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Allergies are a common chronic disease and considerably decrease the quality of life for affected individuals. Understanding the immune responses during allergic diseases is essential for both diagnosis and the development of effective therapies. The route of sensitisation to allergens is one factor that influences the immune response and the outcome of allergic diseases and both human and animal studies have highlighted IL-4Ra as an important component in the induction of allergy. The aim of this study was to investigate the contributions of the route of sensitisation to allergens with focus on the significance of cell specific expression of IL-4Ra in the onset of allergy. The route of sensitization to Anisakis pegreffii influences the outcome of experimental allergic asthma: Worldwide, increasing numbers of allergies to the fish parasite Anisakis pegreffii are reported. Anisakis can cause allergies after accidental infection of humans and in the occupational environment. Currently it is not clear if different exposure routes to Anisakis affect the development of allergic asthma and if they have an influence on the immune response. To address these questions, the present study investigated immune responses and disease development after Anisakis live infection and after nasal sensitisation in a mouse model of allergic airway disease. We showed that the route of sensitisation influences the outcome of Anisakis pegreffii induced allergic asthma and demonstrated important contributions of IL-4Ra to the underlying immune response. Alternatively activated macrophages are not necessary for the development of experimental allergic lung inflammation: Development of alternatively activated macrophages (AAM) is induced by signals of IL-4Ra. Alternatively activated macrophages (AAM) are a feature of allergic asthma in clinical and experimental investigations but their role in the development of allergy is not defined. To address this, a model of acute allergic asthma was used to compare mice deficient in AAM (LysMcrelL-4Ra-110x mice) with control mice. We found that the presence of AAM at early stages of allergic airway inflammation these cells was not required for the onset of the disease. Smooth muscle IL-4Ra is not required for experimental allergic asthma: In vitro studies have suggested that IL-4Ra signalling on airway smooth muscle cells (ASMC) is critical for airway irrflammation and airway hyperresponsiveness. Using mice deficient for IL-4Ra in ASMC, the in vivo effects of impaired IL-4Ra signalling in ASMC on the outcome of asthmatic disease were investigated. The impairment of IL-4Ro: on SMC had no effect on major aetiological markers of allergic asthma. These findings suggest that IL-4Ra responsiveness in airway SMC during the acute phase of allergic asthma is not critical for the outcome of the disease. Conclusions: The present study showed the importance of the route of sensitisation and IL4Ra in the development of allergy to Anisakis pegreffii. The use of in vivo models of experimental allergic asthma revealed that the route of sensitisation can influence the underlying immune response of the disease. Furthermore, by using mice with cell specific deficiencies in IL-4Ra it was demonstrated that expression of this receptor on smooth muscle cells and macrophages is not essential for the development of acute experimental allergic airway disease, as it has been previously suggested.

Healthcare organizations now consider increased efficiency, reduced costs, improved patient care and quality of services, and safety when they are planning to implement new information and communication technology (ICT) based applications. However, in spite of enormous investment in health information systems (HIS), no convincing evidence of the overall benefits of HISs yet exists. The publishing of studies that capture the effects of the implementation and use of ICT-based applications in healthcare may contribute to the emergence of an evidence-based health informatics which can be used as a platform for decisions made by policy makers, executives, and clinicians. Health informatics needs further studies identifying the factors affecting successful HIS implementation and capturing the effects of HIS implementation. The purpose of the work presented in this thesis is to increase the available knowledge about the impact of the implementation and use of HISs in healthcare organizations. All the studies included in this thesis used qualitative research methods. A case study design and literature review were performed to collect data. This thesis’s results highlight an increasing need to share knowledge, find methods to evaluate the impact of investments, and formulate indicators for success. It makes suggestions for developing or extending evaluation methods that can be applied to this area with a multi-actor perspective in order to understand the effects, consequences, and prerequisites that have to be achieved for the successful implementation and use of IT in healthcare. The results also propose that HIS, particularly integrated computer-based patient records (ICPR), be introduced to fulfill a high number of organizational, individualbased, and socio-technical goals at different levels. It is therefore necessary to link the goals that HIS systems are to fulfill in relation to short-term, middle-term, and long-term strategic goals. Another suggestion is that implementers and vendors should direct more attention to what has been published in the area to avoid future failures. This thesis’s findings outline an updated structure for implementation planning. When implementing HISs in hospital and primary-care environments, this thesis suggests that such strategic actions as management involvement and resource allocation, such tactical action as integrating HIS with healthcare workflow, and such operational actions as user involvement, establishing compatibility between software and hardware, and education and training should be taken into consideration.

A process called class switching recombination (CSR) regulates the production of isotypes by enabling the switch of producing unspecific IgM or IgD to producing IgG, IgE, or IgA by causing an irreversible genomic rearrangement. Recent studies indicate a gap in the identification of the molecular mechanisms underlying CSR. This interdisciplinary project between bioinformatics and immunology aims to shed light onto these mechanisms and highlight differences in physicochemical properties in the B-cell repertoire to identify factors contributing to the decline in immune response with age and its relationships to CSR. The project is developed in line with the hypothesis that effective immune responses, and their resolution, require coordinated action from multiple different subclasses of antibodies. This is enabled by improvements in the high throughput sequencing techniques, which allows the B-cell repertoire to be revealed. The most variable portion of antibody molecules is the third complementarity determining region (CDR3) of the heavy chain. Hence, differences in hydrophobicity, pK value of the C-terminus peptide fragment, and the length of CDR3 were identified and accounted as factors that contribute to the decline in the immune response with age. Our understanding of how the immune response alters with age, is important for research applications in designing tailored vaccine strategies to ensure safety and efficacy. Development of in silico tools for the analysis of the B-cell repertoire is useful in extracting principles and functioning mechanisms that can be tested experimentally, helping in further characterizing CSR.

This project had a focus on the effect of digitoxin on inflammation in cancer Panc-1 cell line compared to BxPC-3 cell line. Pancreatic cancer, especially the form pancreatic adenocarcinoma is the fourth cause for cancer deaths, seen in the Western world. The progression and the initiation of the disease is a consequence of an interplay between genetic and inflammation events that are linked. Digitoxin is a cardiac glycoside with effect on various cancer types. Panc-1 cells and BxPC-3 cells were treated with different concentrations of digitoxin for 48 hours. Cell viability was measured, ELISA to measure expression of pro-IL-1β and IL-1β, since they are involved in the pathway and qPCR to measure gene expression. Gene expression was done to see if digitoxin affected the genes in the inflammasome pathway. The cell viability decreased with increasing concentration of digitoxin for both cell lines. TNFα was mostly downregulated in both Panc-1 and BxPC-3. NF-κB was upregulated in both cell lines. IL-1β was upregulated in BxPC-3 while gene expression was not seen in Panc-1. Lastly, IL-18 was downregulated in Panc-1, but upregulated in BxPC-3. A downregulation of IL-1β protein expression was seen in Panc-1 and in BxPC-3, a downregulation of pro IL-1β in Panc-1 and a downregulation of pro IL-1β in BxPC-3 was seen in ELISA. This study might provide an insight that is valuable for the researchers in the future to treat cancer from the perspective of an immune disorder.

Cancer has been found not only to be a disease of genetic mutations, but also a metabolic state by which insulin and glucagon has an impact on cancer cells. Pancreatic adenocarcinoma (PDAC) is a highly lethal cancer with high risk of recurrence of cancer cells after cancer therapy treatment with a worse outcome. Healthy individuals are reported to have imbalance of blood glucose homeostasis, and an imbalance between secreted insulin and glucagon, which contribute to diabetes onset and might create a new complex between human insulin and glucagon. An increased risk of developing cancer has been seen in patients with type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D). Investigations were done on human insulin and glucagon and its formation into a new complex. Pancreatic cancer cell lines, Panc-1, were treated with these different peptides, in different concentrations, to find out the impact on cell viability. Lactate-Glo Assay were performed, investigating if there was a change of metabolism within the cells. A complex formation of insulin and glucagon from bovine and porcine, receptively, has previously been shown. Here it is reported of the existence of a new insulin-glucagon (I-G) complex made from human peptides. The I-G complex increase cancer cell viability, change the metabolism within the cells and act differently than from insulin and glucagon alone. The I-G complex interaction in cancer and diabetes, are to be further investigated.

Lipids serve numerous different processes in biological cell communication. As for the case ofPhosphatidylinositol‐(4,5)‐biphosphate (PIP2), which serves actin‐dynamics, endocytosis, and ofrecent importance, exocytosis. PIP2 proceeds these functions at the cell's plasma membrane, whichyields the possibility to also exist at the membrane of large dense‐core vesicles. With the lipidsfunctions previously known, what factor does PIP2 serve if located on the membrane? This studyintends to use confocal imaging and vesicle impact electrochemical cytometry to study the locationand function respectably of the lipid membrane. Analysis was carried out on both PC12 cells as cell lineand bovine chromaffin as primary cells for each respective analysis. Phospholipase C delta‐1 (PLCδ1)markers were used in the microscopy experiments. The external application of PIP2 on extracted largedense‐core vesicles (LDCV) experimentally was performed. This study observed the location of PIP2 isindeed on large dense‐core vesicles well apart from the plasma membrane. In the extracted largedense‐core vesicles which was used a model to study how the changes in PIP2 levels affect fusion,increasing PIP2 levels significantly reduced the half‐time of LDCV. Indicating that PIP2 effect is on themembrane stability, resulting in rapid breakup of LDCV membrane. Which is probably resulted byaffecting membrane order from clustering PIP2. These findings broaden our understanding of the lipidPIP2, as it also lay way for future research, among cell‐to‐cell communication, vesicles, and hormonaltreatment. It also indicates the useability of combining imaging and amperometric for observationalstudies.

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