| 221. |
- Prenkert, Malin, 1967-
(författare)
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On mechanisms of drug resistance in acute myeloid leukemia
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis focus has been to increase the knowledge and understanding of some of the mechanisms responsible for drug resistance in acute myeloid leukemia, as well as identify possibilities to predict drug resistance at diagnosis.We have studied the intracellular behavior of cytostatic drugs and their main metabolites (paper I) and the cellular response to cytostatic drugs (paper III). A new flow cytometry in vitro chemosensitivity assay was developed, to enable identification of viable myeloid cells and determination of drug sensitivity (paper II). Finally, possible new markers involved in drug resistance were investigated (paper IV).In conclusion we found that idarubicin and daunorubicin are equally toxic at the same intracellular concentrations. The contribution of the main metabolites to the cytotoxic effects of idarubicin and daunorubicin, in both drug sensitive and drug resistant human myeloid leukemia cells, is low. It is most likely the pharmacokinetic properties of idarubicin and daunorubicin that confer their main cytotoxic effect. With the new flow cytometry chemosensitivity assay we selectively identified viable CD13/CD33 expressing myeloid cells and found that the cytotoxicity results correlated to clinical parameters, such as secondary AML and resistant disease. Short-term exposure of leukemia cell lines with different levels of drug resistance to ara-C revealed that Pgp mRNA and protein ex-pression levels, as well as GSTπ mRNA levels, were rapidly up-regulated. Clinically, this up-regulation may be of importance for the sequential scheduling of daunorubicin and ara-C during the induction treatment of AML. CRIM1 hasnever been studied in the context of drug resistance before. We show for the first time that baseline expression of CRIM1 mRNA is much higher in drug resistant leukemia cells compared to drug sensitive cells. We also found a co-variance between CRIM1 and Pgp mRNA expression levels in leukemia cell lines with different levels of drug resistance, suggesting that CRIM1 may be useful as a marker of drug resistance.
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| 222. |
- Probert, Noelle, 1994-
(författare)
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Patients with hip fracture : A decade of morbidity and surgery
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hip fracture is a devastating condition causing excess mortality in older people. Over recent time, incidence has declined while mortality remains unchanged, suggesting changes in morbidity. Swedish national guidelines recommend preoperative full-body disinfection (FBD) to prevent surgical site infection (SSI) despite little evidence, a method causing patients’ substantial pain. The aim of this thesis was to investigate differences in comorbidity, malnutrition, sarcopenia, mortality, surgical characteristics, and functional outcome in patients with hip fracture, ten years apart (I-II). Another aim was to compare preoperative FBD with local disinfection (LD) of the surgical site regarding SSI incidence (III) and experiences of nursing personnel (IV). Patients with hip fracture from 2008 and 2018 (I-II)respectively from 2018 to 2019 (III) and orthopedic nursing personnel (IV) were included. Anthropometric measurements were collected prospectively (I-II) and data from medical records (I-III) and the Swedish hip fracture register (II) were collected retrospectively. Focus group discussions were conducted and analyzed by content analysis (IV). Results suggest increasing levels of comorbidity over time while malnutrition and sarcopenia decreased, potentially explaining the unaltered mortality (I). Concurrently, choice of surgical method seems to have changed, potentially contributing to the seen improvements in functional outcome (II). Study III presented no significant difference in SSI incidence between 2018 (FBD) and 2019 (LD) in the adjusted regression analysis and in study IV nursing personnel testified to an increased wellbeing in patients after the switch to LD. In conclusion, patients who succumb to hip fracture today are not the same as they were yesterday, highlighting the importance of continuous adjustment of treatment and care.
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| 223. |
- Rajan, Sukithar K, 1978-
(författare)
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Metagenomic Characterization of the Gut Microbiome in Cohorts of Elderly
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human gut microbiota plays a vital role in maintaining host health. This thesis aims to investigate the gut microbial population and function using next generation sequencing (NGS) data from faecal samples. Paper I examines the influence of sequencing depth and analysis methods in microbiota profiling using NGS whole genome sequencing (WGS) data. By subsampling the metagenomic data, the influence of varying sequencing depths on different phylogenetic classification methods is investigated. This suggests that necessary sequencing depth would be dependent on the individual research plan. This paper recommends the need for a consensus approach and an informed choice of NGS analysis method selection for a reliable prediction. Paper II relates the gut microbiota to general health, nutrient intake, physical activity, medications, and psychological distress in community-dwelling older adults and senior orienteers. A higher abundance of F. prausnitzi in the faecal microbiota of senior orienteers confirms the hypothesis that senior orienteers can be seen as a model for healthy ageing in the perspective of the microbiota. Paper III focuses on assessing the validity of function prediction using LC-MS at multiple annotation levels. Predicted and quantified protein-pathway profiles were subjected to correlation analyses, which showed statistically significant association between predicted and quantified proteins as well as predicted and quantified pathways. This study also showed a direct relation between protein abundance and correlation for predicted and quantified proteins at higher function levels. Paper IV investigates the effects of faecal microbiota transfer (FMT) on functional microbiota profiles. This study showed that allogenic FMT did not alter the metabolite profiles, but it seems to disturb the gut microbiota-metabolite interactions when compared to autologous FMT.This thesis reiterates the need for carefully selecting prediction tools and methods for microbiome analysis. The findings of this thesis could stimulate more focused studies using NGS in medicine and aid in better understanding of host-microbe interactions.
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| 224. |
- Raoof, Mustafa, 1966-
(författare)
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Long term effects of gastric bypass on quality of life and bone mineral density
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is a worldwide disease. Surgery is currently the only available management option which offers an adequate long-term effect on comorbidity, quality-of-life and weight loss. It is evident that overweight and obesity are associated with low health-related quality-of life (HRQoL) and multiple comorbidities. The aim of this thesis has been to explore the long-term effect of gastric bypass surgery on HRQoL and bone mineral density.In study 1: 486 patients (average age 50.7±10.0 years, 84 % female) operated with gastric bypass (GBP) from 1993 to 2003 at the University Hospitals of Örebro and Uppsala. Mean follow-up after GBP was 11.5±2.7 years (range 7–17). The study group was compared with two control groups. The study group scored better in the SF-36 domains and OP scale compared to obese controls, but their HRQoL scores were lower than those of the general population. HRQoL was better among younger patients and in the following subgroups: men; patients with satisfactory weight loss; those satisfied with the procedure; those free from comorbidity and gastrointestinal symptoms; employed; good oral status; and those not hospitalised or regularly followed up for non-bariatric reasons.In study 3: Patients operated with a primary GBP between January 2008 and December 2012 were identified in the Scandinavian Obesity Surgery Register (SOReg). Patients with HRQoL data available at both baseline and 5 years after surgery were included. The study sample comprised 6998 patients (21% men). Gender differences in change in HRQoL were minor. Younger patients showed greater improvements in physical health scales. In general linear regression model analyses, age and weight loss correlated significantly with improvement in HRQoL after 5 years. Patients treated medically for depression preoperatively (13%) experienced less improvement in HRQoL than patients without such treatment. Patients with a postoperative complications (26%) had significantly less improvement in all aspects of HRQoL compared to those without any form of postoperative complication.This study confirmed the importance of weight loss for improvement in HRQoL after bariatric surgery. Preoperative medication for depression and suffering a complication during the five-year follow-up period were associated with less improvement in HRQoL.Studies 2 and 4: Included patients operated with laparoscopic gastric bypass at the department of surgery at the Örebro University Hospital between January 2004 and December 2005. Thirty-two females were prospectively recruited for this longitudinal study. In both studies, the following were measured at baseline, 2, 5 and 10 years postoperatively: bone mineral density (BMD); weight; height; S-calcium; S-albumin; S-creatinine; S-25(OH)-vitamin D; and fP-PTH. In study 4: Nine of the patients declined follow-up. BMD showed a statistically significant decline over the study period. The fall in BMD of the spine and femoral neck between baseline and 5 years after surgery was 19% and 25%,respectively. During the next five years period BMD continued to decline but at a lower rate. At 5 years 58 % had elevated PTH, this number declined at the next 5 years.
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| 225. |
- Rasmussen, Gunlög, 1973-
(författare)
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Staphylococcus aureus bacteremia, molecular epidemiology and host immune response
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Staphylococcus aureus is a major pathogen responsible for a considerable disease burden worldwide. It may cause a wide array of infections, from superficial skin infections to invasive bacteremia and complications such as infective endocarditis (IE) and osteomyelitis. This thesis aimed to investigate aspects of the molecular epidemiology of S. aureus and host immune response in relation to disease manifestation, severity, and over time during S. aureus bacteremia (SAB).Genotypic characteristics in isolates causing colonization, bacteremia, and bacteremia with IE were studied. The S. aureus population was genetically diverse and certain clones with their set of often lineage-specific virulence genes were associated with invasive disease. Characterization of the long-term molecular epidemiology of MSSA bacteremia showed an increased prevalence of CC5 and CC15, while CC8, CC25 and CC30 declined. Antibiotic resistance pattern was favorable and unaffected.Further, different aspects of host immune response were explored in patients with SAB during the acute phase of bacteremia. When investigating the NLRP3 inflammasome signaling, induced caspase-1 activity was found, with a great inter-individual variation between patients, and subsequent release of IL-18, indicating inflammasome activity. Finally, the dynamics of MHC class II related genes HLA-DRA and CD74 were analyzed as markers of immunosuppression. Patients with complicated SAB had significantly lower HLA-DRA expression than patients with uncomplicated bacteremia, demonstrating an association between complicated SAB and impaired immune function.In conclusion, the S. aureus genotype, as well as host factors reflected by inter-individual variations in inflammasome signaling and immune function, may all contribute to disease manifestation and outcome during SAB. An ability to measure the immune response early and continuously during the hospital stay and course of bacteremia could offer a way to tailor patient management and treatment in an individualized way.
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| 226. |
- Roca Rubio, María Fernanda, 1989-
(författare)
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Challenge models and biomarkers of human intestinal barrier function
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The intestinal barrier is an essential component in maintaining human health, and several diseases and disorders have been associated with a disrupted intestinal barrier function. To evaluate the efficacy of different interventions intended to strengthen intestinal barrier function, there is a need for both appropriate challenge models as well as easily accessible biomarkers. The overall aim of this thesis was to explore new challenge models of human gut barrier as well as to investigate potential biomarkers to assess its function. Paper I shows that a sauna-induced dehydration protocol increased intestinal permeability without causing major damage to the intestinal barrier, suggesting it as a potential challenge model of the gut barrier. Paper II shows that the acute intense psychological stress generated by skydiving did not affect intestinal permeability, indicating that gut barrier disruption likely requires sustained psychological stress. Paper III describes the systemic effect of an established strenuous exercise challenge on various biomarkers of gut barrier and immune function, as well as their correlations. Paper IV used a cohort of patients with diarrhoea-predominant irritable bowel syndrome (IBS-D) to show how several biomarkers linked to increased permeability correlated with other markers associated with IBS-D. All papers also explored potential surrogate permeability markers for the urinary excretion ratio of lactulose and rhamnose which is a common in vivo method for measuring small intestinal permeability. In conclusion, this thesis provides insights into different challenge models of the human intestinal barrier function and addresses important considerations about the application of currently used biomarkers for its assessment.
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| 227. |
- Rode, Julia, 1992-
(författare)
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Gut microbiota, its modifications and the gut-brain axis
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human intestinal microbiota has a major impact on host physiology and might play an important role in several diseases. Therapeutic interventions aimed at modifying the gut microbiota might exert their effects locally as well as systemically, for example via the gut-brain axis, a bidirectional communication system.The overall aim of this thesis was to investigate potential modes of action via which modifications of the gut microbiota might influence health and disease. Paper I shows that faecal microbiota transfer could improve gastrointestinal symptoms in a subset of patients with collagenous colitis– a chronic low-grade inflammation of the large intestine. Papers II – IV describe the effects of an oral probiotic intervention on different aspects of the gut-brain axis in young, healthy adults. Paper II shows that brainactivity and functional connectivity during negative emotional stimuli were altered after probiotic intervention without major effects on the gut microbiota composition itself. Paper III shows that brain response patterns to an acute stressor were altered, whereas cortisol stress response, autonomic nervous system function and cognitive performance were not affected by the probiotic intervention. Paper IV describes the effect of the probiotic intervention on mental health in daily life. Amongst others, altered resting state brain function, slight improvements in depression symptoms and sleep quality were observed. Furthermore, serum levels of serotonin were slightly altered, indicating a potential mechanism of how probiotics might affect brain function. Paper V is an in vitro study that aimed to further elucidate a potential mechanism behind the microbiota-gut-brain axis. The short-chain fatty acid butyrate, an important microbial metabolite, rescued the disturbed uptake of the serotonin precursor tryptophan into fibroblasts mimicking cells of the nervous system.This thesis provides insights into whether and how gut microbiota modifications could improve health by affecting the gut-brain axis. Uncovering the underlying mechanisms might facilitate the development of personalised medicine.
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| 228. |
- Rosdahl, Anja, 1972-
(författare)
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The impact of viral vaccines in immunosuppressed and at-risk individuals
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vaccines have saved millions of lives, but for some individuals with a defective immune system the protection may be uncertain. This thesis aims to assess the immune response following viral vaccines in immunocompromised patients and in other groups at-risk.In paper I the immune response to a modified vaccine schedule against hepatitis A, adding an extra vaccine dose, was tested in patients with rheumatoid arthritis (RA) on immunomodulating drugs. Following two doses,88% of RA patients developed seroprotective antibodies against hepatitis A compared to 94% of healthy controls. In paper II 53 cases of Tick borne encephalitis (TBE) vaccine failure were characterized. The majority of cases were seen in men, 81% were 50 years or older and 51% had co-morbidities. Vaccine failure was most common after three or four doses only, but was seen in up to nine doses. Four out of five had a moderate to severe disease. In paper III the immune response to mRNA vaccines was compared in SARS-CoV-2 experienced and naïve health care workers. Experienced individuals had an increased innate immune cell activation, cytokine and chemokine production and changes in innate gene expression following the first vaccine dose as well as a stronger adaptive response with higher antibody titres and B-cell and CD4+ T-cell activity. The differences were less after the second dose, but three doses were required before an equal immune response was observed in naïve and experienced individuals. In paper IV the immune response to SARS-CoV-2 mRNA vaccine was assessed in patients with chronic kidney disease (CKD) stage 4 and 5 prior to renal replacement therapy. CKD patients were found to have an immune response comparable with healthy controls, with the exception of lower secreted anti-spike antibodies in the saliva and a decreased cytotoxic CD8+ T-cell activity.In conclusion, a deeper understanding of the immune response to vaccines is needed to be able to adapt recommendations and improve outcome in vulnerable groups
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| 229. |
- Rådman, Lisa, 1983-
(författare)
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Effects of electrical accidents : occupational and health perspectives
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Professionals working in the electrical industry are at risk of accidental injuries caused by electricity. Electrical accidents can cause persistent neurological symptoms, previously mainly described in patients whose injuries were initially extensive. The overall aim of this thesis was to study the prevalence of persisting, self-reported symptoms after electrical accidents and to explore their relationship to results obtained using clinical methods that are commonly used to study nerve function and hand-arm function. Another aim was to increase knowledge about the work situation and the safety culture of Swedish electricians and to describe the frequency with which electricians seek health care after electrical accidents. Study I was a retrospective survey of 523 Swedish male electricians. In study II, the electricians who reported persistent symptoms were further invited to undergo clinical examinations that included quantitative sensory testing (QST), assessment of fine motor skills and tactile gnosis. The most common self-reported symptoms were pain, reduced sensation and reduced muscle function. For a few, these symptoms persisted at the time of survey. Roughly half of the group exhibited abnormal warm and cold perception thresholds and tactile gnosis test values. Study III included 24 participants with persisting self-reported sensory symptoms, 1-5 years after an accident. Observations of nerve function; QST, laserevoked potentials (LEP) and nerve conductions studies, were performed. At least one neurosensory impairment was present- in at least one of the tests in 67% of the participants. The participants in study III were also evaluated in study IV, in which a control group of 24 healthy persons was added. Hand function was affected in many participants assessed with the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire as was tactil gnosis and manual dexterity, for the participants in the case group. Only a quarter of the participants in study I sought health care after their accidents, and the safety culture questionnaire revealed deficiencies, particularly in the reporting culture. The conclusions of this thesis are that self-reported neurosensory symptoms can persist for years after an electrical accident and that these symptoms can be evaluated using standard neurophysiological and functional tests that reflect changes in nerve function. Accordingly, hand function, examined using both objective and subjective measures, may be affected after work-related electrical accidents. This thesis highlights some aspects of safety culture and the work situations of professionals within the electrical industry. These areas need to be improved so that reporting routines provide opportunities to learn from and prevent accidents.
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| 230. |
- Röckert Tjernberg, Anna, 1975-
(författare)
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Celiac disease and Infections
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Celiac disease (CD) is a chronic immune-mediated enteropathy affecting about 1% of the population worldwide. CD is triggered by ingestion of gluten in genetically predisposed individuals but additional factors (e.g. infections) are required for the disease to develop. CD also seems to be associated with infectious complications.Aim: The main objective of this thesis was to increase the knowledge about the associations between CD and infections.Methods: Epidemiological and laboratory approaches. Studies I-III used a data set consisting of small intestinal biopsy reports. The biopsies were taken in 1969-2008 and collected in 2006-2008. A total of 29,096 individuals with CD, 13,306 with inflammation and 3,719 with potential CD were identified. Each individual was matched with up to 5 controls from the general population (n= 228,632). Through linkage of the data to the Patient Register study I examined the risk of hospital visits due to respiratory syncytial virus (RSV) in children <2 years prior to onset of CD. Study II used the Patient Register and Cause of Death Register to assess whether CD affects the outcome in sepsis. Study III linked the data to microbiological data bases and the Public Health Agency to estimate risk of invasive pneumococcal disease (IPD) in CD. In study IV children with CD and controls were recruited from Kalmar County Hospital. Complement activation (C3a and sC5b-9) in plasma were analysed after incubation with pneumococci.Results: Study I found that children with CD were more likely than controls to have attended hospital due to RSV infection prior to diagnosis (odds ratio 1.46; 95% confidence interval (CI)=1.02-2.07). CD did not seem to influence survival in sepsis (adjusted hazard ratio (HR) 1.10 95%CI=0.72-1.69) (study II). Study III indicated a 46% risk increase for individuals with CD to acquire IPD (HR 1.46; 95%CI=1.05-2.03) but study IV did not reveal any differences in complement response in regard to CD status (p=0.497and p=0.724), explaining this excess risk.Conclusion: This thesis supports associations between CD and infections preceding and complicating diagnosis. However, CD does not seem to influence the outcome in a severe infection like sepsis and altered complement function is unlikely to be responsible for the excess IPD risk in CD.
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