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  • Alenius Dahlqvist, Jenny, 1972- (författare)
  • Heart rate variability and pacemaker treatment in children with Fontan circulation
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background: Fontan surgery is performed in children with univentricular heart defects. Arrhythmias are frequent complications, occasionally requiring pacemaker treatment. Previous data regarding indications and risk factors for pacemaker treatment in Fontan patients is limited and conflicting. Heart rate variability (HRV) reflects autonomous nervous activity controlling the sinus node and has been associated with tachyarrhythmias in both adults and children, as well as in adults with sinus node dysfunction (SND).Aim: To study HRV, arrhythmia and pacemaker treatment  in children with Fontan circulation— with the purpose of contributing to the reduction of long term complications in this patient group.Methods: We have retrospectively reviewed pacemaker therapy in all Swedish patients who underwent Fontan surgery from 1982 to 2017 (n=599). We have also analysed HRV from 24-hour Holter ECG recordings in 112 children with Fontan circulation and in children with univentricular heart defects before bidirectional Glenn (BDG) procedure (n=47), before and on completion of Fontan surgery (n=47 and 45 respectively). Analysis was performed by power spectral analysis and Poincaré method, and results compared with healthy controls. Furthermore, HRV was analysed in Fontan patients who later required a pacemaker due to severe SND. Results were compared with Fontan patients who had SND, without indication for pacemaker treatment, with patients with Fontan circulation without SND and healthy controls. In addition we evaluated the possibility to analyse arrhythmias and HRV in 27 Fontan children using intermittent ECG recordings with a handheld devices at home during a 14-day period.Results: After a mean follow-up of 12 years, 13% (78/599) of patients with Fontan circulation had received a pacemaker. Patients operated with the extracardiac conduit (EC) had a significantly lower prevalence of pacemaker implantation (6%) than patients with a lateral tunnel (LT) (17%). The most common pacemaker indication in patients with Fontan circulation was SND (64%). Children with Fontan circulation showed significant reductions in several HRV parameters, compared with controls. No significant differences were found between patients operated with LT versus EC (paper I). After BDG the RR interval and SD2 (representing changes in heart rate over 24-hours) significantly increased compared to pre-BDG. Compared with healthy controls, patients post-BDG, had significantly longer RR intervals and reduced overall HRV. PHF (reflecting parasympathetic control of the heart) was significantly reduced after TCPC as compared to before (paper II). Fontan patients with SND showed significantly elevated SD2 (representing changes in heart rate over 24-hours), somewhat reduced in patients that later required a pacemaker (Paper V). Handheld ECG analysis revealed frequent ventricular extra systoles in one patient and episodes of supraventricular tachycardia in another. Seven Fontan patients showed reduced HRV recorded with the handheld device over a 14-day period (paper III).Conclusions: Overall HRV was reduced in patients with univentricular heart defects during the different surgical stages of Fontan surgery, compared to healthy controls. HRV was reduced in both patients with LT and EC with no significant difference between them. After BDG heart rate was significantly reduced as compared to before. PHF, reflecting the parasympathetic innervation of the heart was reduced after as compared to before TCPC. Pacemaker treatment is commonly needed in patients with Fontan circulation, and SND was the most prevalent indication for implantation. The prevalence of Fontan patients requiring pacemaker treatment was significantly lower in patients with EC. HRV analysis can contribute to management when following-up patients with Fontan circulation.  
  • Alenius, Gerd-Marie, 1957- (författare)
  • A Clinical and Genetic Study of Psoriatic Arthritis
  • 2003
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. PsA has a heterogeneous pattern, expressed by different manifestations such as mild mono-oligoarthritis or very severe, erosive and destructive polyarthritis. Measurable inflammatory activity is not always prominent. The aetiology is unknown but genetic factors are believed to be of importance. The pattern of inheritance is proposed to be polygenic. The aim of this study was to estimate the prevalence of joint and axial manifestations, characterise the disease in relation to inflammatory and genetic markers, and to identify disease susceptibility gene(s) for PsA in patients from northern Sweden.All patients from the city of Umeå (n=276), selected from a community and hospital based psoriasis register (n=1737) at the Dept of Dermatology, were invited to a prevalence study. Two hundred-two patients were examined and 97 (48%) had inflammatory manifestations such as peripheral arthritis, axial disease, undifferentiated spondylarthropathy (uSpA) and enthesopathies. Of the 67 patients (33 %) with peripheral arthritis and/or axial disease, 30 were not previously diagnosed.The association of clinical manifestations and potential markers of aggressive joint disease with HLA associations were analysed in 88 patients with PsA. We were not able to confirm findings of other groups reporting strong association with several HLA-antigens. The prevalence of HLA-B17, B37 and B62 was increased compared with controls, but the strongest predictive factors among our patients for an aggressive disease, in a multiple logistic analysis, were polyarthritic disease and distal interphalangeal engagement.In order to investigate for disease susceptibility genes, five genetic loci were analysed with microsatellites and single nucleotide polymorphisms in an association study of 120 patients with PsA. There was a significant association with the TNFB locus on chromosome 6p but not with any other loci examined; 1q21 (PSORS4), 3q21 (PSORS5), 8q24 and CTLA4. When stratifying for the TNFB alleles the association was confined to allele 123. In a subgroup of patients who were HLA-typed (n=83), we were not able to verify linkage disequilibrium with the TNFB allele 123 and the HLA antigens; B17, B27, B37, B62 or Cw*0602.The presence of renal abnormalities was evaluated as a manifestation of systemic inflammation in 73 patients with PsA. Renal abnormalities defined as decreased creatinine-clearance (≤ mean - 2SD) and/or urinary albumin >25 mg/24 h was found in 23% of the patients. The predictive factors for renal abnormalities was inflammatory activity (ESR > 25 mm/h and/or CRP >15 mg/L) indicating a systemic effect in some of the patients.In conclusion, we found high prevalence of inflammatory manifestations in patients with psoriasis. There was no strong association between PsA and HLA antigens and predictive factors for aggressive disease were polyarthritic disease and DIP joint engagement. The TNFB locus was associated with PsA and there were no linkage disequilibrium with the HLA antigens B17, B27, B62 or Cw*0602. There were evidence for systemic effects as renal abnormalities in patients with PsA and measurable inflammatory activity.
  • Aléx, Jonas, 1975- (författare)
  • Cold exposure and thermal comfort among patients in prehospital emergency care innovation research in nursing
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • BackgroundPatients’ cold exposure is a neglected problem in prehospital emergency care. Cold stress increases pain and anxiety and contributes to fear and an overall sense of dissatisfaction. When left untreated, cold stress disturbs vital body functions until ultimately reaches hypothermia.AimThe overall aim was to investigate patients’ experiences of thermal comfort and reactions to cold exposure in prehospital emergency care and to evaluate the effects of an intervention using active warming from underneath.MethodStudy I:Persons (n=20) injured in a cold environment in the north of Sweden were interviewed. Active heat was given to 13 of them.Study II:In wintertime, 62 patients were observed during prehospital emergency care. The field study was based on observations, questions about thermal discomfort, vital signs, and temperature measurements.Study III:Healthy young persons (n=23) participated in two trials each. Data were collected inside and outside a cold chamber. In one trial, the participants were lying on a regular ambulance stretcher and in a second trial on a stretcher supplied with a heated mattress. Outcomes were the Cold Discomfort Scale (CDS), back, finger, and core body temperature, four statements from the State-TraitAnxiety-Inventory (STAI), vital signs, and short notes about their experiences of the two stretchers.Study IV:A quantitative intervention study was conducted in prehospital emergency care in the north of Sweden. The patients (n=30) in the intervention group were transported in an ambulance supplemented with a heated mattress on the stretcher, whereas only a regular stretcher was used in the ambulance for the patients (n=30) in the control group. Outcomes were the CDS, finger, core body, and air temperature, and questions about cold experiences.ResultsStudy I:Patients suffered more because of the cold than from the pain of their injuries. The patients were in a desperate need of heat.Study II:Patients are exposed to cold stress due to cold environments. There was a significant decrease from the first measurement in finger temperature of patients who were indoors when the ambulance arrived, compared to the measurement taken in the ambulance. In the patient compartment of the ambulance, 85% of the patients had a finger temperature below the comfort zone and almost half of them experienced the patient compartment in the ambulance to be cold. The regular mattress surface temperature at the ambulance ranged from -22.3 to 8.4 ºC.Study III:A statistical increase of the participants’ back temperature was found between those lying on the heated mattress compared to those lying on the regular mattress. The heated mattress was experienced as warm, comfortable, providing security, and easy to relax on.Study IV:Thermal comfort increased for the patients in the intervention group and decreased in the control group. A significant higher proportion of the participants rated the stretcher as cold to lie on in the control group compared to the intervention group.ConclusionThe ambulance milieu is too cold to provide thermal comfort. Heat supply from underneath increased comfort and might prevent cold stress and hypothermia
  • Aléx, Lena (författare)
  • Äldre människors berättelser om att bli och vara gammal tolkade utifrån genus- och etnicitetsperspektiv
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The overall aim of the five studies that make up this thesis is to elucidate constructions of being old from the perspectives of gender and ethnicity. One of the studies uses quantitative data and four use qualitative data.The sample in study I consisted of 125 participants from the Umeå 85+ study, aged 85 to 103 years old, who were able to use Likert scales in responding to questions. Studies II and III involved content analysis of interviews with old persons scoring on the extremes of the resilience scale. In study IV, interviews with nine Sami women were analysed using grounded theory. In study V, four interview situations were subjected to discourse analysis.Study I showed statistically significant correlations between the scales measuring resilience, sense of coherence, purpose in life and self-transcendence. These scales were supposed to measuring a common dimension, which is here interpreted as “inner strength”. There was a significant correlation between women’s “inner strength” and perceived mental health.The femininities found were associated with “being connected”, “being an actor”, “living in the shadow of others” and “being alienated”. The masculinities found were associated with “being in the male centre”, “striving to maintain the male facade” and “being related”. The femininity associated with “being an actor” and the masculinity associated with “being in the male centre” were pronounced in those participants assessed as having high resilience.Old Sami woman were found to be balancing within various discourses, including being a reindeer owner versus not owning reindeer, being Sami versus being Swedish, speaking in Sami versus speaking in Swedish, dreaming about the past versus looking to the future, being equal to men versus living in the shadow of the male herders, and changing for survival versus striving to retain uniqueness as a Sami.Study V revealed that shifts in power between the interviewer and the interviewed can be related to the discourses of age, gender, education, body, ethnicity and ideology.This thesis presents a complex picture of what it means to be among the oldest old. The ageing, gendered and ethicised selves cannot be seen as socially and culturally fixed. For the women, the femininity expressed in “being connected” involved being satisfied, content and having positive relationships. “Being an actor” involved a stress on the person’s own strength and own choices. The femininities experienced as “living in the shadow of others” and “being alienated” generated narratives about dissociation and loneliness. For the men, it seemed important to relate to themselves and to other men. However, the masculinity expressed in “being related” involved an alternative form of masculinity, focusing on the importance of daily work, new relationships, and reflecting on the meaning of life. The Sami women showed strength in being able to position themselves between various discourses, but their narratives also showed tender sadness when they spoke of their longing for the past and for their mother tongue. The reflection on how narratives are constructed by both the interviewed and the interviewer in relation to their access to various discourses of age, gender, education, ethnicity and ideology in different interview situations can be important for increasing awareness of the role of these discourses. Various ways of constructing femininities and masculinities must be studied if we are to avoid ageism developing in society. Analyzing and reflecting on the importance of age, gender and ethnicity from a constructivist perspective may reduce stereotypical descriptions of the oldest old.
  • Allard, Annika, 1958- (författare)
  • Enteric adenovirus type 41 genome organization and specific detection procedures
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Enteric adenoviruses (EAd) types 40 and 41 (Ad40 and Ad41) representing subgenus F, are primary pathogens of children being second only to rotaviruses as the most important cause of infantile diarrhea.The EAds differ from all other adenoviruses in their inability to grow in most conventional established cell lines and have been suggested to be deficient in some early gene functions since they could be complemented by Ad 5 early regions EIA and E1B. In order to search for differences that could explain its characteristic growth restriction, the early regions EIA and E1B of Ad41 (strain D389) were sequenced, analysed and compared with the corresponding regions of Adl2, Ad7, Ad2, and Ad4. As revealed by the analysis of Ad2, three major mRNAs of 9S, 12S and 13S are generated from region EIA. The EIA region of Ad41 encodes two mRNAs corresponding to the 12S and 13S mRNAs. Only the 13S mRNA is transcribed at detectable levels. This mRNA can be translated into a 251 aa putative protein that contains the three highly conserved domains found in all other human adenoviruses and shown to be responsible for many important regulatory functions during infection.The E1B region of Ad41 encodes three transcripts that correspond to 22S, 14S and 9S mRNA of Ad2. No equivalent to the 13S mRNA of Ad2 E1B is found. In addition the Ad41 14S mRNA exhibits an additional exon of 23 bp created by a donor and an acceptor splice sites not desribed for other adenovirus E1B sequences.Due to their growth restriction in conventional cultures, rapid diagnostic procedures developed for the enteric adenovirus infections have mainly been aimed at the detection of viral antigens or nucleic acids. This thesis also describes several procedures developed for the general detection of adenoviruses and specific detection of the enteric types in stools specimens. General and specific hybridization assays were developed by use of two BamHI clones obtained from the EIA region of Ad41. One- and two-step PCR procedures were also developed for the general detection of adenoviruses using primers corresponding to highly conserved sequences within the hexon gene. Subgenus F specific one- and two-step PCRs were developed by using primers located in the Ad41 E1B region.The one-step PCR systems were tested and validated against isolation in tissue culture, DNA restriction enzyme analysis and a commercial latex agglutination test in the study of 60 specimens obtained from children with rotavirus negative diarrhea. The asymptomatic fecal excretion of adenoviruses was evaluated by two-step PCR amplifications on samples from 50 healthy children, 50 healthy adults, and 50 adults suffering from diarrhea.Finally, a simplified procedure for detection, discrimination and typing of EAd was also designed by combining the one-step PCR amplification of the hexon region with the restriction of the 300 bp product.
  • Alvehus, Malin, 1975- (författare)
  • Obesity-associated inflammation in adipose tissue
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background: Excess body fat, particularly in the visceral depot, is linked to increased mortality and morbidity, including the development of diseases such as type 2 diabetes, cardiovascular disease, and cancer. Chronic low-grade inflammation in adipose tissue may be a key mediator of obesity-associated diseases. Importantly, specific pro-inflammatory cytokines have been shown to influence adipose tissue function and could therefore be a link to metabolic disorders. Circulating cytokine levels may also be increased in obesity and metabolic diseases. However, although fat distribution and inflammation are clearly linked to metabolic disorders, inflammatory gene expression in the different abdominal adipose depots has not been investigated in detail. The menopausal transition is followed by a centralization of body fat and increased adiposity. Notably, inflammatory changes in fat during the menopausal transition have not been characterized. Finally, there is a lack of studies investigating the long-term effects of weight loss on low-grade inflammation. The aim of this thesis was to characterize differences between fat depots and investigate putative changes in low-grade inflammation in adipose tissue and circulation following menopause or weight loss. Materials & Methods: The expression of inflammation-related genes was investigated in abdominal adipose tissue depots obtained from women with varying adiposity, before and after menopause or weight loss induced by surgery or dietary intervention. Circulating cytokine levels were analyzed using immunoassays. Results: Visceral fat displayed a distinct and adverse inflammatory profile compared with subcutaneous adipose tissues, and the higher gene expression in visceral fat was associated with adiposity. Postmenopausal women exhibited a higher expression of pro-inflammatory genes than premenopausal women that associated with central fat accumulation. There was also a menopause-related increase in circulating cytokine levels in postmenopausal women. After surgery-induced weight loss, there was a dramatic reduction in inflammatory gene expression followed by increased insulin sensitivity. We observed no alterations in circulating cytokine levels. Long-term dietary intervention, associated with weight loss, had favorable effects on inflammation in both adipose tissue and serum. Conclusion: Fat accumulation is linked to low-grade inflammation in abdominal adipose tissue. The unique inflammatory pattern of visceral fat suggests a distinct role in adipose tissue inflammation that is aggravated with increasing adiposity. In postmenopausal women, the adverse adipose inflammatory profile was associated with central fat accumulation, while higher circulating cytokine levels correlated with menopausal state/age. Our data from severely obese women undergoing surgery-induced weight loss clearly supports a link between adipose inflammation and insulin resistance. The long-term beneficial effects of weight loss were also demonstrated by the improved inflammatory profile after dietary intervention. In summary, excess body fat is clearly linked to adipose tissue inflammation. Long-term weight loss is accompanied by improved metabolic profile and reduced low-grade inflammation in fat.
  • Anderl, Ines, 1973- (författare)
  • Activation of the Cellular Immune Response in Drosophila melanogaster Larvae
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • During the last 40 years, Drosophila melanogaster has become an invaluable tool in understanding innate immunity. The innate immune system of Drosophila consists of a humoral and a cellular component. While many details are known about the humoral immune system, our knowledge about the cellular immune system is comparatively small. Blood cells or hemocytes constitute the cellular immune system. Three blood types have been described for Drosophila larvae. Plasmatocytes are phagocytes with a plethora of functions. Crystal cells mediate melanization and contribute to wound healing. Plasmatocytes and crystal cells constitute the blood cell repertoire of a healthy larva, whereas lamellocytes are induced in a demand-adapted manner after infection with parasitoid wasp eggs. They are involved in the melanotic encapsulation response against parasites and form melanotic nodules that are also referred to as tumors.In my thesis, I focused on unraveling the mechanisms of how the immune system orchestrates the cellular immune response. In particular, I was interested in the hematopoiesis of lamellocytes.In Article I, we were able to show that ectopic expression of key components of a number of signaling pathways in blood cells induced the development of lamellocytes, led to a proliferative response of plasmatocytes, or to a combination of lamellocyte activation and plasmatocyte proliferation.In Article II, I combined newly developed fluorescent enhancer-reporter constructs specific for plasmatocytes and lamellocytes and developed a “dual reporter system” that was used in live microscopy of fly larvae. In addition, we established flow cytometry as a tool to count total blood cell numbers and to distinguish between different blood cell types. The “dual reporter system” enabled us to differentiate between six blood cell types and established proliferation as a central feature of the cellular immune response. The combination flow cytometry and live imaging increased our understanding of the tempo-spatial events leading to the cellular immune reaction.In Article III, I developed a genetic modifier screen to find genes involved in the hematopoiesis of lamellocytes. I took advantage of the gain-of-function phenotype of the Tl10b mutation characterized by an activated cellular immune system, which induced the formation blood cell tumors. We screened the right arm of chromosome 3 for enhancers and suppressors of this mutation and uncovered ird1.Finally in Article IV, we showed that the activity of the Toll signaling pathway in the fat body, the homolog of the liver, is necessary to activate the cellular immune system and induce lamellocyte hematopoiesis.
  • Andersson, Anne, 1966- (författare)
  • Long-term side effects after treatment of Hodgkin's lymphoma
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background Long-term side effects associated with the treatment of Hodgkin’s lymphoma (HL) have frequently been reported during the last decades. Studies have shown increased mortality in HL survivors. Following Hodgkin’s lymphoma, second malignancies (SM) and cardiovascular disease (CVD) are the most common causes of death in individuals treated for HL. This study investigates the incidence of side effects such as SM, CVD and infections in a cohort diagnosed with HL in Sweden between 1965 and 1995. In addition, this study identifies covariate risk factors for late side effects in order to develop strategies that prevent morbidity and mortality in HL survivors. Methods Using the Swedish Cancer Registry (SCR) at the National Board of Health and Welfare and the Multi-Generation Registry at Statistics (MGR) Sweden, we identified 6946 individuals diagnosed with HL between the years 1965 and 1995, and their first degree relatives (FDR) (n=17 858). In addition we identified the malignancies and inpatient care for CVD and infections for the HL cohort and their FDR. The standard incidence ratio (SIR) was calculated for the risk of SM, CVD and infections. For SM and CVD the risk also was stratified and calculated for family history of disease. The Swedish Hodgkin Intervention and Prevention study (SHIP), a prospective study, invited 702 individuals treated for HL at the age of 45 years or younger and who were treated in the region of Skåne, Uppsala or Umeå. The participants completed a questionnaire and were invited to an out-patient visit to an oncologist with clinical examination and blood tests. Any pathological findings were referred for further investigation. Results An increased risk for SM in HL long-term survivors was observed and seems to increase with the number of FDRs with cancer. There was also an increased risk for inpatient care due to congestive heart failure (CHF) and coronary artery disease (CAD). A family history of CHF and CAD further increased the risk for these diseases. The risk for inpatient care due to infections was increased and remained increased after 20 years or longer. The risk for infections was associated with splenectomy and hypothyroidism. Radiotherapy was an independent risk factor for cardiovascular disease in the cohort of the prospective study. ConclusionLong-term survivors from HL have an increased risk for developing late side effects such as SM, CVD and infections. Since many HL patients are young and the cure rate from the disease is high, it is of great importance to offer focused surveillance programs to selected individuals who are at high risk, e.g. individuals who received radiotherapy as part of their treatment and who have other known risk factors for cardiovascular disease such as hypertension, hypercholesterolemia, family history and smoking.
  • Andersson, Britta, 1979- (författare)
  • Manipulation of potassium ion fluxes to induce apoptosis in lung cancer cells
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Apoptosis is a special form of cell death that if non-functional may lead to diseases such as cancer. A reduction of the intracellular potassium ion (K+) content is necessary for activating enzymes important for the execution of apoptosis. Pharmacological modulation of K+ fluxes to reduce intracellular K+ in cancer cells might therefore force the cells into apoptosis and decrease tumour cell mass.Human malignant pleural mesothelioma (MPM) is a form of cancer often caused by asbestos exposure. Although asbestos has been banned in the Western World, the incidence of MPM is expected to increase. Cisplatin is the first-line chemotherapy for MPM, but acquired resistance to the drug is a clinical problem.This thesis is mainly based on work with the human malignant pleural mesothelioma cell line (P31 wt) and a cisplatin-resistant sub-line (P31 res). The aim was to first characterize K+ fluxes in P31 wt and P31 res cells, and then manipulate them in order to reduce intracellular K+ and induce apoptosis with K+ manipulation alone or in combination with cisplatin.Characterization of K+ fluxes in P31 wt cells showed that: 1) ouabain, a digitalis-like drug, and specific blocker of the Na+, K+, ATPase pump, effectively inhibited K+ uptake, 2) bumetanide, a diuretic, and an inhibitor of the Na+, K+, 2Cl-¬-cotransporter, had a transient effect on K+ uptake, and 3) the antifungal drug amphotericin B stimulated K+ efflux.In order to determine intracellular K+ content, the potassium-binding fluorescent probe PBFI-AM was used in a 96-well plate assay. After a 3-h incubation with ouabain, with or without bumetanide, combined with amphotericin B, the intracellular K+ content was reduced in P31 wt cells but not in P31 res cells.Ouabain induced apoptosis in both P31 wt and P31 res cells. P31 res cells were sensitized to cisplatin by ouabain, since 10 mg/L cisplatin in combination with ouabain induced about the same percentage of apoptotic cells as 40 mg/L cisplatin. Apoptosis was executed via caspase-3 activation in both P31 wt and P31 res cells. Amphotericin B enhanced ouabain-induced apoptosis in P31 wt cells via caspase-9 activation, with increased caspase-3 activation and DNA fragmentation as consequences. Ouabain-induced apoptosis in P31 res cells was executed via increased expression of pro-apoptotic Bak. The combination of cisplatin with ouabain and amphotericin B was stressful to both P31 wt and P31 res cells, since SAPK/JNK a known factor in stress-induced apoptosis was activated.In conclusion, K+ flux manipulation with clinical used drugs can induce apoptosis per se and also enhance cisplatin-induced apoptosis in P31 wt and P31 res cells.
  • Andersson, Christopher, 1987- (författare)
  • Regulatory pathways and virulence inhibition in Listeria monocytogenes
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Listeria monocytogenes is a rod-shaped Gram positive bacterium. It generally exist ubiquitously in nature, where it lives as a saprophyte. Occasionally it however enters the food chain, from where it can be ingested by humans and cause gastro-intestinal distress. In immunocompetent individuals L. monocytogenes is generally cleared within a couple of weeks, but in immunocompromised patients it can progress to listeriosis, a potentially life-threatening infection in the central nervous system. If the infected individual is pregnant, the bacteria can cross the placental barrier and infect the fetus, possibly leading to spontaneous abortion.The infectivity of L. monocytogenes requires a certain set of genes, and the majority of them is dependent on the transcriptional regulator PrfA. The expression and activity of PrfA is controlled at several levels, and has traditionally been viewed to be active at 37 °C (virulence conditions) where it bind as a homodimer to a “PrfA-box” and induces the expression of the downstream gene.One of these genes is ActA, which enables intracellular movement by recruiting an actin polymerizing protein complex. When studying the effects of a blue light receptor we surprisingly found an effect of ActA at non-virulent conditions, where it is required for the bacteria to properly react to light exposure.To further study the PrfA regulon we tested deletion mutants of several PrfA-regulated virulence genes in chicken embryo infection studies. Based on these studies we could conclude that the chicken embryo model is a viable complement to traditional murine models, especially when investigating non-traditional internalin pathogenicity pathways. We have also studied the effects of small molecule virulence inhibitors that, by acting on PrfA, can inhibit L. monocytogenes infectivity in cell cultures with concentrations in the low micro-molar range.
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