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Several large‐scale epidemiological studies have demonstrated the prognostic significance of psychosocial factors and stress for coronary artery disease (CAD). Observations of sudden changes in CAD incidence have led to the proposal of mechanisms regarding atherosclerotic plaque vulnerability. The collagen‐degrading enzyme matrix metalloproteinase-9 (MMP-9) is increased in rupture‐prone plaques with high inflammatory activity, and circulating levels of MMP-9 are raised in patients with acute coronary syndrome. However, the distribution of MMP‐9 levels and its relations to psychosocial factors and the stress hormone cortisol have not been previously explored in a normal population.The aim of this dissertation was to examine in a normal population the association of circulating levels of MMP-9 with traditional cardiovascular risk factors including levels of C-reactive protein (CRP), with psychosocial factors, and with saliva levels of cortisol. In addition, the reliability of a new method of ambulatory saliva sampling for assessment of cortisol levels was evaluated. A sub‐sample of the Life conditions, Stress, and Health (LSH)-study, a population based study exploring psychoneuroendocrinological pathways mediating the differences in CAD incidence over socioeconomic status, was used. Plasma levels of MMP-9 were examined in a sample randomly drawn from the LSH‐study (n=400), aged 45 to 69 years at enrollment.The main findings were: 1) there was a positive association between plasma MMP-9 levels and total risk load of cardiovascular risk factors. The findings were persistent after adjusting for CRP and could not be attributed to a single risk factor. 2) After adjusting for traditional cardiovascular risk factors and CRP, MMP-9 levels were positively associated with psychosocial risk factors and negatively associated with psychosocial resources. 3) Pooling saliva samples prior to laboratory analysis were as reliable as arithmetic means for assessment of diurnal cortisol variation in a field research setting. 4) There was a positive association between circulating levels of MMP‐9 and saliva levels of cortisol, both diurnal peak level and evening level of cortisol. The observed associations between MMP‐9 and traditional cardiovascular risk factors, psychosocial factors, and saliva cortisol levels suggest a psychoneuroendocrinological pathway linking stress to plaque vulnerability and provide increased understanding of the association between psychosocial factors and CAD.

This thesis is focused on the subject of cell-cell interaction. Our body is composed of cells, most of them are integrated in a network with other cells that together forms tissues and organs. Every cell type in these complex organs has its special task and location. This is true whether we are doing research on humans or, as we have been, investigating mice. Mice are excellent models for studies of blood cell development since this process in mice resembles human blood cell generation in many regards. Cells communicate with each other by sending out small molecules or by directly binding to surrounding cells; to cells of the same kind as well as to cells with different origins and tasks. A cell is surrounded by hundreds of different signal-carrying entities; soluble, bound to the extra cellular matrix or bound to its surface. Every cell has to distinguish and respond to the environment according to its own specific nature. In the first article interleukin 7 (IL-7) a growth factor expressed by the stroma cells was studied. Results show that IL-7 is crucial for the immature progenitor cell in its development towards antibody producing B-lymphocytes. The second article is about stroma cells and their ability to support the development of B-cells. It is a comparative study on two different cell lines, where we focus on transcription factors and their regulation of protein induction of factors supporting B-cells. This study increased our knowledge of stroma cells. In the third paper we combined our knowledge from the first two papers in regard to stroma cells as well as B-cell development by testing if there is a possibility to theoretically find new factors of importance for the maturing B-cell. We achieved this by the development of GCINT, a database investigating possible receptorligand interactions between two cells, verifying these results in vitro with cell lines as well as primary cells. This revealed a two way communication between blood cells and stroma cells, highlighting the complexity of the bone marrow environment. In the last article we continued this work with primary FACS sorted stroma cells investing the potential connections between each of the stroma cell populations with primary blood cells in different stages of development. This work supports a model where hematopoietic cells can interact with stroma cells in a stage-specific manner and that the exchange between cells is of importance for their maturation.

Oxygenic photosynthesis is the process of solar energy conversion into chemical energy in the form of carbohydrates. This event is carried out by plants, algae and cyanobacteria and represents the starting point of the food chain in which most organisms are fed. Due to never-ending changes in the surrounding environment, these photoautotrophic organisms have evolved different acclimatizing strategies to optimize photosynthesis. Many of these fine-tuning mechanisms are dependent on reversible modifications of proteins on a post-translational level. In my research I have been focused on such reversible modifications of proteins in the organelle where photosynthesis takes place – the chloroplast – using the model plant Arabidopsis thaliana. Within chloroplasts, light-driven reactions of photosynthesis are catalyzed by several multi-subunit protein complexes in the thylakoid membrane. Proteins need to be folded properly in order to function correctly. A rate-limiting step of protein folding is the isomerization of the peptide bond around proline, a step that is catalyzed by enzymes possessing peptidyl-prolyl cis-trans isomerase (PPIase) activity. Within the thylakoid lumen, only two proteins have been found to possess PPIase activity, FKBP13 and CYP20-2. Both these enzymes belong to a protein superfamily called immunophilins - ubiquitous proteins attributed with several different functions. By characterization of Arabidopsis mutants lacking FKBP13 and CYP20-2 I found that PPIase activity is a dispensable function of immunophilins in the thylakoid lumen. A common post-translational modification of chloroplast proteins is phosphorylation. Protein phosphorylation alters protein functions and is a reversible mechanism utilized by plants for rapid acclimation to changes in the incident light. These events require the action of kinases and phosphatases that either add or remove phosphate groups on proteins, respectively. I have characterized mutants deficient in protein phosphatases responsible for dephosphorylation of thylakoid proteins. These phosphatases, PPH1 and PBCP, represent key players in acclimation of the photosynthetic machinery to changes in light quality/quantity. In addition, I discovered that phosphorylation of pTAC16, a protein associated with the chloroplast gene-expression machinery, depends on the presence of STN7; a light-regulated protein kinase located in the thylakoid membrane. This finding could provide a link between the redox state of the photosynthetic apparatus and chloroplast gene expression.

The present study aims at demonstrating phosphorus metabolite concentration changes and alterations in uptake/excretion of a hepatocyte specific contrast agent in patients with diffuse - or suspected diffuse - liver disease by applying two non-invasive quantitative MR techniques and to compare the results with histo-pathological findings, with focus on liver fibrosis. In the first study phosphorus-31 MR spectroscopy using slice selection (DRESS) was implemented. Patients with histopathologically proven diffuse liver disease (n = 9) and healthy individuals (n = 12) were examined. The patients had significantly lower concentrations of phosphodiesters (PDE) and ATP compared with controls. Constructing an ‘anabolic charge’ (AC) based on absolute concentrations, [PME] / ([PME] + [PDE]), the patients had a significant larger AC than the control subjects. The MRS technique was then, in a second study, applied on two distinct groups of patients, one group with steatosis and none-to-moderate inflammation (n = 13) and one group with severe fibrosis or cirrhosis (n = 16). A control group (n = 13) was also included. Lower concentrations of PDE and a higher AC were found in the cirrhosis group compared to the control group. Also compared to the steatosis group, the cirrhosis group had lower concentrations of PDE and a higher AC.  A significant correlation between fibrosis stage and PDE and fibrosis stage and AC was found. Using an AC cut-off value of 0.27 to discriminate between mild (stage 0-2) and advanced (stage 3-4) fibrosis yielded an AUROC value of 0.78, similar as for discriminating between F0-1 vs. F2-4. Dynamic contrast enhanced MRI (DCE-MRI) was performed prospectively in a third study on 38 patients referred for evaluation of elevated serum alanine aminotransferase (ALT) and/or alkaline phosphatase (ALP) levels. Data were acquired from regions of interest in the liver and spleen by using single-breath-hold symmetrically sampled two-point Dixon 3D images time-series (non-enhanced, arterial and venous portal phase; 3, 10, 20 and 30 min) following a bolus injection of Gd-EOB-DTPA (0.025 mmol/kg). A new quantification procedure for calculation of the ‘hepatocyte specific uptake rate’, KHep, was applied on a two-compartment pharmacokinetic model. Liver-to-spleen contrast ratios (LSC_N) were also calculated. AUROC values of 0.71, 0.80 and 0.78, respectively, were found for KHep, LSC_N10 and LSC_N20 with regard to severe versus mild fibrosis. Significant group differences were found for KHep (borderline), LSC_N10 and LSC_N20. In study four no significant correlation between visual assessments of bile ducts excretion of Gd-EOB-DTPA and histo-pathological grading of fibrosis or the quantified uptake of Gd-EOB-DTPA defined as KHep and LSC_N. In conclusion 31P-MRS and DCE-MRI show promising results for achieving a non-invasive approach in discriminating different levels of fibrosis from each other.

Hysterectomy is the surgical removal of the uterus and it is the most common major gynaecological surgical procedure worldwide. Hysterectomy is most often indicated by benign conditions such as irregular uterine bleeding with or without uterine fibroids. Several modes of hysterectomy are available each using a different surgical approach. Psychological well‐being and recovery after hysterectomy have not been carefully investigated in randomised settings. The aims of this thesis were to evaluate different modes of hysterectomy regarding postoperative psychological well‐being in long‐term follow‐up 6 and 12 months after surgery and recovery of general well‐being in short‐term up to five weeks after surgery. Additional objectives were to study the influence of the women’s stress‐coping ability on postoperative psychological well‐being and also to analyse other factors associated with postoperative psychological well‐being and recovery of general well‐being. In a randomised trial (trial 1) of 125 women who had undergone laparoscopic hysterectomy (LH) and abdominal hysterectomy (AH), no significant difference was found between the postoperative psychological well‐being of women in the two groups as indicated by four different psychometric measures up to 6 months after surgery. Neither did the day‐by‐day recovery of general well‐being differ between the women in the two hysterectomy groups, even when adjusted for consumption of analgesics. A high stress‐coping ability was strongly associated with a higher level of psychological well‐being preoperatively and a significantly faster recovery of general well‐being regardless of surgical method. In another randomised trial (trial 2) of 179 women who had undergone subtotal abdominal hysterectomy (SH) and total abdominal hysterectomy (TH), with a follow‐up time of one year, no significant difference in psychological well‐being was found between the two methods. The day‐by day recovery of general well‐being was the same in both groups. In both trial 1 and trial 2, longterm psychological well‐being improved over time during the study period regardless of the mode of hysterectomy. The occurrence of postoperative complications and a low preoperative level of psychological well‐being impair postoperative recovery significantly and prolong the duration of sick‐leave. In conclusion, the suggested benefits of the less invasive modes of hysterectomy, LH and SH, could not be proven in this study Recovery of general well‐being is associated with the woman’s stress‐coping and preoperative psychological well‐being and the studied modes of hysterectomy seem to be of less importance. This should be taken into account in preoperative counselling. Doing this will give patient and surgeon an open choice of the mode of hysterectomy to be chosen, since short‐term recovery and long‐term psychological well‐being seem to be the same in both groups in the long term.

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Bakgrund: Nedbrytningen av neuroner vid Parkinsons sjukdom har visat sig gå långt innan tydliga motoriska symtom uppkommit. Subtila talförändringar kan förekomma långt innan dessa symtom debuterar och drabbade personer kan länge ha kompenserat för detta omedvetet. I dagsläget finns ingen enkel objektiv kvantifiering som kan ligga till grund för identifiering av artikulatorisk nedsättning hos patienter med Parkinsons sjukdom. Oral diadochokinesi (oral-DDK) har använts av kliniker för att bedöma dysartri då det pressar det artikulatoriska systemet. Ingen tidigare forskning har närmare undersökt vad som händer inuti stavelserna i oral-DDK utan fokuserat på andra faktorer. Mål: Att med enkla akustiska mått på vokalduration undersöka om den skiljer sig mellan personer med Parkinsons sjukdom och normaltalare. Metod: Studiens deltagare bestod av 40 personer med Parkinsons sjukdom och 40 normaltalare. Testdeltagarna fick utföra oral-DDK där stavelserna /pa, ta, ka/ upprepades i normalt respektive snabbt tempo. Vokaldurationen mättes ut av tre uppmärkare. Statistiska analyser utfördes för att se om det fanns skillnader i vokalduration mellan talargrupperna. Resultat: Denna studie visade att det fanns en statistiskt signifikant skillnad i vokalduration mellan personer med Parkinsons sjukdom och normaltalare i samtliga stavelser med undantag för /pa/ i normalt tempo. Slutsatser: Oral-DDK skulle kunna medverka som en komponent i ett tidigt diagnostiseringsverktyg för dysartri. Testet är objektivt och kräver ingen fullständig logopedisk träning och kan således användas av flera yrkesgrupper. Vidare forskning behövs för att närmare undersöka om enskilda ljudsegment är påverkade även vid andra neurologiska sjukdomar. Nyckelord: Parkinsons sjukdom, subtil talpåverkan, oral-DDK, vokalduration, dysartri, neurologiska sjukdomar / <p>2017 VT</p>