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Sökning: L4X0:0345 0082 > (2010-2014)

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51.
  • Chéramy, Mikael (författare)
  • Characteristics of GADA in Type 1 Diabetes following Immunomodulation with GAD65
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Type 1 diabetes (T1D) is a serious autoimmune disease which increases worldwide and affects children at a young age, but there still is no cure available. Clinical intervention trials in recent onset T1D patients are therefore very important, since even a modest preservation of β-cell function has proven to reduce end-organ complications. Glutamic acid decarboxylase 65 (GAD65) is one of the major antigens in T1D, to which autoantibodies (GADA) are formed. Immunomodulation with aluminum-formulated GAD65 (GAD-alum) has been considered both in the prevention and intervention of T1D. In a phase II trial using GADalum we showed clinical benefits in C-peptide preservation, but unfortunately a following larger European phase III trial failed to reach primary end-point. The general aim of this thesis was to study the characteristics and phenotypes of GADA following immunomodulation with GAD-alum in T1D patients during a phase II and III trial.In the phase II trial, a transient increase of the GADA IgG3 and IgG4 subclasses, and a decrease in IgG1 was detected as part of the treatment-induced GADA levels after 2 GADalum doses, a result interpreted to be T helper (Th) 2-associated. This Th2-associated immune response was also observed, in parallel to increased GADA levels, during the following phase III trial including a larger group of patients. However, enhanced Th2-like IgG subclass distribution, reflected as increased IgG4 frequency, was in contrast only observed in the group treated with 4 doses of GAD-alum. In addition, the GADA fold-change was associated with in vitro GAD65-stimulated cytokine secretion, but only in patients receiving 2 GAD-alum doses. Furthermore, a 4-year follow-up of the phase II trial showed that the effect of GAD-alum treatment was long-lasting as GADA titers remained elevated. Even though the phase III trial did not reach primary end-point, and was closed after 15 months, preservation of β-cell function was observed in the small sub-group of Swedish patients receiving 2 GAD-alum doses that completed the 30 months trial-period. During the trials, concerns were raised whether the elevated GADA titers might induce Stiff person syndrome (SPS), a disease affecting the nervous system, but in vitro analysis of GADA phenotypes showed that the GAD65-enzyme activity and GADA epitope distribution differed from that detected in SPS patients.Continued research to clarify how immunomodulation with autoantigens affects immune responses and also to identify which patients are suitable for treatment, is crucial for optimizing future T1D intervention- and prevention trials.
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52.
  • Claesson, Carina, 1970- (författare)
  • Staphylococci and Enterococci : Studies on activity of antimicrobial agents and detection of genes involved in biofilm formation
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The Gram-positive cocci, Staphylococcus aureus, coagulase negative staphylococci (CoNS), Enterococcus faecalis and Enterococcus faecium, are the bacteria most often isolated from patients with hospital acquired infections. S. aureus is one of the most important pathogens and have a variety of virulence mechanisms which help it to infect the patient and cause tissue damage. CoNS and enterococci are low virulent bacteria and predominantly cause infections in individuals with underlying illness, individuals that have undergone surgery or with suppressed immune-system. The aims of this thesis were i) to investigate the susceptibility to different antimicrobial agents among S. aureus, CoNS, E. faecium and E. faecalis isolates from primary care centres, general hospital wards and intensive care units in Denmark, Finland, Norway and Sweden and ii) to study the prevalence of the cytolysin genes and genes involved in biofilm formation among CoNS, E. faecium and E. faecalis. The results in this thesis show that the resistance rates among S. aureus and E. faecalis is still rather low in the north European countries. Among CoNS and E. faecium resistance rates are higher and comparable with rates in other European countries and US. CoNS had statistically significant differences in susceptibility rates between the ward levels with the lower susceptibility rates found at ICUs. Continued surveillance of resistance rates to antimicrobial agents among both staphylococci and enterococci are important internationally, nationally and locally. The results in this thesis also show that all multidrug resistant and 96% of the susceptible CoNS isolates carried at least one of the atlE and aap genes or the ica operon. Among E. faecalis isolates with HLGR, belonging to a cluster of genetically related isolates, both the esp and asa1 genes were carried in a high degree while the cyl operon was less frequently found. In addition, about 30% of unique E. faecalis isolates carried two or more of the virulence genes. Among E. faecium isolates the esp gene was common but asa1 and the cyl operon was not found in any of the isolates. Both CoNS and E. faecalis isolates from hospitalised patients are well equipped with genes involved in biofilm formation. These genes, when expressed and even more in combination with resistance to antimicrobial agents, might give these isolates an advantage compared to other isolates when it comes to adhesion to artificial surfaces, persistence in the hospital environment, colonisation of hospitalised patients and to cause nosocomial infections. Further studies are needed to be able to determine which isolates that causes hospital acquired infections and to evaluate the importance of the genes involved in biofilm formation as virulence factors and about how to prevent biofilm related infections from emerging
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53.
  • Claesson, Ing-Marie, 1953- (författare)
  • Weight gain restriction for obese pregnant women : An Intervention study
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: Obesity is a growing global public health problem and is as prevalent among pregnant women as in the general population. It is well known that obese women have an increased risk for several complications during pregnancy and delivery and this is also true for the neonate. Excessive gestational weight gain among obese women seems to further increase these risks for adverse outcomes. It has not been known up to the time of this study whether a behavioral intervention program designed for obese pregnant women could result in a reduction of gestational weight gain.Aim: The overall aim of the present thesis was to study the effect of an intervention program designed to control weight gain among obese pregnant women during pregnancy and to then observe the outcomes of their pregnancies. In addition we wanted to learn if this behavioral intervention program could result in a weight gain of less than seven kilograms.Material and methods: The intervention group consisted of 155 obese (BMI >30 kg/m2) pregnant women at the antenatal care clinic (ANC) in Linköping; the control group consisted of 193 obese pregnant women in two other cities. The women in the intervention group were offered, in addition to regular care at the ANC, motivational interviewing in weekly visits to support them in making this behavioral change. They were also offered aqua aerobic class once or twice a week. The women in the control group attended the routine antenatal program in their respective ANCs. Outcome measures were: weight in kg, pregnancy-, delivery and neonatal outcomes, prevalence of anxiety- and depressive symptoms and attitudes and experiences of participating in an intervention program.Results: The women in the intervention group had a significantly lower gestational weight gain and also had a lower postnatal weight than the women in the control group. The percentage of women in the intervention group who gained <7 kg was greater than the percentage in the control group. There were no differences between the two groups in pregnancy-, delivery- and neonatal outcomes. In addition, there was no difference in prevalence of symptoms of anxiety and depressions between the intervention- and control group and the gestational weight gain did not have any effect on symptoms of depression or anxiety. The women in the intervention group with gestational weight gain <7 kg, weighed less at the two years follow-up than the women in the control group. Most of the women who participated in the intervention program expressed positive attitudes and were positive towards their experiences with the intervention program and their efforts to manage the gestational weight gain.Conclusion: The intervention program was effective in controlling weight gain during pregnan-cy and did not change the pregnancy, delivery or neonatal outcomes or the prevalence of anxie-ty- and depressive symptoms. The group with a gestational weight gain <7 kg showed the same distribution of complications as the group with a higher weight gain. The intervention program seems to influence the development of weight in a positive direction up to two years after childbirth. The women were also satisfied with their participation in the intervention program.
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54.
  • Dahlén, Elsa, 1975- (författare)
  • Markers of subclinical atherosclerosis and arterial stiffness in type 2 diabetes
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Type 2 diabetes is a common disease with increased mortality and morbidity due to cardiovascular disease (CVD). This thesis is based on three studies that evaluated traditionally used and emerging risk markers to identify individuals with high-risk of developing CVD in middle-aged men and women with type 2 diabetes. One study was conducted to compare the equivalence between two different ultrasound techniques to measure intima-media thickness since IMT was used to evaluate subclinical atherosclerosis as a surrogate endpoint.Methods: Data from the cohort study, cardiovascular risk in type 2 diabetes – a prospective study in primary care (CARDIPP) was used in paper I, III and IV. In paper I, baseline data from the first 247 subjects was analysed. Associations between traditionally measured lipids, apolipoproteins, glycaemic control and low-grade inflammation and IMT were analysed.In paper III, the full baseline cohort, with data from 761 subjects from the CARDIPP study was cross-sectionally analysed regarding correlations between abdominal obesity measured as waist circumference (WC) and sagittal abdominal diameter (SAD), inflammatory markers and IMT and pulse wave velocity (PWV). In paper IV, the associations reported in paper I and III were prospectively investigated with data from the first year of follow-up four years after the baseline investigations in CARDIPP-revisited.In paper II a study was performed on 24 young healthy subjects, both men and women. IMT was measured in the common carotid artery (CCA) and in the abdominal aorta (AA), by two skilled ultrasonographers, with 2 different ultrasound techniques in a randomised order.Results: ApoB/apoA-I ratio (r=0.207, p=0.001), apoB (r=0.166, p=0.009) and non HDLcholesterol (nHDL-c) (0.129, p=0.046) correlated with IMT.In CCA IMT was equivalent using B-mode- and M-mode respectively. However in AA, IMT was 11.5% thicker using B-mode.Abdominal obesity were significantly correlated with; IL-6 and CRP (both p<0.001, WC and SAD respectively), IMT (WC p=0.012, SAD p=0.003) and PWV (p<0.001 WC and SAD respectively). Adjusting for age, sex, treatment with statins, systolic blood pressure (SBP), Body Mass Index (BMI), CRP and HbA1c, SAD (p=0.047) but not WC, remained associated with IMT.There were significant correlations between apoB (r=0.144, p=0.03) and CRP (r=0.172, p=0.009) measured at baseline and IMT measured at follow-up. After adjustment for sex, age, treatment with statins and Hba1c, the associations remained statistically significant. HbA1c, total cholesterol or LDL-cholesterol did not correlate to IMT at follow-up. Baseline body mass index (BMI) (r=0.130, p=0.049), WC (r=0.147, p=0.027) and SAD (r=0.184, p=0.007) correlated to PWV at follow-up. Challenged with sex, SBP and HbA1c, the association between SAD, not WC nor BMI, and PWV remained statistically significant (p=0.036).Conclusions: There was a significant association between apoB/apoA-I ratio and IMT. The association was independent of conventional lipids, CRP, glycaemic control and use of statins. Both SAD and WC were associated with inflammation, atherosclerosis and arterial stiffness. However, SAD was slightly more robustly associated to subclinical organ damage, compared with WC. Prospectively; apoB and CRP, but not LDL-cholesterol predicted increased subclinical atherosclerosis. Furthermore, SAD was more independent in predicting arterial stiffness over time, compared with WC, in middle-aged men and women with type 2 diabetes.The two different ultrasound techniques, B-mode and M-mode, measured different IMT thickness in the aorta, emphasizing the importance of using similar technique when comparing the impact of absolute values of IMT on cardiovascular disease.
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55.
  • Dahlström, Nils, 1969- (författare)
  • Quantitative Evaluation of Contrast Agent Dynamics in Liver MRI
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The studies presented here evaluate the biliary, parenchymal and vascular enhancement effects of two T1-shortening liver-specific contrast agents, Gd-BOPTA and Gd-EOB-DTPA, in Magnetic Resonance Imaging (MRI) of healthy subjects and of patients.Ten healthy volunteers were examined with both contrast agents in a 1.5 T MRI system using three-dimensional gradient echo sequences for dynamic imaging until five hours after injection. The enhancement of the common hepatic duct in contrast to the liver parenchyma was analyzed in the first study. This was followed by a study of the image contrasts of the hepatic artery, portal vein and middle hepatic vein versus the liver parenchyma.While Gd-EOB-DTPA gave an earlier and more prolonged enhancement and image contrast of the bile duct, Gd-BOPTA achieved higher maximal enhancement and higher image contrast for all vessels studied during the arterial and portal venous phases. There was no significant difference in the maximal enhancement obtained in the liver parenchyma.In a third study, another 10 healthy volunteers were examined with the same protocol in another 1.5 T MRI system. Using signal normalization and a more quantitative, pharmacokinetic analysis, the hepatocyte-specific uptake of Gd-EOB-DTPA and Gd-BOPTA was calculated. A significant between-subjects correlation of the uptake estimates was found and the ratio of these uptake rates was of the same magnitude as has been reported in pre-clinical studies. The procedure also enabled quantitative analysis of vascular enhancement properties of these agents. Gd-BOPTA was found to give higher vessel-to-liver contrast than Gd-EOB-DTPA when recommended doses were given.In the final study, retrospectively gathered datasets from patients with hepatobiliary disease were analyzed using the quantitative estimation of hepatic uptake of Gd-EOB-DTPA described in the third study. The uptake rate estimate provided significant predictive ability in separating normal from disturbed hepatobiliary function, which is promising for future evaluations of regional and global liver disease.In conclusion, the differing dynamic enhancement profiles of the liver-specific contrast agents presented here can be beneficial in one context and challenging in another. Diseases of the liver and biliary system may affect the vasculature, parenchyma or biliary excretion, or a combination of these. The clinical context in terms of the relative importance of vascular, hepatic parenchymal and biliary processes should therefore determine the contrast agent for each patient and examination. A quantitative approach to analysis of contrast-enhanced liver MRI examinations is feasible and may prove valuable for their interpretation.
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56.
  • De Basso, Rachel (författare)
  • Influence of genetics and mechanical properties on large arteries in man
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Arterial pathology is the major contributor to cardiovascular diseases and mortality. The mechanical properties of arteries are independent factors for cardiovascular disease and mortality, where genetics influence the structure of the arterial wall, which may result in change in arterial stiffness. The aims of this thesis were to study the mechanical properties of the popliteal artery (PA) in healthy subjects and the influence of angiotensin-converting enzyme (ACE) polymorphism and Fibrillin-1 (FBN1) polymorphism on large arteries. Further, the impact of FBN1 polymorphism on cardiovascular morbidity and mortality was investigated.The PA is, after the abdominal aorta, the most common site of aneurysmal development. The PA was studied in healthy subject with ultrasound and the diameter increased and the distensibility decreased with age, with men having lower distensibility than women. This seems not to be the behavior of a true muscular artery but rather of a central elastic artery such as the aorta, and might have implications for the susceptibility to aneurysm formation, as well as the association of dilating disease between the PA and the aorta. The wall stress in the PA was low and unaffected by age, probably caused by a compensatory remodeling response with an increase in wall thickness. This indicates that other mechanisms than wall stress contribute to the process of pathological dilatation in the PA.The ACE D allele may be associated with abdominal aortic aneurysm. Elderly men with the ACE D allele were associated with increased abdominal aortic stiffness compared to men carrying the I/I genotype. This suggests that the ACE D allele impairs arterial wall integrity, and in combination with local hemodynamic and other genetic factors it may have a roll in aneurysm formation.The FBN1 2/3 genotype has been associated with increased systolic blood pressure. The FBN1 2/3 genotype in middle-aged men was associated with increased abdominal aortic stiffness and blood pressure which indicates an increased risk for developing cardiovascular disease. The increased presence of plaque in the carotid artery of middle-aged men with the FBN1 2/3 genotype indicates a pathological arterial wall remodeling with a more pronounced atherosclerotic burden, but did however not affect the risk of cardiovascular events and/or death in this population. This relationship needs to be studied further.
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57.
  • Edström, Måns, 1984- (författare)
  • Regulation of immunity in Multiple Sclerosis : CD4+ T cells and the influence of natalizumab
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) and the most common neurological cause of disability in young adults. In most cases, the disease course is characterised by the cycling of relapses and remissions, so called relapsing-remitting MS (RR-MS). Although extensively studied, the underlying mechanisms are not fully elucidated, yet CD4+ T cells have been shown to be of importance in disease pathology. A range of treatments are available; the most effective to date being natalizumab, a monoclonal antibody directed against the adhesion molecule VLA-4 on the lymphocyte surface, thereby preventing entry into the CNS.The aim of this thesis was to assess the nature of lymphocyte populations in MS. This was achieved by studying CD4+ T helper cells (TH) and regulatory T cells (TREG) in peripheral blood. In addition, the influence of natalizumab was also investigated, both regarding the effect of the drug on the composition of the peripheral lymphocyte compartment as well as its effects on CD4+ T cells in vitro.We showed an imbalance in the mRNA expression of CD4+ T helper cell lineage specific transcription factors in peripheral blood. While TH1 and TH17 associated TBX21 and RORC expression was comparable in MS and healthy individuals, the TH2 and TREG associated GATA3 and FOXP3 expression was decreased in RR-MS. Given the reciprocally inhibitory nature of TH subsets, this might imply not only diminished function of TH2 and TREG cells but also a permissive state of harmful TH1 and TH17 cells. The size of the peripheral TREG population was unaltered in RR-MS. When analysed in detail, activated and resting TREG were distinguished, showing clear differences in FOXP3 and CD39 expression. Furthermore, when investigating these subpopulations functionally, the ability of activated TREG to suppress proliferation of responder T cells was found to be decreased in RR-MS patients compared to controls. To further investigate this defect, the global gene expression of TREG was compared between patients and controls. Gene set enrichment analysis revealed an enrichment (over-expression) of chemokine receptor signalling genes in RR-MS TREG, possibly suggesting a role for  chemokines in TREG function.A sizable effect of natalizumab treatment was seen in the composition of peripheral lymphocyte populations after one year of treatment. While the number of lymphocytes increased over all, the largest increase was seen in the NK and B cell compartments. Furthermore, T cells from patients with MS displayed decreased responsiveness towards antigens and mitogens in vitro. Natalizumab treatment was able to normalise the responsiveness in blood, an effect not solely dependent on the increased number of cells.The importance of CD4+ T cells in human disease, including MS, was shown by a systems biology approach; using GWAS data, genes associated with CD4+ T cell differentiation were enriched for many, not only immunerelated, diseases. Furthermore, global CD4+ T cell gene expression (by microarray) could discriminate between patients and controls. Lastly, using in vitro treated CD4+ T cells, we could show that natalizumab perturbated gene expression differently in patients responding to the drug compared to those not responding.In conclusion, our results demonstrate an imbalance of peripheral CD4+ T cells in MS, along with a functional deficiency in the case of TREG. Taken together, these aberrations might result in differentiation and activation of harmful TH1 and TH17 cells, resulting in CNS tissue damage. The importance of CD4+ T cells was further demonstrated by the finding that genes associated with CD4+ T cell differentiation constitute a pleiotropic module common to a number of diseases. Investigation of natalizumab revealed drastic changes in the peripheral lymphocyte compartment caused by treatment. It also appears as treatment might influence the responsiveness of peripheral T cells to antigens. In addition, by using CD4+ T cell transcriptomics after in vitro drug exposure, prediction of treatment outcome may be possible.
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58.
  • Ekberg, Joakim, 1976- (författare)
  • Online health promoting communities : Design, implementation and formative evaluation of an intervention
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • In Sweden, obesity among children has not yet reached the epidemic proportions reported from other parts of the world. However, among adolescents, being overweight and self-consciousness regarding body shape, diet and exercise influence social, psychological and physical health. Obese children may be in need of secondary prevention because of adverse effects related to obesity, but it is less obvious exactly what to prevent in the rest of the population. General interventions to prevent overweight and obesity are problematic because of the lack of associations for general application; there is a need for personalized community-based health promotion. Online interventions are especially suitable considering the amount of time adolescents spend online.This thesis takes a design approach to interventions and describes the design of an online health promoting community as a path to health promotion among adolescents. The first two studies use data from the first 15 years of a 1991 cohort living in Östergötland to determine the predictability of obesity from childhood body mass index and to investigate interventions and available evidence to suggest appropriate interventions. The next two studies use these findings to design and formatively evaluate a health promotion intervention.In Study I we found reasons for offering population-based interventions systematically from 5 years of age. It would be worthwhile identifying at an early age those relatively few children with substantially increased risk of maintaining obesity in adulthood and offering them interventions; but interventions must be avoided when they are not necessary. The projections in Study II indicate that more specified interventions would benefit adolescents without increasing the costs. In Study III, we found than an online health promoting community can be designed simply at relatively low cost and can be negotiated to satisfy both the needs of the user community and public health goals and service capabilities. In Study IV, a checklist for pre-launch evaluation of online health promoting communities was developed and the most important result was the delicate balance between community autonomy and quality control. Future studies addressing health outcome constructs for use in online health promoting community evaluations are warranted.
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59.
  • Ekerstad, Niklas, 1969- (författare)
  • Micro Level Priority Setting for Elderly Patients with Acute Cardiovascular Disease and Complex Needs : Practice What We Preach or Preach What We Practice?
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Demographic trends and other factors are expected to continue widening the gap between health care demands and available resources, especially in elder services. This growing imbalance signals a need for priority setting in health care. The literature has previously described problems in constructing useable means of priority setting, particularly when evidence is sparse, when patient groups are not satisfactorily defined, when interpretation of the term patient need is unclear, and when uncertainty prevails on how to weigh different ethical values. The chosen study object illustrates these problems. Moreover, the Swedish Government recently stated that care for elderly persons with complex health care needs remains underfunded. The general aim of this thesis is: to study micro-level priority setting for elderly heart patients with complex needs, as illustrated by those with non-ST-elevation myocardial infarction (NSTEMI); to relate the findings to evidence-based priority setting, e.g. guidelines for heart disease; and to analyse how complex needs could be appropriately categorised from a perspective of evidence-based priority setting.Paper I presents a register study that uses data from the Patient Register to describe inpatient care utilization, costs, and characteristics of elderly patients with multiple diseases. Paper II presents a confidential survey study from a random sample of 400 Swedish cardiologists. Paper III presents a prospective, clinical, observational multicentre-study of elderly patients with myocardial infarction (NSTEMI). Paper IV presents a questionnaire study from a purposeful, stratified sample of Swedish cardiologists.The results from Paper I show that elderly patients with multiple diseases have extensive and complex needs, frequently manifesting chronic and intermittently acute disease and consuming health care at various levels. A large majority have manifested cardiovascular disease. Results from Paper II indicate that although 81% of cardiologists reported extensive use of national guidelines in their clinical decision-making generally, the individual clinician’s personal clinical experience and the patient’s views were used to a greater extent than national guidelines, when making decisions about elderly multiple-diseased patients. Many elderly heart disease patients with complex needs manifest severe, acute or chronic, comorbid conditions that constitute exclusion criteria in evidence-generating studies, thereby limiting the generalisability of evidence and applicability of guidelines for these patients. This was indicated in papers I-IV. Paper III reports that frailty is a strong independent risk factor for adverse, short-term, clinical outcomes, e.g. one-month mortality for elderly NSTEMI patients. Particularly frail patients with a high comorbidity burden manifested a markedly increased risk.In the future, prospective clinical studies and registries with few exclusion criteria should be conducted. Consensus-based judgments based on a framework for priority setting as regards elderly patients with complex needs may offer an alternative, estimating the benefitrisk ratio of an intervention and the time-frame of expected benefits in relation to expected life-time. Such a framework, which is tentatively outlined in this thesis, should take into account comorbidity, frailty, and disease-specific risk.
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60.
  • Eklund, Daniel, 1984- (författare)
  • Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Mycobacterium tuberculosis is a very successful pathogen and tuberculosis constitutes a major threat to global health worldwide. The World Health Organization (WHO) estimates that almost nine million new cases and 1.5 million deaths occur annually and the situation is worsened by increased antibiotic resistance and an extreme synergism with the HIV pandemic. M. tuberculosis primarily affects the lungs where the infection can lead to either eradication of the bacteria or the initiation of an immune response that culminates in the formation of a large cluster of immune cells termed granulomas. In these granulomas, the bacteria can either replicate and cause disease with the ultimate goal of spreading to new hosts or cause latent tuberculosis, which can persist for decades. The tools available to manage the disease are currently suboptimal and include lengthy antibiotic treatments and an inefficient vaccine resulting in poor protection. On a cellular level, M. tuberculosis primarily infects the cell designed to recognize, ingest and eradicate bacteria, namely the human macrophage. Following recognition, the macrophage phagocytoses the bacterium and tries to kill it using an array of different effector mechanisms including acidification of the bacterium-containing vacuole, different degradative enzymes and the generation of radicals. However, the bacterium is able to circumvent many of these harmful effects, leading to a tug-of-war between the bacterium  and host macrophage. This thesis aims at studying the interaction between the human macrophage and M. tuberculosis to identify host factors critical for controlling growth of the bacteria. More specifically, it focuses on the role of an intracellular receptor protein called NLRP3 and its downstream effects. NLRP3 is activated in human macrophages infected by M. tuberculosis and upon activation it forms a multi-protein complex known as the inflammasome. This protein complex is known to induce the production of the proinflammatory cytokine IL-1β and specialized forms of macrophage cell death. We hypothesized that stimulating this pathway would have a beneficial effect for the host macrophage during infection with M. tuberculosis.To allow us to follow interaction between M. tuberculosis and the human macrophage, we first developed a luminometry-based method of measuring bacterial numbers and following bacterial growth over several days in infected cells. With this new assay we showed that low numbers of bacteria induced very low levels of IL-1β and failed to induce any type of cell death in the macrophage. However, when a critical number of bacteria were reached, the infected macrophages underwent necrosis, which was accompanied by high levels of IL-1β. We were also able to show that addition of vitamin D, which has been implicated as an important factor for increased killing capacity of infected macrophages, increased the production of IL-1β, which coincided with increased killing of M. tuberculosis. This effect was seen specifically in cells from patients with active tuberculosis, suggesting that these cells are primed to respond to vitamin D and increased levels of IL-1β. Furthermore, we also showed that increasing production of IL-1β by stimulating infected macrophages with apoptotic neutrophils in turn drives the production of other proinflammatory cytokines. Lastly, we showed that gain-of-function polymorphisms in inflammasome components linked to increased inflammasome activation and IL-1β production promotes bacterial killing in human macrophages. In conclusion, the work presented in this thesis shows  that by enhancing the functions of the inflammasome, it is possible to tip the balance between the human macrophage and M. tuberculosis in favor of the host cell.
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