Reumatoid artrit (RA) är en kronisk inflammationssjukdom som symmetriskt drabbar kroppens leder och går i skov. En inflammationsprocess uppstår i synovialmembranet (ledhinnan) som börjar förtjockas och utsöndra ett exsudat till synovialvätskan, Exsudatet innehåller mycket erosiva inflammatoriska molekyler, inklusive cytokinerna TNF, IL-1 (interleukin) pch IL-6. De onormala cytokinkoncentrationerna förstör med tiden leden. Detta leder till leddeformationer, smärta och stelhet. Sjukdomen involverar även andra organ än enbart rörelseapparaten. RA drabbar strax under 1% av befolkningen, varav kvinnor är överrepresenterade. Diagnosen av RA kan vara mycket svår att ställa eftersom sjukdomen saknar ett enskilt laboratorietest eller ett standardiserat mätinstrument som korrelerar till sjukdomsaktivitet. Till följd därav används mätinstrument av sammanslagan parametrar för att utvärdera sjukdomen. Methotrexat (MTX) räknas som förstahandspreparat vid RA och kombineras standarsdmässigt med biologiska läkemedel, vid svårare sjukdomsförlopp. Det anses att biologisk kombinationsterapi är nödvändig för maximal behandlingseffekt, emellertid visar kliniska behandlingsregister att 1/3 av RA-patienter förskrivs biologisk monoterapi. Kombinationsterapi kan även orsaka mer biverkningar och försämrad följsamhet. Syftet med studien är att undersöka effekten och säkerheten av receptorantagonisten Tocilizumab (TCZ) med avseende på onoterapi vid RA. Arbetet är en litteraturstudie som genomförts genom sökningar i PubMed. Totalt lästes 7 artiklar i fulltext, varav 5 inkluderades i studieanalysen. Utifrån de primära effektmåtten i artiklarna, visade TCZ-monoterapi en signifikant behandlingsskillnad hos RA patienter med medelhög till hög sjukdomsaktivitet. Resultatet visar ingen bättre behandlingseffekt av att kombinera MTX med TCZ jämfört med monoterapi. TCZ-monoterapi hämmar även strukturella ledskador. TCZ-monoterapi anses som en säker och generellt tolererbar behandling.

The aim of this study was to compare the effect between the drugs rituximab and infliximab in rheumatoid arthritis (RA). RA is an autoimmune disease that affects the peripheral joints and is associated with exacerbations. Various immune reactions in the body cause inflammation of the joints which further results in cartilage and bone damage. The diagnosis is made by the classification system "The 2010 American College of Rheumatology (ACR) / European league against rheumatism (EULAR) classification criteria for rheumatoid arthritis", which is an update of the older system called "The 1987 American College of Rheumatology classification criteria for RA". Approximately 0.5-1% of the population is developing the disease, but it varies slightly between different parts of the world. The disease is 2-3 times more common in women and the median age of onset is 60 years. Methotrexate is the first line drug for treatment of RA, but in more severe disease, monoclonal antibodies such as infliximab and rituximab are used. Infliximab and rituximab are only used for combination therapy with methotrexate. Infliximab is a tumor necrosis factor (TNF) α inhibitor, while rituximab inhibits B cells. The method for this work was study of literature. The Pubmed database was used and the following terms were used as keywords: "Rheumathoid Arthritis", "Rheumatoid Arthritis rituximab" and "Rheumatoid Arthritis infliximab." A total of 6 studies were elected, 3 for each drug. When evaluating the results it should be kept in mind that the study approaches vary. The study endpoints were ACR 20, ACR 50, ACR 70 and disease activity score (DAS) 28. Based on these measurements there were no significant difference between the drugs. ACR 20 for infliximab was reached by 50 %, 62.4 % and 59.4 % of the patients, respectively in three different studies. ACR 20 for rituximab was reached by 50.6 %, 51 % and 73 % of the patients in three different studies. The DAS 28 reduction for infliximab was 2.6 and 2.3, while the same numbers for rituximab were 1.6, 1.9 and 2.6. In conclusion, both rituximab and infliximab are good treatment options for severe RA. Because of the small difference between the drugs in the results, other aspects become more important. For example, costs and safety profile should be further investigated.

Northern pike or pike Esox lucius is total piscivorous fish species found in the brackish and freshwater ecosystems of the Northern hemisphere. It is a top predator and keystone species that causes cascading effects in these ecosystems. Otoliths have been used to estimate age and growth rates in most fishes. Cleithra have generally have been used in Pike due to opaque nature of the otoliths. The aim of this study was to develop a method for age and growth estimation of pike using sagittal otoliths and carry out age and growth rates estimation of four sub populations; Dunöbäcken, Kårehamn, Oknebäcken and Väderön that represent freshwater and brackish water spawning sites. Determination of growth rates differences between sub populations was done for the first 2 years of their life. The methods included burning of the otoliths, fixing the otoliths in the epoxy resin, polishing of otoliths and staining with Alizarin red, Silver nitrate solution, Tetracycline and alkaline Lugol's solution with observation under light, dissecting and epifluorescence microscopes. Four methods tested based on staining with Alizarin red, Silver nitrate, alkaline Lugol's solution and burning otoliths. Provided useful results and not the method with Tetracycline. Alkaline Lugol's solution staining method was chosen and further developed. There was a significant difference in the relative growth rates between the sub population from brackish water spawning site of Väderön and the sub population from freshwater spawning site of Kårehamn in the first year (One-way ANOVA:F value 3.18, p value 0.0356) and after Tukey post hoc test (p value 0.0362). No difference among sub populations from the freshwater spawning sites. There was no difference in growth rates between any other sub populations in the second year. The importance of the study is successful application of Lugol's solution staining method for age and relative growth estimation studies with otoliths in pike. / EcoChange

Advancements in the field of modified messenger RNA (mRNA) has led to new ventures in the pharmaceutical industry. However, new drug products demand new analytical methods to ensure the efficacy and purity of the drug. Capillary gel electrophoresis (CGE) with UV detection shows great potential for separation of mRNA samples due to the equal mass-to-charge ratio of mRNA and the flexible parameters of the CGE methods. This thesis investigates the optimal parameters of the capillary electrophoresis method, sample treatment procedure and sieving medium composition for enhanced shortmers separation of mRNA by CGE analysis. An RNA ladder with 100-1000 nucleotides and EPO mRNA with 900 nucleotides were used as model compounds. The effect of capillary dimensions and separation temperature on the resolution of the RNA peaks was established through comparative experiments. Sample treatment processes were evaluated to achieve an optimal conformation of the mRNA for CGE analysis. By heating the mRNA sample for 15 min at 80°C all multimers were seemingly eradicated. Moreover, it was found that addition of 4 M of urea to mRNA sample before heating resulted in improved peak shape. A sieving medium consisting of a mix of the two polymers polyvinylpyrrolidine (PVP) and hydroxyethyl cellulose (HEC) proved to have beneficial qualities for separation. The addition of sucrose as viscosity modifier in the sieving medium surprisingly further enhanced the resolution. Moreover, during the project a heavy wash was established which drastically improved repeatability of the analyses through more efficient regeneration of the capillary. ISSN:

Trade-offs prevent selection from driving all fitness-enhancing traits towards values that would maximize fitness. Life-history trade-offs, such as the one between survival and reproduction are well-studied, yet trade-offs can also involve behavioural or cognitive traits. Because males and females have different routes to successful reproduction, the optimal resolution of life-history trade-offs can differ between the sexes. However, shared genome can constrain the evolution of sex-specific adaptations. In this thesis, I explore the links between sex-specific life histories, cognition and behaviour. I start by linking sex differences in life histories to sex differences in learning performance in the outcrossing nematode Caenorhabditis remanei (Paper I). I report that age-related learning differs between the sexes and that it corresponds to sexual dimorphism in life history. Then, I use experimental evolution to select for learning performance to study the patterns of genetic correlations between learning and life-history traits in both sexes (Paper II). The results demonstrate the correlated evolution of sexual dimorphism in life history indicating sex-specific fitness costs and benefits of learning. In Paper III I use the fruit fly Drosophila melanogaster to ask about the extent to which cognitive and demographic aging are independent. The results reveal that selection for late-life reproduction alone bears no effect on late-life learning and that joint selection on late-life learning and reproduction does not yield lifespan benefits. The selection might have affected, however, female age-specific reproductive effort. Motivated by the questions on aging I proceed to ask why a potent lifespan extending drug – rapamycin affects sexes differently (Paper IV). I take a closer look at the trade-off between growth, lifespan and reproduction and propose that the sex experiencing a stronger relationship between size and fitness pays a higher cost of lifespan extension. Finally, I focus on another sex-specific trait – dispersal (Paper V). I conduct experimental evolution to uncover a negative genetic correlation between dispersal and reproduction and show sex-specific genetic variation for dispersal. In summary, my thesis unravels the complex pattern of interdependence between life-history, behavioural and cognitive traits, where sex emerges as an important factor that can maintain genetic variation for trade-offs.

Mixed radiation fields, where different ionizing particles act together, are very important in radiobiology and in radiation protection. Mixed beams are not only the most common form of radiation exposure, but the prediction of their biological effect is also full of uncertainties. Currently, prediction of the biological damage of exposure to mixed radiation fields is based on the default assumption of simple additivity between the effects of all the radiation in the field. This assumption has been proven to be incorrect. Indeed, the simultaneous effect of different radiation qualities has been shown to be greater than additive, namely synergistic. This implicates that, for instance, the predicted cancer risk for astronauts, that remain a prolonged time in space, is currently underestimated as well as the risk of developing secondary cancer for radiotherapy patients. This thesis aims at understanding the mechanisms behind the cellular response to simultaneous exposure to alpha particles and X-rays (that is referred as mixed beam). Paper I describes the cell killing and the mutagenic effect of mixed beam exposure in human lymphoblastoid wild type and in cells with impaired capacity to repair oxidative DNA damage .We found that oxidative DNA damage plays an important role in the lethal, synergistic effect of mixed beams. Paper II and III investigates whether mixed beams exposure leads to an augmented DNA double strand breaks (DSB) induction or to an altered response of the cellular DSB repair machinery. We found that mixed irradiation resulted in synergistic induction of DSB, and that those lesions were repaired with slow kinetics. Paper IV focuses on the effect of mixed beams at the level of DNA damage in normal cells. Induction and repair of DNA lesions such as DSB, single strand breaks and apurinic sites was quantified using the alkaline comet assay. We found that alpha particles and X-rays interacted in inducing DNA damage. Moreover, although mixed beam exposure resulted in strong activation of the DNA damage response, it resulted in delayed repair. Although more research is needed to fully elucidate the mechanisms behind the detected synergistic effects, our results strongly suggest that an overwhelmed DNA-repair system causes delay in repair of damage. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Accepted. Paper 3: Manuscript. Paper 4: Manuscript.</p>

Syftet med studien var att åskådliggöra vilka konsekvenser uppdraget som familjehem kan få för de biologiska barnen när det sker förändringar i syskonskaran. Vi fann flera motsägelser i de biologiska barnens berättelser vilket vi tolkar som att uppdraget är komplext. Förändringen i syskonskaran upplevs delvis som utmanande. En av utmaningarna för våra respondenter har varit att de ska agera utifrån en ny roll vilket är en process som har tagit olika lång tid att hantera. Majoriteten av våra respondenter pratar positivt om sin förändrade situation och uppdraget i sin helhet. De menar att det ökade ansvaret som uppdraget inneburit gjort att de fått en annan roll i familjen som bidragit till att de upplever sig mer tagna på allvar. Den nya rollen har visat sig innebära en större frihet men också givit dem nya möjligheter. Förändringen har likväl väckt ett behov av att bibehålla en viss struktur inom familjen och att ibland få möjlighet att få återgå till det som familjen gjorde innan uppdraget påbörjades. Flera av våra respondenter uttrycker en önskan om en tillflyktsort där de får tillfälle att vara som “vanligt”, vilket vi tolkat som innan de fått en ny position i syskonskaran. Studiens resultat pekar på att uppdraget är komplext. Konsekvensen av att få en ny position i syskonskaran upplevs delvis som utmanande och delvis som en möjlighet. Vi har funniten paradox; att de biologiska barnen å ena sidan finner uppdraget och de nya förväntningar som kommer med den nya syskonpositionen som befriande och å andra sidan uttrycker de ett behov av att låta allt vara som vanligt.       Studien har genomförts med nio respondenter genom både kvalitativa semistrukturerade intervjuer via en intervjuguide och strukturerade intervjuer i enkätform. För att förstå det empiriska materialet har det analyserats med hjälp av flera teoretiska begrepp från systemteorin samt en sociologisk rollteori. Vi har också valt att relatera empirin till den tidigare forskning som gjorts i ämnet. Utgångspunkten i studien har varit att placeringen i syskonskaran spelar roll då det finns olika förväntningar på de olika rollerna. Föreställningen om att ens position i syskonskaran påverkar en individ gör det intressant att lyfta de biologiska barnen i familjehem för att förstå viktiga aspekter av att agera syskon och samtidigt ändra den position som man är van vid. Studien syftade till att klargöra hur de biologiska barnen upplevde den förändring i syskonskaran som uppdraget innebar. / The purpose of the study was to illustrate the consequences of the family home for the biological children when there are changes in the siblingship. We found several contradictions in the children's stories, which we interpret as the mission is complex. The change in the siblingship is partly experienced as challenging. One of the challenges for our respondents has been that they act on a new role, which is a process that has taken a long time to handle. The majority of our respondents speak positively about their changed situation and the assignment as a whole. They believe that the increased responsibility that the assignment meant meant that they had a different role in the family that helped them feel more seriously taken. The new role has proved to mean greater freedom, but also given them new opportunities. However, the change has aroused the need to maintain a certain structure within the family and sometimes to get back to what the family did before the mission began. Several of our respondents express a wish for a place of refuge where they have the opportunity to be "common", which we interpreted as before they got a new position in the siblings. The study results indicate that the assignment is complex. The consequence of getting a new position in the siblingship is partly experienced as challenging and partly as an opportunity. Paradoxically, we have found that the biological children, on the one hand, find the mission and the new expectations that come with the new sibling position as liberation, and on the other hand they express a need to let everything be as usual.      The study has been conducted with nine respondents through both qualitative semistructured interviews via an interview guide and structured interviews in questionnaire. To understand the empirical material, it has been analyzed using several theoretical concepts from system theory and a sociological role theory. We have also chosen to relate empirin to the previous research done on the subject. The starting point of the study has been that the position in the siblings carries a role as there are different expectations of the different roles. The idea that one's position in sibling carries an individual affects an individual makes it interesting to raise the children in family homes to understand important aspects of acting siblings while changing the position that is used to. The study aimed at clarifying how the biological children experienced the change in the siblingship that the mission meant.

Stream ecosystems and their riparian zones have previously been regarded as two different ecosystems, linked through numerous reciprocal subsidies. Today, ecologists agree that the stream and the riparian zone should be regarded as one system, the stream-riparian ecosystem, which is characterised largely by the subsidies between land and water. The terrestrial subsidies to the stream affect stream-living biota in several ways, some of which are well-known while others less so. The input of wood to the stream from the riparian zone is believed to play an important role in the population dynamics of stream-living fish. In this doctoral thesis, I explore effects of fine stream wood (FW, &lt;10 cm diameter) on wild stream-living young-of-the-year brown trout (Salmo trutta) by reporting and discussing results from laboratory, semi-natural and field experiments. My results show that the local density of drifting prey is higher in the presence of FW than in its absence, and also that young-of-the-year brown trout decrease their diurnal foraging time and prey capture success when FW is added to their habitat. I show that trout decrease their swimming activity in the presence of FW, aggregate in FW bundles, and have lower growth rates than trout without FW access. Also, the degree of sheltering in FW bundles was higher during day than at night in a study performed at low water temperatures; moreover, the presence of an ectothermic nocturnal predator (burbot, Lota lota) did not affect the degree of sheltering in FW bundles by trout. Taken together, my results indicate that young-of-the-year brown trout with access to FW bundles spend considerable amounts of time sheltering in the FW, and by doing so they miss the opportunity for higher growth and foraging rates outside of the shelter. The most probable explanation for this behaviour is that growth is traded off against survival, i.e., the predation risk is higher outside of the shelter. / Stream ecosystems and their riparian zones have previously been regarded as two different ecosystems, linked through numerous reciprocal subsidies. Today, ecologists agree that the stream and the riparian zone should be regarded as one system, the stream-riparian ecosystem, which is characterised largely by the subsidies between land and water. In this doctoral thesis, I explore one such subsidy – the input of fine stream wood (FW) to streams. Wild stream-living young-of-the-year brown trout (Salmo trutta) was chosen as study species. My results show that the local density of drifting prey is higher in the presence of FW than in its absence, and that young-of-the-year brown trout decrease their diurnal foraging time and prey capture success when FW is added to their habitat. I show that trout decrease their activity in the presence of FW, aggregate in FW bundles, and have lower growth rates than trout without FW access. Taken together, my results indicate that young-of-the-year brown trout spend considerable amounts of time in FW bundles, and by doing so they miss the opportunity for higher growth and foraging rates outside of the shelter. The most probable explanation for this behaviour is that growth is traded off against survival. / <p>Artikel 3 publicerades i avhandlingen som manuskript med samma titel.</p>

No description available.

Domestication has resulted in animals with broad variations between as well as within breeds, which allows for the selection and breeding of animals for preferred traits. This selection has affected both the genotypes and phenotypes of animals. In dogs, it has allowed for breeding for different purposes, such as companionship or the performance of specific tasks, e.g., herding, hunting, searching and protecting. Each of these types of working dogs has specific traits that are, in part, controlled by genes; however, genes are not solely responsible for the variations in the traits of an individual. The environment also plays a role, which has been studied in rodents and primates in recent decades. For instance, it has been shown that the amount of maternal care that a rat receives as a pup affects its temperament later in life; the more maternal care, i.e., licking, grooming and arched-back nursing (LG-ABN), that a rat receives, the more stress resistant, less reactive and more explorative it will be as an adult. However, the question is whether this is also true for dogs, and the investigation of how temperament in dogs is affected by environmental factors early in life is the main objective of this thesis. Three of the studies presented in this thesis focused on investigating the general parameters, particularly maternal care, that influences offspring behaviour to contribute to the understanding of temperament development in military working dogs. One of these studies concentrated on the environmental factors that influence dogs early in life, and the results indicated that some factors, such as parity, litter size and birth season, affect temperament later in life. Another study investigated how females take care of their young, and the results demonstrated that females consistently vary in their maternal style during the first three weeks postpartum and that this variation affects the temperament of the offspring. The third study focused on factors in the home environment, and the results showed that dogs approved through the evaluative temperament test were significantly associated with being hyperactive or restless and having difficulty settling down in the home environment. However, those dogs were also left home alone for more hours in a day than non-approved dogs. To be able to operate functionally, a military working dog needs to possess certain traits, or a certain temperament, and a vital characteristic is the way it responds to and copes with stress. This was investigated during an evaluative temperament test used to select dogs suitable for further training. Surprisingly, the results showed that the dogs approved for further training had significantly higher levels of salivary cortisol both before and after the test compared with the non-approved dogs. These findings may be of profound importance for understanding individual variations in behaviour and improving breeding schemes for working dogs. / För över 15 000 år sedan började våra anfäder avla på vargar och lade då grunden för den uppsjö av olika hundraser vi ser idag. Exakt hur den här processen såg ut, när eller vart den startade vet vi faktiskt inte med säkerhet, men att vargen/hunden var det första djur att påbörja en sådan förändring, det vet vi. Att aktivt välja ut och avla på önskvärda egenskaper påverkar och förändrar gradvis djuret. Den här förändringen styrs i hög grad av gener, vilket medför att ett djurs s.k. genotyp förändras. Den här förändringsprocessen, där ett djur gradvis anpassas till ett liv som tamdjur, kallas för domesticering och innebär inte bara att djuret förändras genetiskt, utan också att den ändrar utseende och beteende, dvs. djurets fenotyp ändras också. Det är därför vi bl. a. ser så många olika hundraser som vi gör idag, allt från en liten hårlös Chihuahua till en stor raggig St. Bernard. Alla är de hundar, men de ser väldigt olika ut och har delvis olika egenskaper eller temperament. Det medför att de passar till att göra olika saker och därför också kan vara till stor nytta i samhället i allt från sällskapshunden som kan lära sig leta kantareller, till olika typer av tjänstehundar. Bra ledarhundar åt synskadade, polishundar som söker försvunna människor och narkotika, och försvarsmaktens tjänstehundar som kan förhindra angrepp eller terrorverksamhet genom att leta efter t ex. bomber och vapen - alla kan i förlängningen innebära ökad livskvalité och räddade människoliv. Men för det krävs att hunden passar för jobbet. Det är både generna, arvet och olika miljöfaktorer i den tidiga uppväxten som avgör egenskaperna hos en individ. Det är något som har visat sig gälla till exempel för råttor och primater. Studier på råttor har exempelvis pekat på att mängden omvårdnad en råtta får som liten (t ex hur mycket mamman slickar sina barn) påverkar dess egenskaper som vuxen. Och att ju mer omvårdnad de fått, desto mer stresståliga, mindre nervösa och mer nyfikna blev de. Även i studier på människor pekar resultaten i samma riktning. Men gäller detta även för våra hundar? För att öka kunskapen om och förståelsen för hur tidiga erfarenheter påverkar temperament, stress och arbetsförmåga hos våra blivande tjänstehundar i försvarsmakten har därför en rad olika studier på området genomförts. Den här avhandlingen fokuserar således på att undersöka vilka generella tidiga erfarenheter och faktorer i den tidiga uppväxtmiljön som tycks kunna vara med och påverka temperamentet hos våra tjänstehundar. Specifikt undersöker den hur tikens omvårdnad påverkar vissa egenskaper. Avhandlingen undersöker vidare hur stresståliga våra hundar är och hur detta yttrar sig i samband med de lämplighets test som hundarna genomgår i syfte att bedöma vilka individer som bör gå vidare till fortsatt träning efter ett och ett halvt års ålder. Resultaten i en studie visar att de hundar som bedömts som lämpliga vid lämplighetstestet något oväntat uppvisade ett högre påslag av stresshormonet kortisol, och i en annan studie att lämpliga hundar bedömts vara hyperaktiva/rastlösa och ha vissa svårigheter att ta det lugnt i hemmiljö. Detta samtidigt som de uppvisade en önskvärd temperamentsprofil vid uttagningsprovet, vilket kan antyda att dessa hundar är mer flexibla och motståndskraftiga mot stress, vilket skulle kunna vara resultatet av en lyckad avel. Vidare visade resultaten att det finns generella faktorer i den tidiga uppväxtmiljön, såsom tikens tidigare erfarenhet av att vara mamma, kullstorlek och när på året kullen föds, som är med och påverkar olika egenskaper. Den visar också att tikarnas sätt att ta hand om sina valpar varierade men var konsekvent under den första omvårdnadstiden på tre veckor och att det finns en koppling mellan mammans omvårdnads-stil och hur deras valpar blir som vuxna. Sammantaget visar avhandlingen att det finns faktorer i den tidiga uppväxtmiljön som påverkar temperamentet senare i livet på våra tjänstehundar. / <p>The ISBN <strong>987</strong>-91-7685-945-2 in the thesis is incorrect. Correct ISBN is <strong>978</strong>-91-7685-945-2.</p>