Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the deactivation of macrophages 34 wk after a compression-injury of rat spinal cord. To explore whether reactivation of endogenous macrophages might be beneficial for spinal cord repair, we have studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in the same paraplegia model and in cell cultures. There is significant, though transient, improvement of locomotor recovery after a single delayed intraperitoneal injection of 2g GM-CSF. This improvement is associated with an increased expression of 5HT at the level of the CPG (T13-L2). At longer survival delays, axonal regeneration is significantly enhanced in GM-CSF-treated rats. We then studied the effects of GM-CSF on brain-derived neurotrophic factor (BDNF)secretion by macrophages/microglia, inflammatory reaction and phagocytosis by macrophages/microglia. In vivo, at short post-treatment delays, we found that GM-CSF increases significantly the expression of Cr3 and BDNF by macrophages at the lesion site. In vitro, BV2 microglial cells expressed higher levels of BDNF in the presence of GM-CSF and neurons cocultured with microglial cells activated by GM-CSF generated more neurites, an effect blocked by a BDNF antibody. In vivo, we showed that GM-CSF treatment (either immediate or delayed) does not increase IL-6 expression by macrophages/microglia or astrocytes. We showed that a delayed GM-CSF treatment down regulates IL-1 expression by astrocytes. In vivo, we showed that a delayed GM-CSF treatment can decrease MAG expression at the lesion site. These experiments suggest that GM-CSF could be an interesting treatment option for spinal cord injury and that its beneficial effects might be mediated by BDNF.

In this thesis, two different vaccines were evaluated as adjuvant therapy for patients with colorectal cancer. The ability of the two candidate vaccines to generate antigen-specific cellular and humoral responses, respectively, was studied. The effectiveness of granulocyte colony stimulating factor (GM-CSF) as a cytokine adjuvant to augment the immune response was also examined. The first vaccination strategy involved immunization with the recombinant tumor-associated protein, carcinoembryonic antigen (CEA). Recombinant CEA was administered at 4 different dose levels 7 times during one year. Peripheral blood samples were regularly analyzed during 36 months. This vaccination regimen induced a strong immunoglobulin 1 (IgG1) and IgG4 response, a moderate IgG2 response and a weak IgG3 response against CEA. GM-CSF markedly augmented the effect on IgG1 and IgG4 as well as the T cell response. In contrast, dose of rCEA had no or modest effect on induced immune responses. The response gradually increased during the 12 months immunization period. Responses of all three IgG subclasses and of T cells were protracted up to 36 months. The anti-CEA IgG titers related significantly to survival. Functional HLA-DR epitopes of CEA could be defined. These major histocompatibility class II epitopes may serve as putative components of a peptide-based vaccination strategy. The other vaccine strategy consisted of the tumor-associated antigen epithelial cell adhesion molecule (Ep-Cam) expressed as a transgene in a viral vector, ALVAC. Patients were immunized subcutaneously/intradermally 3 times over 6 weeks and monitored for immune responses for 46 weeks. No anti-Ep-Cam specific humoral response was induced, but Ep-Cam specific type 1 T cells (interpheron-gamma production) were induced, mainly in the GM-CSF group. The cytotoxic cellular response appeared late, or a few months after the last immunization. Both vaccines were well tolerated. Since GM-CSF was an important component for both regimens, immungenicity of this cytokine was assessed. Multiple immunizations with low dose GM-CSF were associated with a low incidence of GM-CSF antibodies that did not neutralize the biological effect of GM-CSF. In conclusion, both vaccines are promising candidate vaccines. GM-CSF is necessary to induce a strong humoral and cellular immune response. Large clinical trials are urgently warranted to evaluate the clinical efficacy.

Introduction: Corporate limits becoming more diffuse due to the globalization taking place and requirements for analytical strategies are becoming more fundamental parts of organizations. Business Intelligence systems are hot and not without reason, today's world is spinning faster and with a flow of information that is constantly increasing Business Intelligence promises to introduce a support that will render a better decision-making, something that everyone wants. Problem Discussion: The local government business has today demands from the Swedish School-inspection to analyze and create adequate target images to the school and students meet curriculum goals and guidelines. Therefore, local government activities has increasingly begun to implement Business Intelligence tools, with the purpose to facilitate strategic and operational decisions were the result plays an increasing role in today's society. Purpose: This study evaluates how the analysis tool Qlikview fulfills the function of monitoring and controlling the improved student achievement in public schools. Method: The evaluation has been conducted qualitative interviews with staffs that have leadership positions in each municipality and management and possess a deep knowledge of the analysis tool and its processes. Conclusion: The evaluation has shown positive effects on the monitoring and control of student performance through better control of school operations.

The O’Brien lab has demonstrated that Heat shock protein 27 (HSP27)shows attenuated expression in human coronary arteries as the degree of atherosclerosis progresses. Moreover, over-expression of HSP27 reduces atherogenesis in mice. The precise mechanism(s) for HSP27-mediated "atheroprotection" are incompletely understood. Nuclear Factor-kappaB (NF-κB) is a key signaling modulator in atherogenesis. Hence, this project sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling to affect atheroprotection. Treatment of THP1 macrophages with rHSP27 resulted in degradation of IκBα, coincided with nuclear translocation of the p65 subunit and produced transcriptional evidence of activation of NF-κB signaling. When the transcriptional profile of THP1 macrophages treated with rHSP27 was analyzed using NF-κB-pathway-specific qRT-PCR arrays, among the regulated genes, IL-10 and GM-CSF mRNA levels were markedly increased, as were parallel translational effects observed. These data provide new mechanistic insights into the atheroprotective effects of HSP27.

The O’Brien lab has demonstrated that Heat shock protein 27 (HSP27)shows attenuated expression in human coronary arteries as the degree of atherosclerosis progresses. Moreover, over-expression of HSP27 reduces atherogenesis in mice. The precise mechanism(s) for HSP27-mediated "atheroprotection" are incompletely understood. Nuclear Factor-kappaB (NF-κB) is a key signaling modulator in atherogenesis. Hence, this project sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling to affect atheroprotection. Treatment of THP1 macrophages with rHSP27 resulted in degradation of IκBα, coincided with nuclear translocation of the p65 subunit and produced transcriptional evidence of activation of NF-κB signaling. When the transcriptional profile of THP1 macrophages treated with rHSP27 was analyzed using NF-κB-pathway-specific qRT-PCR arrays, among the regulated genes, IL-10 and GM-CSF mRNA levels were markedly increased, as were parallel translational effects observed. These data provide new mechanistic insights into the atheroprotective effects of HSP27.

Dendritic cells (DCs) function mainly as antigen presenting cells (APCs) and as such they play a significant role in activating the adaptive immune system. Dendritic cells express toll-like receptors (TLR), and when these receptors are engaged by their cognate agonists, they promote DC maturation, which is critical in the induction of potent T helper (Th) cell -1 responses. Due to the multifunctional abilities of DCs, they have been explored as vaccine carriers, largely in cancer immunotherapy and some infectious diseases including hepatitis C. Previous studies showed that DCs loaded with mRNA of hepatitis C virus (HCV) antigen(s) induced strong immune responses but immune protection was not complete. Therefore, I expected that adoptive transfer of DCs transfected with HCV NS3/4A and/or NS5A mRNA and further treated with TLR agonist(s) ex vivo would induce HCV-specific immunity in vivo. Bone marrow-derived DCs generated with Flt3L (FL-DCs) or GM-CSF (GM-DCs), and loaded with HCV NS3/4A and/or NS5A mRNA showed maturation characteristics and produced substantial amounts of IL-12 after ex vivo activation with CpG ODN or CpG ODN plus Poly I:C, when compared to their untreated counterparts. Treatment with a combination of CpG ODN and Poly I:C synergized to augment IL-12 production in comparison with stimulation with CpG ODN alone. IL-12 secretion by DCs is pivotal in directing immune responses towards a Th1-bias response, which is needed to eliminate HCV. However, the ex vivo responses of stimulated DCs bearing HCV antigen(s) were not efficiently translated in mice to potentiate vigorous antigen-specific T cell responses. This resulted in a lack of protection after challenge with recombinant vaccinia virus expressing HCV NS3/NS4/NS5 in immunized mice. In contrast, both antigen-specific humoral and cell-mediated immune responses were induced in mice vaccinated with HCV recombinant NS3 or NS5A protein co-formulated with CpG ODN, host defense peptide and polyphosphazene. These responses, however, did not mediate viral clearance, as vaccinated mice remained unprotected from infection with recombinant vaccinia virus expressing HCV antigens. Taken together, these results suggest HCV recombinant protein co-formulated with triple adjuvant to be a better vaccine candidate than the DC-based vaccine.

A Quick Test (AQT) Färg och Form är ett test av snabb automatiserad benämning avsett att detektera kognitiva störningar. Det består av tre delar som var och en utgörs av 40 visuella stimuli som skall benämnas så snabbt som möjligt. Tidigare studier har indikerat att AQT skiljer personer med Alzheimers sjukdom från friska kontroller med högre precision än det ofta använda Mini-Mental-Testet (MMT). I denna studie undersöktes för första gången om AQT-resultat kunde predicera diagnosen hos en konsekutiv serie patienter vid en minnesklinik samt relationen mellan AQT-resultat och biomarkörer (likvorproteiner) för neurodegenerativ sjukdom. 492 svarsblanketter från AQT Färg och Form analyserades och diagnostisk prediktion samt korrelation med nivån av likvorproteiner fastställdes för de 374 första patienterna i serien. Resultaten tyder på att AQT Färg och Form kan vara känsligt för vissa lindriga kognitiva sviktsymptom som förekommer hos personer remitterade för minnesbesvär men inte alltid känsligt för lindriga grader av demens. AQT-data korrelerade måttligt med nivån av patologiska likvorproteiner, troligen avspeglande förhöjda nivåer i Alzheimergruppen. Ytterligare forskning på konsekutiva fallserier behövs för att fastställa testets diagnostiska diskriminationsförmåga i klinisk praxis. / A Quick Test (AQT) Color-Form is a test that uses rapid automatized naming in order to identify cognitive impairment. It is divided into three parts, each of which consists of 40 stimuli that are to be named as quickly as possible. Previous studies have indicated that AQT separates patients with Alzheimer’s disease from normal controls with higher accuracy than the commonly used Mini-Mental State Examination (MMSE). The purpose of this study was to investigate, for the first time, whether AQT results collected from a consecutive series of patients at a Memory Clinic would be able to predict the diagnosis. Another aim was to study the possible relation between AQT results and Cerebrospinal Fluid (CSF) biomarkers for neurodegenerative diseases. 492 forms from AQT Color-Form tests were analyzed and diagnostic prediction and correlation with level of CSF biomarkers were determined for the first 374 patients. The results imply that AQT Color-Form may be sensitive to some symptoms of benign memory impairment that is found in patients admitted to a Memory Clinic, but that it is not always sensitive to mild degrees of dementia. Further research consecutive series of patients is needed in order to determine the diagnostic abilities of discrimination in clinical practice.

Idiopathic normal pressure hydrocephalus (iNPH) is a condition with dilated cerebral ventricles but intracranial pressure within normal limits. The symptoms of gait impairment, cognitive decline and urinary incontinence develop gradually. Treatment with shunt insertion results in improvement in eight out of ten patients. The cerebrospinal fluid tap test (CSF TT) and preoperative magnetic resonance imaging (MRI) are methods used to select patients who may benefit from shunt surgery, but they are performed and interpreted differently in different centers throughout the world. The aim of this thesis was to evaluate the performance of the CSF TT and the underlying mechanisms of improvement in gait function after CSF removal, and to investigate the prognostic value of preoperative MRI scans. Improvement in gait and changes in cerebral blood flow (CBF) after a CSF TT were investigated in two prospective studies that included 39 and 20 patients, respectively. Gait assessment and perfusion MRI were done before and several times during the first 24 hours after a CSF TT. Perfusion was investigated with pseudo-continuous arterial spin labeling. At the group level, gait function was significantly improved at all investigation times, but only one-third of individual CSF TT responders were improved at all investigation times. In patients with increased CBF in lateral and frontal white matter after the CSF TT, gait function improved more than it did in patients with decreased CBF in these regions. However, in the whole sample, there was no significant increase in CBF after CSF removal. Preoperative MRI scans were retrospectively evaluated in 109 patients with iNPH who had undergone shunt surgery. The callosal angle was smaller in shunt responders compared with non-responders. The following findings showed the highest association with a positive outcome after shunting: a small callosal angle, wide temporal horns, and occurrence of disproportionally enlarged subarachnoid space hydrocephalus. In conclusion, CBF in white matter close to the lateral ventricles may play a role in the reversibility of symptoms after CSF removal in patients with iNPH. The CSF TT should be reevaluated if the patient does not initially improve, and preoperative MRI investigations can add prognostic information regarding the selection of shunt candidates.

The O’Brien lab has demonstrated that Heat shock protein 27 (HSP27)shows attenuated expression in human coronary arteries as the degree of atherosclerosis progresses. Moreover, over-expression of HSP27 reduces atherogenesis in mice. The precise mechanism(s) for HSP27-mediated "atheroprotection" are incompletely understood. Nuclear Factor-kappaB (NF-κB) is a key signaling modulator in atherogenesis. Hence, this project sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling to affect atheroprotection. Treatment of THP1 macrophages with rHSP27 resulted in degradation of IκBα, coincided with nuclear translocation of the p65 subunit and produced transcriptional evidence of activation of NF-κB signaling. When the transcriptional profile of THP1 macrophages treated with rHSP27 was analyzed using NF-κB-pathway-specific qRT-PCR arrays, among the regulated genes, IL-10 and GM-CSF mRNA levels were markedly increased, as were parallel translational effects observed. These data provide new mechanistic insights into the atheroprotective effects of HSP27.

<p>Finding an indicator that can point to a high risk group for suicide has long been a desirable aid for the prevention of completed suicides. The studies reviewed in this essay presume that a biological aspect can point out the high risk individual. The focus of the studies lies on the serotonin 5-hydroxytryptamine (5-HT) monoamine neurotransmitter and cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) which is the principal metabolite of 5-HT in depression. The studies on 5-HT metabolites have led to the belief that these may play a key role in the neurochemistry of suicidal behaviour. It is suggested that the core behavioural effect of low CSF 5-HIAA concentration might result in an increase in impulsive and violent behaviour to self and others. The predictability is based on the fact that patients with low CSF 5-HIAA are more prone to reattempt and complete suicide by violent means. A number of well-designed studies concerning suicidal individuals and control subjects have however not shown any difference in concentration of CSF 5-HIAA in suicide attempters compared to non-suicide attempters which could be explained by methodological flaws. Low CSF 5-HIAA does seem to characterize the high risk individual, but it is not yet determined what role it plays in actual suicidality.</p>