Bedingt durch oftmals schnelle und fortschreitende Änderungen im wirtschaftlichen Umfeld stehen Unternehmen vor zahlreichen externen sowie internen Anforderungen und Herausforderungen, was wiederum eine effektive Steuerung und Koordination der innerbetrieblichen aber auch der überbetrieblichen Geschäftsprozesse und -abläufe erfordert. Um diesen Herausforderungen zu begegnen, ist der Einsatz von adäquaten Anwendungssystemen zwingend. Speziell die Nutzung von Enterprise Resource Planning-(ERP-)Systemen, die als standardisierte Systeme die gesamten unternehmerischen Aktivitäten und Geschäftsprozesse unterstützen können, ist zu einem wichtigen Bestandteil der Unternehmen geworden. Ein richtig ausgewähltes und implementiertes ERP-System bietet zahlreiche Vorteile sowohl für Großunternehmen aber auch für klein- und mittelständische Unternehmen (KMU). Die Implementierung eines ERP-Systems stellt jedoch ein komplexes und zeitintensives Projekt dar, welches den Unternehmen große Möglichkeiten eröffnet, diese aber gleichzeitig mit enormen Risiken konfrontiert. Dabei realisieren immer mehr KMU die möglichen Vorteile dieser Systeme, woraus eine konstante Nachfrage nach ERP-Systemen für kleine und mittlere Unternehmen resultiert. Um jedoch von den Vorteilen zu profitieren anstatt von den Risiken „verschlungen“ zu werden, ist es zwingend erforderlich, sich genau auf die Faktoren zu fokussieren, die zur einer erfolgreichen Einführung eines ERP-Systems beitragen. An diesem Punkt knüpft die vorliegende Dissertation mit einem ersten Forschungsschwerpunkt an. Dieser Schwerpunkt befasst sich mit kritischen Erfolgsfaktoren im Zusammenhang mit der ERP-System-Einführung und der ERP-System-Nutzung in klein- und mittelständischen Unternehmen. Ziel dieses ersten Schwerpunktes ist es, einen Einblick in die Erfolgsfaktoren bei ERP-System-Implementierung in KMU zu geben und die Unterschiede zu den Faktoren bei ERP-Projekten in Großunternehmen aufzuzeigen. Als konkretes Ergebnis dieses Forschungsstrangs wird dabei ein Vorgehensmodell für ERP-Einführungen in KMU entwickelt, welches auf Basis der Erfolgsfaktoren von ERP-Projekten aus bestehenden Modellen abgeleitet und an die Bedürfnisse und Anforderungen der KMU angepasst wird. Hierbei werden die Erfolgsfaktoren direkt in das Modell mit einbezogen. Des Weiteren resultiert ein zweiter Schwerpunkt dieser Dissertation erneut aus der hohen und konstanten Nachfrage nach ERP-Systemen, welche zu einem sehr stark fragmentierten ERP-Markt vor allem im Bereich der KMU geführt hat mit einer Vielzahl von Herstellern und Systemen. Hier erschwert es diese hohe Marktfragmentierung den Anwenderunternehmen nicht nur, die „richtige“ Software zu finden, sondern auch für das von ihnen ausgewählte System entsprechende Fachkräfte an sich zu binden. Daraus ergibt sich unter anderem auch die Notwendigkeit für Hochschulen, ihren Studierenden und späteren Absolventen dieses geforderte und benötigte Fachwissen, insbesondere in informationssystembezogenen Studiengängen zu vermitteln. Jedoch gibt es dafür keinen standardisierten Ansatz. Die Systemwahl und die Anzahl der Systeme sowie der Aufbau und die Anzahl der ERP-Kurse divergieren von Hochschule zu Hochschule, wobei in diesem Punkt eine Dominanz großer ERP-System Hersteller zu verzeichnen ist. Allerdings ist eine diversifiziertere Einbindung von ERP-Systemen vor allem aus dem Bereich der KMU sinnvoll. An diesem Punkt stehen die Hochschulen und die Lehrenden vor der Herausforderung, wie viele Systeme in die Curricula integriert werden sollten und auf welche Art und Weise und in welchem Umfang diese Systeme vermittelt werden sollten. Daher werden im Rahmen dieses zweiten Schwerpunktes Möglichkeiten und Kursmodelle beschrieben, durch die eine praktische Vermittlung einzelner oder auch mehrerer ERP-Systeme ermöglicht und unterstützt wird. Ziel dabei ist es, einen Beispielcurriculum zu entwickeln, in dem über verschiedene Kurse hinweg, Kenntnisse zu ERP-Systemen vermittelt werden. Die Kurse dieses Curriculums werden dabei auf Basis der Literatur und der Anforderungen von Unternehmen an spätere Absolventen (vor allem resultierend aus den Erfolgsfaktoren des ersten Forschungsstrangs) entwickelt. Des Weiteren werden diese Kurse und die darin eingesetzten Systeme mit den Ergebnissen einer Umfrage an Universitäten und Fachhochschulen zum ERP-System-Einsatz in der Lehre verglichen und auf Basis dieser Ergebnisse angepasst und modifiziert. Als konkrete Resultate dieses Forschungsstrangs werden mit dem zu entwickelnden Beispielcurriculum Handlungsempfehlungen gegeben, mit denen Hochschulen sowohl Kenntnisse zu ERP-Systemen für Großunternehmen als auch zu Systemen für KMU vermitteln können. Dabei steht auch die praktische Kenntnisvermittlung von kleineren Systemen im Fokus, um den Studierenden einen weiteren Blick auf die Verschiedenartigkeit von ERP-Systemen zu bieten.

The volume defined by the rigid cranium is shared by the brain, blood and cerebrospinal fluid (CSF). With every heartbeat the arterial blood volume briefly increases and venous blood and CSF are forced out of the cranium, leading to pulsatility in CSF flow and intracranial pressure (ICP). Altered CSF pulsatility has been linked to idiopathic normal pressure hydrocephalus (INPH), which involves enlarged cerebral ventricles and symptoms of gait/balance disturbance, cognitive decline and urinary incontinence that may be improved by implantation of a shunt. The overall aim of this thesis was to investigate the fluid dynamics of the CSF system, with a focus on pulsatility, and how they relate to INPH pathophysiology and treatment. Mathematical modelling was applied to data from infusion tests, where the ICP response to CSF volume manipulation is measured, to analyse the relationship between mean ICP and ICP pulse amplitude (AMP) before and after shunt surgery in INPH (paper I-II). The observed relationship, designated the pulsatility curve, was found to be constant at low ICP and linear at high ICP, corresponding to a shift from constant to ICP dependent compliance (paper I). Shunt surgery did not affect the pulsatility curve, but shifted baseline ICP and AMP along the curve towards lower values. Patients who improved in gait after surgery had significantly larger AMP reduction than those who did not, while ICP reduction was similar, suggesting that improving patients had baseline ICP in the linear zone of the curve before surgery. Use of this phenomenon for outcome prediction was promising (paper II). The fluid dynamics of an empirically derived pulsatility-based predictive infusion test for INPH was also investigated, with results showing strong influence from compliance (paper III). Clinical ICP data at different body postures was used to evaluate three models describing postural effects on ICP. ICP decreased in upright positions, whereas AMP increased. The model describing the postural effects based on hydrostatic changes in the venous system, including effects of collapse of the jugular veins in the upright position, accurately predicted the measured ICP (paper IV). Cerebral blood flow and CSF flow in the aqueduct and at the cervical level was measured with phase contrast magnetic resonance imaging, and compared between healthy elderly and INPH (paper V). Cerebral blood flow and CSF flow at the cervical level were similar in INPH patients and healthy elderly, whereas aqueductal CSF flow differed significantly. The pulsatility in the aqueduct flow was increased, and there was more variation in the net flow in INPH, but the mean net flow was normal, i.e. directed from the ventricles to the subarachnoid space (paper V). In conclusion, this thesis introduced the concept of pulsatility curve analysis, and provided evidence that pulsatility and compliance are important aspects for successful shunt treatment and outcome prediction in INPH. It was further confirmed that enhanced pulsatility of aqueduct CSF flow was the most distinct effect of INPH pathophysiology on cerebral blood flow and CSF flow. A new model describing postural and hydrostatic effects on ICP was presented, and the feasibility and potential importance of measuring ICP in the upright position in INPH was demonstrated. / <p>Forskningsfinansiär: </p><p>European Union, ERDF: Objective 2, Northern Sweden (grant no. 158715-CMTF). </p>

The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology. This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease. A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD. Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity. LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion. In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

Le traitement du cancer à l’aide d’une exposition aux radiations ionisantes peut mener au développement de plusieurs effets secondaires importants, dont un retard de réparation et de régénération du tissu hématopoïétique. Les mécanismes responsables de ces effets demeurent encore inconnus, ce qui limite le développement de nouvelles approches thérapeutiques. À l’aide d’un modèle murin de prise de greffe, nos résultats démontrent que l’endommagement du microenvironnement par l’irradiation a un impact limitant sur le nichage hématopoïétique. Parce que le microenvironnement est composé principalement de cellules dérivées des cellules souches mésenchymateuses (CSM), nous avons évalué le potentiel des CSM à régénérer le tissu hématopoïétique par la reconstitution de la niche osseuse. Cette thérapie a mené à une augmentation remarquable du nichage hématopoïétique chez les souris irradiées. Les causes moléculaires impliquées dans le nichage hématopoïétiques sont encore inconnues, mais nous avons remarqué l’augmentation de la sécrétion de la cytokine « granulocyte-colony stimulating factor » (G-CSF) dans l’espace médullaire suite à l’irradiation. Le G-CSF est impliqué dans la mobilisation cellulaire et est fort possiblement nuisible à une prise de greffe. Nous avons évalué le potentiel d’une thérapie à base de CSM sécrétant le récepteur soluble du G-CSF afin de séquestrer le G-CSF transitoirement et les résultats obtenus démontrent que le blocage du G-CSF favorise le nichage hématopoïétique. Globalement, les données présentées dans ce mémoire démontrent que le microenvironnement osseux et le niveau de G-CSF dans la moelle sont importants dans le processus de nichage hématopoïétique et que la baisse du potentiel de régénération du tissu hématopoïétique suite à l’irradiation peut être renversée à l’aide d’une thérapie cellulaire de CSM génétiquement modifiées ou non. / Cancer treatment using ionizing radiation may lead to significant side effects, including delayed hematopoietic tissue repair and regeneration. The mechanisms mediating these defects remain unknown, thus limiting the development of new therapeutic approaches. Using a mouse engraftment model, our results show that microenvironment damage by irradiation limits hematopoietic homing. Since the microenvironment is mainly composed of mesenchymal stem cells (MSCs)-derived cells, we evaluated the potential of MSCs to improve hematopoietic tissue regeneration by bone marrow niche reconstitution. This therapy led to remarkable enhancement of hematopoietic homing in irradiated mice. The molecular causes involved in hematopoietic homing remain unknown, but we noticed an increased in “granulocyte-colony stimulating factor” (G-CSF) secretion within the medullary space after irradiation. G-CSF is involved in cellular mobilization and may possibly be harmful to engraftment. We evaluated the therapeutical potential of MSC genetically-engineered to secrete a soluble G-CSF decoy receptor that would transiently sequester G-CSF. Results obtained show that G-CSF blocking improved hematopoietic homing. Overall, the findings presented in this thesis indicate that bone marrow microenvironment and G-CSF levels are important in hematopoietic homing process, and that the decline in hematopoietic tissue regeneration potential following irradiation can be reversed by cellular therapy using MSC genetically modified or not.

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as lOx the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracistemal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracistemal inoculation of a cephalosporinresistant strain of E. cloacae. Untreated  rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC. Using   the same EEG-model, the neurotoxic potential of imipenem/cilastatin (I) and a new penem derivative, FCE 22101 were compared in a cross-over study. Both I and FCE 22101 were significantly more neurotoxic than BPC. While BTF levels of the three antibiotics could be detected in all tested rabbits, detectable CSF levels were only found in one of twelve rabbits treated with I or FCE 22101, indicating that BTF concentrations rather than CSF ones are decisive for neurotoxicity of ß-lactam antibiotics. The EEG-model used was found to be a suitable model for cross-over studies of intravenously administered antibiotics. Using the "silent-second" as EEG-threshold, a CNS interaction between intraperitoneally administered BPC and intravenous thiopental was demonstrated in rats. The most probably site for this interaction is the organic acid transport system out of the CNS. Thiopental distribution in the rat brain seemed to depend not only on its lipid solubility. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1988, härtill 5 uppsatser.</p> / digitalisering@umu

Proteins are fundamental structural, enzymatic and regulatory components of cells. Analysis of proteins, such as by measuring their concentrations, characterizing their modifications, and detecting their interactions, provides insights in how biological systems work physiologically or pathologically at the molecular level. To perform such analysis, molecular tools with good sensitivity, specificity, high multiplexing and throughput capacity are needed. In this thesis, four different assays were developed and applied to detect and profile proteins and protein complexes in human body fluids, and in cells or tissues. These assays are based on targeting proteins or protein complexes by oligonucleotide-conjugated antibodies, and subsequent proximity dependent enzymatic reactions involving the attached DNA reporter sequences. In paper I, a solid-phase proximity ligation assay (SP-PLA) was applied to detect synthetic and endogenous amyloid beta protofibrils. The SP-PLA provided better sensitivity and increased dynamic range than a traditional enzyme-linked immunosorbent assay (ELISA). In paper II, in situ PLA was applied to investigate the correlation between MARK2-dependent phosphorylation of tau and Alzheimer’s disease. Greater numbers of MARK2-tau interactions and of phosphorylated tau proteins were observed in brain tissues from Alzheimer’s patients than in healthy controls. In paper III, a multiplex SP-PLA was applied to identify protein biomarker candidates in amyotrophic lateral sclerosis (ALS) disease and in the analgesic mechanism of spinal cord stimulation (SCS). Among 47 proteins in human cerebrospinal fluid (CSF) samples, four were found at significantly lower concentrations (p-values &lt; 0.001) in the samples from ALS patients compared to those from healthy controls (follistatin, IL-1α, IL-1β, and KLK5). No significant changes of the analyzed proteins were found in the CSF samples of neuropathic pain patients in   the stimulated vs. non-stimulated condition using SCS. In paper IV, a new technology termed the proximity barcoding assay (PBA) was developed to profile individual protein complexes. The performance of PBA was demonstrated on artificially assembled streptavidin-biotin oligonucleotide complexes. PBA was also proven to be capable of profiling transcriptional pre-initiation complexes from nuclear extract of a hepatic cell line.

The fetus and its placenta, collectively called the conceptus, are semi-allogeneic to the mother, as they express transplantation antigens of paternal origin. Foreign tissues generally experience immunological rejection by the host immune system; however in a normal healthy pregnancy the conceptus does not undergo immune attack. Emerging evidence indicates the conceptus avoids rejection through a number of mechanisms including the induction of active maternal immune tolerance specific for paternal antigens. However, the mechanisms responsible for establishing this tolerance remain undefined, including the timing of the first encounter with paternal antigen and the cellular processes by which paternal antigen is presented to the maternal immune system. Exposure to paternal transplantation antigens occurs in two waves: initially in the context of male seminal fluid at conception, and secondly after placental trophoblast invasion of maternal tissues in mid-gestation pregnancy. Therefore the aim of this research was to evaluate the female immune response to paternal antigens in seminal fluid and those associated with the conceptus. The mechanisms of antigen presentation, the impact of the cytokine environment and the consequences of T cell activation on pregnancy were also investigated. A transgenic system using ovalbumin (OVA) as the model paternal antigen was established. The transgenic Act-mOVA mouse expresses OVA constitutively and ubiquitously under a B-actin promoter and OVA was shown to be present in seminal fluid and in the fetal and placental tissue of sired progeny. The OVA-reactive CD8+ OT-I and CD4+ OT-II T cells were employed to gauge the relative amount of OVA antigen presented, with the strength of the maternal immune response quantified based upon the extent of T cell proliferation, as assessed by CFSE dye-dilution. Utilising bone marrow chimeric mice, it was demonstrated that upon insemination by an Act-mOVA male, seminal fluid-derived OVA was processed and indirectly presented by maternal bone marrow-derived antigen presenting cells to induce activation and proliferation of the CD8+ OT-I T cells within the uterinedraining para-aortic lymph nodes of the female. Likewise, OT-II T cells were responsive to MHC class II-restricted presentation of seminal fluid OVA. Post-implantation conceptus-derived OVA was detected within peripheral lymph nodes and the spleen where it was presented via the MHC class I and class II-restricted pathways to induce systemic proliferation of both OT-I and OT-II T cells. Furthermore, as gestation advanced the extent of OVA presentation and hence T cell proliferation intensified. Conceptus-derived OVA was still presented systemically until 20 days pp. The impact of the uterine cytokine environment was assessed to determine its influence on seminal OVA antigen processing and presentation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key factor in regulating the leukocyte population of the female reproductive tract. GM-CSF-deficient female mice were unable to process and present seminal fluid OVA as effectively or efficiently as their wildtype counterparts, as assessed by their reduced capacity to drive OT-I and OT-II T cell proliferation following insemination by an Act-mOVA male. Finally, with highly-reactive OVA-specific T cells activated in response to seminal and conceptus OVA antigen, it was of interest to determine the effect of OT-I T cell activation on fetal survival and pregnancy success. It was found that OT-I T cells activated in vivo to paternal OVA antigen in the context of seminal fluid and pregnancy were not deleterious to pregnancy outcomes. However the transfer of cytotoxic OT-I T cells generated in vitro in the presence of an IL-2 into female mice carrying OVA-expressing conceptuses was detrimental to fetal survival. Collectively these experiments demonstrated that the initial exposure to paternal antigen, and hence the first opportunity to develop paternal antigen-specific tolerance, occurs at insemination. Paternal antigen is presented to the maternal T cell repertoire throughout gestation and may play a role in maintaining immune tolerance during pregnancy. The processing and presentation of paternal-derived antigen is chiefly performed by female bone marrow-derived antigen presenting cells. The cytokine environment of the mated female reproductive tract is critical in allowing optimal antigen processing and presentation, to generate an immune response consistent with maternal immune tolerance of the conceptus. / Thesis (Ph.D.) - University of Adelaide, School of Paediatrics and Reproductive Health, 2008

Allergic asthma is an immunological disease, mediated by CD4+ Th2 cells, and its prevalence has increased over recent decades. Features of allergic asthma include airway hyperresponsiveness (AHR), airway eosinophilia, excessive airway mucus production, and increased IgE and Th2 cytokine levels. Airway remodeling with pulmonary fibrosis is noted in the progress of asthma. In this thesis, a murine model of allergic asthma was used to investigate the effect of cyclophosphamide (CY) on asthma and the involvement of regulatory T cells (Treg), and the role of Granulocyte-macrophage colony stimulating-factor (GM-CSF) in allergic asthma by using GM-CSF knockout mice. CY is a cytotoxic agent, which paradoxically augments several immune responses. The first part of this thesis was aimed to study the effects of CY in a murine model of allergic airway inflammation. BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14, and challenged with aerosolized OVA from days 21 to 27. Some mice additionally received CY on days -2 and 12. In the CY-treated animals, pronounced worsening of inflammatory features was noted, including increases in eosinophil infiltration, epithelial thickness, mucus occlusion and eosinophil numbers in bronchoalveolar lavage fluid (BALF). Increased total and OVA-specific serum IgE were also noted in the CY-treated animals. In cell cultures from peritracheal lymph nodes, the Th2 cytokines IL-4 and IL-5 were elevated in animals treated with CY. It was hypothesized that the effects of CY could be caused by reduced immunosuppression mediated by Treg. mRNA expression of the immunosuppressive cytokines IL-10 and TGF-beta was reduced in the lungs of CY-treated mice. The expression of FoxP3, a marker of naturally occurring Treg, was significantly reduced in spleens, thymuses and peritracheal lymph nodes after the second injection of CY, and in the lung tissue after allergen challenge in CY-treated mice. Furthermore, lung IL-10-producing CD4+ T cells and CTLA-4+-bearing CD4+ T cells were reduced after allergen aerosol challenge in CY-treated mice. Thus CY worsened the features of allergic pulmonary inflammation in this model, in association with increased production of IgE and Th2 cytokines. The reduction in expression of FoxP3 and immunosuppressive cytokines by CY suggests that toxicity to Treg may contribute to the increased inflammation. GM-CSF plays a role in the growth, development, and maturation of bone marrow hemopoietic cells into mature blood cells, and has been proposed to be involved in potentiating the function of inflammatory cells in allergic inflammation. In the second part of this thesis, GM-CSF knockout (KO) mice were used to investigate the role of GM-CSF. In allergic KO mice, airway eosinophils were only shown in the perivascular, but not peribronchial areas in the lung, compared to the allergic wild-type (WT) mice in which eosinophil infiltration appeared in both areas. Eosinophil numbers were drastically reduced in the bronchoalveolar lavage fluid (BALF) of KO mice. IL-5 production in the lung tissue and BALF in allergic KO mice was reduced; similar results were also found in peritracheal draining lymph nodes after in vitro stimulation assays. However, IL-4 and IL-13 production, airway hyperresponsiveness (AHR), and serum IgE production were not affected in allergic KO mice. Surprisingly, lung IFN-gamma mRNA and BALF levels were increased in allergic KO mice. Lung mRNA levels of CCR3, a key chemokine receptor on eosinophils, were significantly reduced in allergic KO mice, whereas expression of the chemokines eotaxin and RANTES were at similar levels in allergic KO and WT mice. Lung mRNA levels of the IFN-gamma-inducible chemokines Mig (CXCL9) and IP-10 (CXCL10), which are antagonists of CCR3, and their receptor CXCR3 were increased in allergic KO mice, compared with allergic WT mice. Data obtained from flow cytometry showed more eosinophils survived in the lung of WT mice than KO mice. Another allergy model, a peritoneal allergy model was performed to investigate inflammation in a different model. Leukocyte subpopulations such as neutrophils, eosinophils, macrophages, and lymphocytes were reduced in the peritoneal lavage fluid of allergic KO mice. The findings revealed that GM-CSF is essential for IL-5 production, pulmonary airway eosinophilia and eosinophil survival. In the absence of GM-CSF, over-production of IFN-???? may induce chemokines, including Mig and IP-10, which are antagonists for CCR3 and may reduce airway eosinophil infiltration. In this thesis, a murine model of allergic asthma has been used to obtain novel findings on the regulation of allergic inflammation. The results with CY are relevant to the treatment of asthma patients with CY and other cytotoxic agents. The findings in the GM-CSF KO mice suggest that GM-CSF is a potential therapeutic target in asthma, and that in assessment of new therapeutic agents for asthma, effects on GM-CSF should be considered.

Title: Critical Success Factors for Integration of Enterprise Resource Planning System   Level: Student thesis, final assignment for Master Degree (one year) in Business Administration   Author: Kambiz Kafi   Supervisor: Dr. Maria Fregidou-Malama   Examiner: Dr. Ehsanul Huda Chowdhury   Date: 2018-11-26   Aim: This study examines the Critical Success Factor (CSF) model and its implementation in a case study where ERP Systems are integrated. The model includes Legacy System as a CSF.   Method: Deductive reasoning and case study were applied to support the research theory. Primary and secondary data were collected. Interviews with managers and staffs were performed.   Result &amp; Conclusions: The study shows the factors that are critical in successful implementation of ERP project and how a successful implementation and integration of ERP projects is executed when two companies are being merged. It also shows how the ERP integration project can be implemented. This work studied an implementation of Holland and Light’s theoretical CSF model empirically and validated that the model is general and robust for successful ERP implementation and managing changes.   Contribution of the research: This study of integration of few Legacy Systems when companies are being merged is a contribution to the theory of CSF. The central role that Legacy Systems plays in ERP project implementation is shown empirically. This study presents Software Alignment (Software Configuration) based on two company’s business processes empirically and found it to be essential in success of ERP projects. The research shows how CSF model manages changes, assisting managers in merging two companies successfully. The research presents a modified Holland and Light CSF model to meet the merging situations.      Suggestions for future research: To gain more knowledge about CSFs for integration of ERPs, this study suggests further cross- industrial empirical studies in wholesale and retail industries with varied sizes. Research about identifying CFSs in extended ERP using e_CRM is recommended.

ERP system har de senaste åren uppträtt som en central faktor vid framgångsrik informationshantering och agerat som en grundpelare i många företagsorganisationer. Implementering av ett nytt affärssystem är en komplex process vilket bidrar till att organisationer får svårigheter med att genomföra processen. Implementering av affärssystem handlar om att kombinera tidigare separerade system med fokus på att tillhandahålla en mer komplett informationsresurs för en organisation. ERP systemen tog fart under millenniumskiftet y2k och många företag hade vid det laget svårt att implementera systemen med ett positivt slutresultat. Arton år senare så kvarstår problematiken trots att ERP systemen har utvecklats och företagen blivit mer kunniga inom området. Detta visar en studie från Panorama Consulting (2017) där det framkom att 26 procent av företagen misslyckats med implementeringen 74 procent går över budget samt att 59 procent passerade den tänkta tidsplanen. För att finna en lösning på problematiken så har flertalet forskare genomfört studier där fokus ligger på att identifiera de negativt bidragande faktorerna vid ERP implementering. Dessa faktorer kallas för ”Critical failure factors”. Det finns idag lite empirisk forskning där information har samlats från ERP leverantörer. Forskningen som finns grundar sig i gamla teorier för vilka faktorer som bidrar positivt respektive negativt för en implementeringsprocess. Dessa teorier utgår de flesta forskare från i sina studier kring implementeringen av ERP system. Denna studie fokuserar därför på ERP leverantörernas perspektiv kring negativt bidragande faktorer vid implementering av ERP system. Stor vikt har legat på att samla in faktorer från ERP leverantörer för att vid ett senare skede i studien ställa dessa mot de faktorer som nämnts i tidigare studier för att finna samband och eventuella avvikelser. Studien använde sig av intervjuer som datainsamlingsmetod och fem intervjuer har genomförts med erfarna ERP leverantörer. Resultatet av det insamlade materialet från ERP leverantörerna identifierar ett antal kritiska faktorer som kan sammankopplas med faktorer från tidigare studier. Intressant är att studien även identifierat ett antal faktorer som avviker från tidigare studier. Slutsatserna som går att dra från studien är att implementeringsprocesserna kan förbättras och bli avsevärt mycket mer effektiva med hjälp av den nya insikten i problematiken som ERP leverantörerna framför. Medvetenhet om dessa negativt bidragande faktorer vid implementering av ett ERP system bidrar med kunskap inom området för implementeringsprocesser som i sin tur kan användas av företag och privatpersoner för att underlätta och förhindra de problem som kan uppstå i en sådan process. / In recent years, the ERP system has been a key factor in successful information management and served as a foundation for many corporate organizations. Implementing a new business system is a complex process, which leads organizations having difficulties implementing the process. Implementation of business systems involves combining previously separated systems focusing on providing a more complete information resource for an organization. ERP systems accelerated during the millennium shift y2k, and many companies at the time had difficulties to implement the systems with a positive end result. Eighteen years later, the problem remains, despite the fact that ERP systems have evolved and businesses become more knowledgeable in the field. This shows a study from Panorama Consulting (2017) where it was found that 26 percent of companies failed with implementation. 74 percent exceed budget and 59 percent passed the intended schedule. To find a solution to the problem, most researchers have conducted studies focusing on identifying the negative contributing factors in ERP implementation. These factors are called "Critical failure factors". There is currently a lack of empirical research where information has been gathered from ERP providers. The research found is based on old theories for which factors contribute positively and negatively to an implementation process. These theories are being used by most researchers in their studies regarding the implementation of the ERP system. This study therefore focuses on ERP suppliers' perspectives on negative contributing factors in implementing ERP systems. Major emphasis has been placed on collecting factors from ERP providers in order that at a later stage in the study they can address the factors mentioned in previous studies to find relationships and possible deviations. The study used interviews as data collection method and five interviews have been conducted with experienced ERP providers. The result of the collected material from ERP providers identifies a number of critical factors that can be linked to factors from previous studies. Interestingly, the study also identified a number of factors that differ from previous studies. The conclusions that can be deduced from the study are that the implementation processes can be improved and become significantly more efficient with the help of the new insight into the problems that the ERP providers lifts up. Awareness of these negative contributing factors in implementing an ERP system contributes knowledge in the field of implementation processes, which in turn can be used by companies and individuals to facilitate and prevent the problems that may arise in such a process.