tissues for functional analysis.  Finally, expression of genes involved in interaction between trophoblasts/NK cells, HLA-G phenotypes and maternal susceptibility genes (PREG1, see below) will be assessed by microarray analysis.
Placental hypo perfusion may evoke maternal responses including endothelial dysfunction and clinical PE manifestations occur (step 2). Genetic factors influence the character of maternal responses, and a region of maternal PE susceptibility on Chrom 2 (PREG1) has been i dentified. Association between genes located within PREG1 and disease will be studied in candidate gene study on cases with several PE pregnancies (n=266) and controls in the HUNT population. Further analysis of gene assossiations will be done in a family  linkage study (n=150 PE families). 


Immune mechanisms and genetics associated with development of pre-eclampsia/eclampsia(PE/E)

Active is a prospective randomised trial of autologous chondrocyte transplantation compared with alternative treatments for patients who have had a failed primary treatment for chondral defect(s) in the knee. 660 patients in 14 cenres (12 in the UK, 2 in Norway) will be recruited over 2-3 years. Patients will be randomised to 1. ACT or 2. Alternative treatment(pre-specified by clinician, individually for each patient)
The primary outcome measure will be time to cessation of benefit of treatment.
Secondary  outcomes will be functional knee scores (Lysholm, Cincinatti, IKDC) and Quality of life measures (EQ5D) at intervals up to 10 years post operation. Health economic analysis will include Resource Usage.

ACTIVE

The liver strictly regulates its own volume relative to body mass. We aim to investigate and manipulate the mechanisms underlying this phenomenon. 

Based on increasing evidence that regeneration after partial hepatectomy (PHx) is triggered immediately by  changes in hemodynamics, we have designed and tested through a series of trials, a surgical experimental model of partial portal vein arterialisation (PPVA) in the pig. The controlled shunting of arterial blood from the aorta to the portal vein branch su pplying liver segments II, II and IV creates a hyperdynamic flow and increased sinusoidal shear stress, hypothetically inducing selective hyperplasia in the arterially perfused area resulting in a supranormal liver weight/body mass ratio surpassing the na tural confinements of liver growth.

The hypothesis that increased sinusoidal shear stress results in induced liver hyperplasia, possibly by the same molecular mechanisms seen after PHx, will be examined in a chronic series where the animals undergo a PPV A, which they bear for 21 days after which liver weight and volume changes and BrDu incorporation are measured. 

To better understand the mechanisms surrounding liver regeneration and hyperplasia, and how these may be manipulated, the molecular-genetic, metabolic, hemodynamic, ultrastructural, biochemical and extracellular matrix component changes occurring during PPVA will be examined in detail in an acute series.

Should the metabolic profiles attained from segments II, III and IV by microdialysis reve al the expression of specific growth factors and cytokines, then further experiments will be planned aimed at inducing liver growth by utilizing these substances.

Induced Liver Hyperplasia

Zinc and common childhood infections - field trials in Nepal

Venous thromboembolism in pregnancy

Ekstragonadale germinalcelle tumores (EGCCT) representerer en klinisk viktig og vitenskapelig meget interessant undergruppe av maligne germinalcelle tumores (MGCT). Norge er nummer 2 på verdenstoppen hva insidens av disse svulster angår, og antall per år  er økende uten at årsaken for denne økningen er kjent. Behandlingen er intensiv og bør gjøres så skånsomt som mulig hos disse unge pasienter pga. risiko for kreftutvikling senere i livet og langtidsbivirkninger. Behandlingen justeres etter prognostiske f aktorer bl.a. ved å identifisere de pasienter som ikke trenger omfattende kirurgi etter gjennomgått kjemoterapi. Det skal brukes fire metoder: 
<h>1. Journalgjennomgang og klinisk oppfølging. 
<h>2. CGH for bestemmelse av genekspressjon i vev fra MGCT. 
< h>3. Etablering av tissue micro array (MTA) for EGCCT til analysering av patogenetisk viktige kandidatgener som tidligere har blitt identifisert for testikkelkreft. 
<h>4. DNA ekstrasjon av tidligere nedfrossete leukocytter og bestemmelse av SNPs for repa rative gener. 
<i>Vitenskapelig betydning</i>: Resultatene vil bidra til å forstå patogenesen av EGCCT og respons til kjemoterapi. Variasjon i SNPs for reparative gener vil øke forståelsen for variabiliteten i behandlingsrelatert bivirkningsnivå. 
<i>Klin isk betydning</i>: Resultatene vil hjelpe klinikeren til å individualisere en risikoadaptert behandling som vedlikeholder dagens høye responsrate (>90%) hos disse unge pasienter samtidig med bivirkningsnivået minimaliseres.

Genetikk i klinisk onkologi: Ætioilogiske og terapeutiske undersøkelser hos pasienter med malign germinalcelletumor (MGCT)

Høy mammografitetthet er en av de sterkeste kjente risikofaktorene for brystkreft. En vet lite om hva høy mammografitetthet innebærer på det molekylære plan, selv om det hevdes at det avspeiler brystcelleproliferasjon. 
Prosjektet ønsker å undersøke om de t er sammenheng mellom mammografitetthet og genekspresjonsmønstre i henholdsvis det tette mammavevet og leukocytter. Grovnål-biopsimateriale fra friske kvinnebryst analyseres ved mikromatriseteknologi. Blodprøver fra kvinnene brukes til analyser av serum,  samt DNA og RNA fra leucocytter. En hypotese er at høy mammografitetthet som skyldes proliferasjon vil ha spesifikke ekspresjonsmønstre i perifere leukocytter da disse er "sensorer" for en pågående proliferasjon et annet sted i kroppen. Kvinnene blir bed t om å fylle ut spørreskjema om bruk av hormonpreparater, antall barnefødsler og andre viktige riskikofaktorer for brystkreft. Prosjektet vil statifisere ekspresjonsdata med hensyn på HRT-bruk for å se om dette påvirker ekspresjonsmønster. 
Resultater fra  en pilotundersøkelse viser at kvinner er positive til deltakelse i en slik studie og at vi får RNA som gir meget bra micro-array resultat. 
Dersom vi kan identifisere spesifikke ekspresjonsmønstre hos kvinner med høy mammografitetthet, vil dette kunne hj elpe oss å identifisere nye vesentlige gener eller genkombinasjoner som kan være vesentlige risikofaktoerer for brystkreft.

A study of global gene expression analysis to evaluate mammographic densities and risk for breast cancer

Pasienter med ansikts-/kjevesmerter og kjevefunksjonsforstyrrelser utgjør en stor og heterogen gruppe som kan ha tildels betydelige plager. Det er vel kjent at myalgi knyttet til "stress" er en stor undergruppe i denne pasientkategorien. Prosjektet ønsker  å fortsette forskning vedrørende en annen undergruppe av denne pasientkategorien, karakterisert ved patologiske kjeveleddsfunn demonstrert med avansert MR diagnostikk. Ved hjelp av detaljerte MR analyser skulle det være mulig å klassifisere pasientene i  vel-definerte undergrupper, som senere kan bli basis for spesifikk diagnose, behandling og prognose-evaluering. Ved University of Rochester Medical Center har en tilgang på MR analyser av kjeveleddene på flere hundre pasienter som gjør det mulig å få uta rbeidet et slikt klassifikasjonssystem, med utgangspunkt i nylig publiserte arbeider som forstudier til prosjektet. Som tilleggsprosjekt vil MR analyser av kjeveledd av pasienter undersøkt på Rikshospitalet bli utført, ved baseline og ved 10 (15) års foll ow-up.

Temporomandibular Joint Disorders: Proposal of a new calssification system for severity using MR imaging

Utvikl. av Dobutamin STress Ekkokardiografi med en ny kvantitativ ultralydsmetode, Strain Rate Imaging Videreutvikling i Brisbane, Australia

Hypotesen, som bl.a. baserer seg på egne originale funn, er at immunologiske og inflammatoriske mekanismer spiller en viktig patogenetisk rolle ved utvikling av koronar ischemisk hjertesykdom, både ved å påskynde den aterosklerotiske prosessen, og ved å m ediere utvikling av plakkruptur. Prosjektet vil studere hvordan det anti-inflammatoriske cytokinet interleukin-10 påvirker faktorer som er avgjørende for plakkstabilitet slik som matrix nedbrytende enzymer og graden av apoptose av skumceller og makrofager . Prosjektet vil videre studere hvordan IL-10 påvirker lipidomsetningen, og hvordan samspillet mellom IL-10 og kjernereseptorer (PPARs og LXRalfa) påvirker lipidhomeostasen. Studiene vil bli gjort i makrofagcellelinjer og på leukocyttsubpopulasjoner fra p asienter med aterosklerose, men også ved bruk av genetisk manipulerte mus. Bl.a. vil cDNA mikromatriser bli brukt som screening verktøy, og vha siRNAs teknikk vil vi spesifikt studere effekter av aktuelle kandidatgener involvert i sykdomsprosessen. Prosje ktet tar utgangspunkt i at immunologiske prosesser kan spille en viktig patogenetisk rolle hos pasienter med aterosklerose og koronarsykdom. Prosjektet vil kunne kaste lys over nye patogenetiske mekanismer ved utvikling av hjerte- og karsykdom og vil på l engre sikt kunne danne grunnlag for nye former for terapi i denne pasientgruppen. Forskningsprosjektet inngår i et større tematiske satsningsområde ved Det medisinske fakultet, Universitetet i Oslo.

Betydningen av interleukin (IL)-10 ved inflammasjon og aterosklerotisk hjerte- karsykdom

Systemisk hypotensjon, enten som følge av hypovolemi eller nedsatt hjertefunksjon, er en viktig årsak til økt morbiditet/mortalitet hos premature barn. Umodne organsystemer gjør den kliniske vurderingen av årsaken til hypotensjonen vanskelig og det foreli gger ingen gode objektive metoder til å vurdere hypovolemi. Signifikante ekstrakardiale shunter (ductus arteriosus og ductus venosus) vil ytterligere komplisere den kliniske vurderingen. Det er også lite kunnskap om hvordan de ulike infusjonsvæsker (kollo ider, krystalloider og blodprodukter) påvirker hjertefunksjonen og væskefordelingen mellom de ulike væskerom i kroppen (intravaskulære-, intestitielle-og intracellulære væskerom). En portocaval shunt (ductus venosus) vil kunne medføre nedsatt produksjon a v plasma proteiner (kolloid osmotisk trykk) og derved påvirke væskebalansen. 
Prosjektet har til hensikt å evaluerer de sentrale hemodynamiske forhold (hjertefunksjon og shunter) og væskebalanse hos premature barn (< 30 uker og i I leveuke) som får ulike  infusjonsvæsker i behandlingen av hypotensjon. Med utgangspunkt i målinger av det sirkulerende blodvolum vil en evaluerer bruken av ekko-kardiografi som diagnostisk verktøy ved vurdering hypotensjon. En vil søke å etablere en matematisk modell for beregn ing av væskefordeling mellom de ulike væskerom etter bruk av ulike typer infusjonsvæsker og blod. Betydningen av de ekstrakardiale shunter for hemodynamikk og væskebalanse vil evalueres ved hjelp av ultralydteknikk og cytokinmålinger

Rationale for væsketerapi hos premature barn - betydningen for hemodynamikk, shunter og cytokiner

Redusert skjelettmuskelfunksjon hos pasienter med hjertesvikt: biokjemiske forandringer i skjelettmuskel

Genetic and epidemiological studies of orofacial deft. in Norway

Parkinsons sykdom skyldes at dopaminproduserende nerveceller i hjernen dør. Behandlingen i dag er rettet mot symptomlindring, men en har forsøksvis implantert nerveceller fra humane fostre. Nyere forskning har imidlertid oppdaget umodne stamceller i den v oksne hjerne, og forskningsgruppen har gjennom et samarbeid med Karolinska Sjukhuset klart å isolere stamceller fra ventrikkelveggen i hjernen til voksne pasienter, og vist at disse kan utvikles til funksjonsdyktige nerveceller som kommuniserer med hveran dre. 
Hovedmålet er å utvikle en teknikk der stamceller fra hjernen til voksne mennesker kontrollert kan isoleres, dyrkes og påvirkes til å bli dopaminproduserende nerveceller. Humane stamceller vil bli dyrket sammen med benmargsceller fra kraniet samtidi g som kjente vekstfaktorer tilsettes for å indusere dopamin-produksjon. Stamceller og benmargsceller høstes fra vev som vanligvis kasseres i forbindelse med nevrokirurgiske inngrep. Prosjektgruppen vil utnytte funksjonelle studier med patch-clamp/konfokal mikroskopi og immunhistokjemi til å påvise funksjonen til nervecellene. 
På sikt kan dette åpne for å høste stamceller ved minimal invasiv kikkhullskirurgi og deretter transplantere tilbake igjen dopaminproduserende nerveceller til pasienten. Dette kan bi dra til en helt ny behandling mot Parkinsons sykdom, som eliminerer etiske betenkeligheter ved bruk av fosterceller og som åpner for autotransplantasjon.

ISPHUM-ISP - Humaniora

Forskningssabbat ved VID Vitenskapelige høgskole (tidligere Misjonshøgskolen)

Tildelt: kr 0,35 mill.

Publikasjoner hentet fra Cristin

Negotiating Norwegian mission education in Zululand and natal during World War II

A time of destiny for Norwegian mission schools in Zululand and Natal under the policy of Bantu Education (1948–1955)

Digital Abstract: A time of destiny for mission schools in Zululand and Natal under the policy of Bantu Education

Digital Abstract: Negotiating Norwegian Mission Education in Zululand and Natal during World War II

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ISPHUM-ISP - Humaniora

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