| 1. |
- Nilsson, Greger
(författare)
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Cardiovascular Side Effects of Radiotherapy in Breast Cancer
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the thesis was to study cardiovascular side effects of radiotherapy (RT) in breast cancer (BC).In a study base of 25,171 women with BC diagnosed 1970-2000, we found a statistically significant 12% increase of stroke, compared to the stroke incidence in the background population.A case-control study of 282 cases with BC followed by a stroke and 1:1 matched controls with BC but not stroke was performed. In women irradiated to internal mammary chain (IMC) and supraclavicular lymph nodes (SCL) vs. a pooled group of women not irradiated or irradiated to targets other than IMC and SCL, a statistically significant increase of stroke with an odds ratio of 1.8 was observed. There were no associations between BC laterality, targets of RT, and hemisphere location of stroke. The radiation targets IMC and SCL, showed a statistically significant trend for an increased risk of stroke with daily fraction dose.A study of 199 patients with BC, examined by coronary angiography, detected a four- to seven-fold increase of high grade coronary artery stenosis in mid and distal left anterior descending artery (LAD), including distal diagonal branch, when comparing women with irradiated left-sided BC to those with right-sided. An increase of clinically significant coronary artery stenosis was found in pre-specified hotspot areas for radiation among women irradiated to the left breast/chest wall or to the IMC. Thus, the coronary arteries should be regarded as organs at risk in RT of BC.In a study of 15 BC patients treated with 3D conformal RT, a marked difference in dose distribution in mid and distal LAD between left- and right-sided BC was demonstrated. Irradiated right-sided BC mainly received low doses of scattered and transmitted radiation to the coronary arteries. On the contrary, tangential RT to the left breast without regional lymph node irradiation yielded coronary artery max doses of approximately 50 Gray to distal LAD, probably not safe concerning late radiation vascular effects.To conclude, we found cardiovascular side effects in women irradiated for BC, resulting in stroke and coronary artery disease, and showed an association between the targets for RT and the anatomical location of these vascular events.
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| 2. |
- Bill-Axelson, Anna, 1965-
(författare)
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Localized Prostate Cancer : Results From a Randomized Clinical Trial
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of the thesis were to• explore whether radical prostatectomy is beneficial compared with watchful waiting in survival and disease progression• find possible effect modifiers• evaluate a protocol of multiple biopsies and investigate if men with previous benign prostate biopsies are a group at risk for later prostate cancer• inquire into patients’ and clinicians’ experiences of randomization in order to find out what made this study possible to conduct, and thereby contribute to improve randomization in the futureThe background material was a large randomized clinical trial, the Scandinavian Prostatic Cancer Group Study Number 4, or SPCG-4, which was open for inclusion from February 1989 through December 1999. It comprised 695 men in Sweden, Finland and Iceland who had localized prostate cancer and were randomized to either radical prostatectomy or watchful waiting. After a mean follow-up time of 6.2 years the first analyses, according to intention-to-treat, showed that radical prostatectomy reduced disease specific mortality, risk of metastases and risk of local progression but did not statistically significantly reduce overall mortality. The second analyses confirmed our earlier findings and furthermore, at ten years, radical prostatectomy also statistically significantly reduced overall mortality. Age appeared as an independent effect modifier that will be further investigated.A total of 547 men, with a suspicion of prostate cancer that had undergone multiple biopsies, and whose biopsies had benign histology were later compared with the background population to evaluate whether they were a group at risk of developing prostate cancer. Within six years of follow-up, there was no increased risk of prostate cancer.Patients as well as clinicians used individual strategies to cope with the situation. The randomizing clinician has to understand the patient’s strategy and his expectations in order to individualize the information accordingly.
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| 3. |
- Nerpin, Elisabet, 1962-
(författare)
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The Kidney in Different Stages of the Cardiovascular Continuum
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum.The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death.This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress.In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease.Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.
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| 4. |
- Aare, Sudhakar Reddy, 1978-
(författare)
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Intensive Care Unit Muscle Wasting : Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.
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| 5. |
- Aarnio, Mikko
(författare)
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Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- An objective visualization and quantification of pain-generating processes in the periphery would alter pain diagnosis and represent an important paradigm shift in pain research. Positron emission tomography (PET) radioligand [11C]-D-deprenyl has shown an elevated uptake in painful inflammatory arthritis and whiplash-associated disorder. However, D-Deprenyl’s molecular binding target and uptake mechanism in inflammation and musculoskeletal injuries are still unknown. The present thesis aimed to gain insight into the mechanisms of D-deprenyl binding and uptake and to verify whether pain-associated sites and inflammation in acute musculoskeletal injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET-computed tomography (PET/CT).To identify the D-deprenyl binding target, a high-throughput analysis and competitive radioligand binding studies were performed. D-deprenyl inhibited monoamine oxidase A (MAO-A) activity by 55%, MAO-B activity by 99% and angiotensin-converting enzyme (ACE) by 70%, which identified these enzymes as higher-affinity targets. Furthermore, radioligand receptor binding assays pointed favorably towards the concept of MAO-B as the primary target. To investigate the biochemical characteristics of the binding site, we used radioligand binding assays to assess differences in the binding profile in inflamed human synovial membranes exhibiting varying levels of inflammation. D-deprenyl bound to a single, saturable population of membrane-bound protein in synovial membrane homogenates and the level of inflammation correlated with an increase in D-deprenyl binding affinity.To verify whether D-deprenyl can visualize pain-generating processes, patients with musculoskeletal injuries were investigated and followed-up with [11C]-D-deprenyl PET/CT. In the study of eight patients with ankle sprain, the molecular aspects of inflammation and tissue injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. The pain coexisted with increased [11C]-D-deprenyl uptake. In the study of 16 whiplash patients, an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self-rated disability.To further evaluate D-Deprenyl’s usefulness as a marker of inflammation, three PET tracers were compared in an animal PET/CT study. Preliminary findings showed that [11C]-D-deprenyl had an almost identical uptake pattern when compared with [11C]-L-deprenyl. The two deprenyl enantiomers showed no signs of specific binding or trapping and therefore may not be useful to study further in models of inflammatory pain, surgical pain, or both.This thesis demonstrates that D-deprenyl visualizes painful inflammation in musculoskeletal injuries and that the probable underlying mechanism of [11C]-D-deprenyl uptake is binding to MAO.
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| 6. |
- Aarnio, Riina
(författare)
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Self-sampling for HPV testing in primary cervical screening : Including clinical and health economic aspects
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Persistent infection with high-risk human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. HPV testing has higher sensitivity for high-grade cervical intraepithelial neoplasia (CIN2+) than cytology, resulting in more effective screening. As HPV testing also offers an opportunity for self-sampling, it could serve as an even more effective and cost-effective method of cervical screening.First, we compared repeated self-sampling for HPV testing with Pap smear cytology in detection of CIN2+ in primary cervical screening for women aged 30–49 years (n=36 390). We found a more than twofold higher detection rate of CIN2+ and a fourfold higher detection rate of CIN2 with self-sampling compared with cytology. However, no difference was seen between the arms in the detection rate of CIN3+. It thus seems that CIN is detected at an earlier stage with self-sampling than with cytology, but the impact of this needs to be further explored.Second, as management of HPV-positive women with normal cytology results is a challenge, we wanted to evaluate the proportion of cases of histological CIN2+ in these women. In this prospective study we performed LEEP and found that 15% (6/40) of the women had undetected CIN2+. These findings can be used in counseling women about the risk of cervical cancer and helping clinicians in decisions on management.Third, we performed a cost-effectiveness analysis on the same study population as in Study I. Self-sampling for HPV testing resulted in a higher participation rate and more detected cases of CIN2+ at a lower cost and was regarded as more cost-effective than Pap smear cytology in cervical screening. These results can guide policy-makers when planning future screening programs.Fourth, we compared self-sampling with sampling by medical professionals for HPV testing in detection of CIN2+, using a combination of an FTA card as storage medium and a PCR-based HPV test (hpVIR) in women aged 30–60 years (n=11 951). No difference in the detection rates of histological CIN2+ was found between the arms.Taken together, self-sampling resulted in a higher participation rate than sampling by medical professionals in cervical screening and that triage with repeated self-sampling resulted in high compliance and detection rate of CIN2+. As repeated self-sampling for HPV testing was also cost-effective, it could serve as an attractive alternative in the development of future cervical screening programs. More research is needed on how to refine the management of HPV-positive women by self-sampling only.
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| 7. |
- Abbasinejad Enger, Shirin, 1975-
(författare)
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Dosimetry Studies of Different Radiotherapy Applications using Monte Carlo Radiation Transport Calculations
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Developing radiation delivery systems for optimisation of absorbed dose to the target without normal tissue toxicity requires advanced calculations for transport of radiation. In this thesis absorbed dose and fluence in different radiotherapy applications were calculated by using Monte Carlo (MC) simulations.In paper I-III external neutron activation of gadolinium (Gd) for intravascular brachytherapy (GdNCB) and tumour therapy (GdNCT) was investigated. MC codes MCNP and GEANT4 were compared. MCNP was chosen for neutron capture reaction calculations. Gd neutron capture reaction includes both very short range (Auger electrons) and long range (IC electrons and gamma) products. In GdNCB the high-energetic gamma gives an almost flat absorbed dose delivery pattern, up to 4 mm around the stent. Dose distribution at the edges and inside the stent may prevent stent edge and in-stent restenosis. For GdNCT the absorbed dose from prompt gamma will dominate over the dose from IC and Auger electrons in an in vivo situation. The absorbed dose from IC electrons will enhance the total absorbed dose in the tumours and contribute to the cell killing.In paper IV a model for calculation of inter-cluster cross-fire radiation dose from β-emitting radionuclides in a breast cancer model was developed. GEANT4 was used for obtaining absorbed dose. The dose internally in cells binding the isotope (self-dose) increased with decreasing β-energy except for the radionuclides with substantial amounts of conversion electrons and Auger electrons. An effective therapy approach may be a combination of radionuclides where the high self-dose from nuclides with low β-energy should be combined with the inter-cell cluster cross-fire dose from high energy β-particles.In paper V MC simulations using correlated sampling together with importance sampling were used to calculate spectra perturbations in detector volumes caused by the detector silicon chip and its encapsulation. Penelope and EGSnrc were used and yielded similar results. The low energy part of the electron spectrum increased but to a less extent if the silicon detector was encapsulated in low z-materials.
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| 8. |
- Abdalaal, Hind
(författare)
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Deciphering molecular mechanisms in the evolution of new functions
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The evolution of new genes and functions is considered to be a major contributor to biological diversity in organisms. Through de novo origination, “duplication and divergence”, and horizontal gene transfer, organisms can acquire new genetic material that can evolve to perform novel functions. In this thesis, we investigate how functional trade-offs, “gene duplication and amplification”, and neutral divergence contribute to the emergence of a new function from a preexisting gene. In Paper i, we investigated the ability of Salmonella enterica to compensate for the loss of peptide release factor 1 (RFI) and the potential of peptide release factor 2 (RF2) to gain a new function to replace RFI. The amplification of RF2 and accumulated mutations within RF2 were the main evolutionary routes by which the fitness cost was restored. However, further characterization of the evolved RF2 showed a toxic effect to the cell due to the termination on tryptophan codon (UGG). This evolutionary trade-off - which we named “collateral toxicity” - might present a serious barrier for evolving an efficient RF2 to replace RF1.In Paper ii, we determined whether we could evolve a generalist enzyme with two functions (HisA + TrpF) from the specialist enzyme HisA, which can only synthesize histidine. In a previous study, we showed that HisA evolved a TrpF activity through strong trade-off trajectories. Here, we developed a selection scheme in which we constantly selected for keeping the original function (HisA), while intermittently selecting for the new function (TrpF). Our results showed that all evolved lineages shared the same “stepping stone” mutations in the hisA gene, which enabled them to grow well in the absence of both histidine and tryptophan. Additional accumulated mutations in the hisA gene gave the strains an increased ability to grow without both amino acids, indicating that the HisA enzyme evolved to be an efficient generalist. In Paper iii, we explored how differences between diverged orthologs influence evolvability. We generated artificial orthologs using a random mutagenesis approach. First, we screened for orthologs with a lower HisA activity and then selected for orthologs with a higher HisA activity; these steps were repeated in alternating rounds. We then tested the ability of each ortholog to evolve TrpF activity. As expected, the orthologs showed varying abilities to evolve the new function. In particular, orthologs with higher HisA activity levels showed both a higher potential to evolve the new function and a higher TrpF activity when they acquired the new function.
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| 9. |
- Abdeldaim, Guma M. K.
(författare)
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PCR detection of Streptococcus pneumoniae and Haemophilus influenzae in pneumonia patients
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- PCR is a rapid, reproducible method for nucleic acid detection. However, this technology displays significant deficiencies when applied in clinical microbiology. This work’s aim was to improve current diagnostics and provide sensitive and quantitative real-time PCRs. Paper I describes the development of a sensitive and specific quantitative real-time PCR for the detection of Streptococcus pneumoniae, based on the Spn9802 DNA fragment. Applied to nasopharyngeal aspirates from 166 pneumonia patients, Spn9802 PCR had a sensitivity of 94% and a specificity of 98%. In Paper II the performance of a ply gene PCR for identification of pneumococcal lower respiratory tract infection (LRTI) was evaluated on bronchoalveloar lavage fluids. At the detection limit 103 genome copies/mL, 89% sensitivity but only 43% specificity was achieved. Paper III shows that S. pneumoniae DNA is detectable in plasma from acutely febrile patients. Sensitivities were low (26-42%) for detection of pneumococcal pneumonia, for bacteraemic pneumococcal pneumonia they were 60-70%. Paper IV describes evaluation of four PCR targets for Haemophilus influenzae detection. A real-time PCR based on the P6 gene was developed and applied to 166 CAP patients, using cut-off of 104 genome copies/mL the assay had a sensitivity of 97% and a specificity of 96%. In paper V, the two real-time PCRs presented in papers I and IV were combined with a PCR for detection of Neisseriae meningitidis. The analytical sensitivity of this multiplex real-time PCR was not affected by using a mixture of reagents and a combined DNA standard (S. pneumoniae/H. influenzae) in single tubes. Applied to 156 LRTI patients, this PCR had sensitivities over 90% for S. pneumoniae and H. influenzae, and specificities of 89% and 96%, respectively. In conclusion, real-time PCR assays are useful for the diagnosis of S. pneumoniae and H. influenzae. They enable detection after antibiotic installation, and quantification increases the etiological specificity of pneumonia.
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| 10. |
- Abdelgadir, Moawia, 1965-
(författare)
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Clinical and Biochemical Features of Adult Diabetes Mellitus in Sudan
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The high prevalence of diabetes mellitus among the Sudanese population is linked to obesity, poor glycaemic control and a high rate of complications. This study investigated 1/ Leptin hormone and its correlations with different biochemical characteristics in Sudanese diabetic subjects, 2/ The impact of glycaemic control on pregnancy outcome in pregnancies with diabetes, 3/ The glycaemic response to Sudanese traditional carbohydrate foods, 4/ The influence of glucose self-monitoring on the glycaemic control among this population, 5/ The health related quality of life in Sudanese subjects with diabetes-related lower limb amputation. Leptin was significantly lower in diabetic subjects compared with controls of same BMI in both females (P =0.0001) and males (P =0.019). In diabetic subjects, serum leptin correlated positively with the homeostatic assessment (HOMA) of both beta-cell function (P =0.018) and insulin resistance (P =.038). In controls, leptin correlated only with insulin resistance. Pregnancy complications were higher among diabetic compared with control women (P<0.0001) and varied with the type of diabetes. Infants of diabetic mothers had a higher incidence of neonatal complications than those of non-diabetic women (P<0.0001). In six Sudanese traditional carbohydrate meals over all differences in incremental AUCs were significant for both plasma glucose (P = 0.0092) and insulin (P = 0.0001). Millet porridge and wheat pancakes displayed significantly lower post-prandial glucose and insulin responses, whereas maize porridge induced a higher post-prandial glucose and insulin response. In type 2 diabetic subjects SMBG or SMUG was not related to glycaemic control. In type 1 diabetic subjects, SMBG was significantly associated with better glycaemic control, as assessed by HbA1c (P=0.02) and blood glucose at clinic visits (P=<0.0001), similar associations were found for SMUG respectively. Neither glycaemic control nor glucose self-monitoring was associated with education level. Diabetic subjects with LLA had significantly poorer HRQL compared to a reference diabetic group (P=<0.0001). Duration of diabetes and amputation had negative impact on HRQL in subjects with LLA (P=<0.0001) respectively. Diabetic subjects with LLA had decreased sense of coherence and high presence of symptoms. Improving health services at the primary level is important to reduce the complications and burden of disease in the Sudanese population.
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| 11. |
- Abdulla, Maysaa
(författare)
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Prognostic signficance of tumor cell markers in diffuse large B-cell lymphoma with special emphasis on lymphoma localization
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diffuse large B-cell lymphoma (DLBCL) is the most common type of high-grade B-cell lymphoma with different clinical, morphological, immunophenotypical, and molecular features. DLBCL is curable in 60-70% of patients when treated with standard immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).The main aim of this thesis is to identify prognostic factors in DLBCL by studying tumor markers (paper I and II), site of disease (paper III) and tumor microenvironment markers in primary DLBCL of the CNS (PCNSL) (paper IV) in order to better identify different risk groups of DLBCL patients.In papers I-III, we studied DLBCL patients treated homogeneously with R-CHOP. The negative prognostic impact of double protein expression of MYC and BCL2 so called “double-expressor lymphoma” (DEL) was a common finding in the three papers. In paper I, we detected DEL in 27% of patients, distributed with no significant difference between the germinal center derived B-cell subgroup (GCB) in 52% of cases and the non-GCB subgroup in 37% of cases. There was no significant difference in survival between GCB and non-GCB patients. The diagnosis in most of the patients with DEL was made on core needle biopsy in this paper. This finding was more thoroughly investigated in paper III with attention paid to the site of biopsy. In paper II, we evaluated the concordance of cell of origin (COO) assignment between gene expression profile (GEP) and immunohistochemistry (IHC) to identify the best predictor of survival in a DLBCL cohort including patients from Sweden and Denmark. The overall concordance between the two methods was 83%. We found that ABC/non-GCB subtype identified by both GEP and IHC is associated with the worst outcome. This finding indicates the importance of precise risk stratification in the era of precision medicine. DEL was more common in ABC patients categorized by GEP. In paper III, we identified abdominal lymph node involvement by radiological examination in 63% of DLBCL patients with an inferior survival, adverse clinical characteristics and significantly more frequent DEL. These findings may indicate a distinct biological behavior in patients with abdominal nodal disease. In paper IV, we demonstrated a significant association between IDO1 and PD-L1 in PCNSL patients. This finding indicates the crucial immunosuppressive role of these two molecules. In addition, in PCNSL low frequencies of MYC and BCL2 translocations and high frequency of BCL6 translocation was observed and DEL was detected in 49% of cases. Contrary to our results in systemic DLBCL in papers I-III, there was no significant prognostic impact of DEL in PCNSL.
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| 12. |
- Abeid, Muzdalifat, 1973-
(författare)
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Improving Health-seeking Behavior and Care among Sexual Violence Survivors in Rural Tanzania
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to assess the effects of providing community education and training to healthcare workers to improve community response, healthcare and support for rape survivors in the Kilombero district of Tanzania. The overall design of the project was to begin with an exploratory study (Paper I) to establish the community’s perceptions towards sexual violence and their perceived recommendations to address this issue. Using a structured questionnaire, the community’s knowledge and attitudes towards sexual violence were determined along with their associations with demographic factors (Paper II). Papers III and IV assessed the effect of healthcare workers’ training and a community information package, respectively, using a controlled quasi-experimental design. The findings highlighted the social norms and variety of barriers that impacted negatively on the survivors’ care-seeking from support services and health outcomes. Increasing age and higher education were associated with better knowledge and less accepting attitudes towards sexual violence. Training on the management of sexual violence was effective in improving healthcare workers’ knowledge and practice but not attitude. Knowledge on sexual violence among the communities in the intervention and comparison areas increased significantly over the study period; from 57.3% to 80.6% in the intervention area and from 55.5% to 71.9% in the comparison area. In the intervention area, women had significantly less knowledge than men at baseline (53% Vs 64%, p<.001).There was a reduction, though not significantly, in acceptance attitudes from 28.1% to 21.8% in favor of women. In conclusion, the current intervention provides evidence that healthcare workers’ training and community education is effective in improving knowledge but not attitudes towards sexual violence. The findings have potential implications for interventions aimed at preventing and responding to violence. The broader societal norms that hinder rape disclosure need to be re-addressed.
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| 13. |
- Abelson, Anna-Karin, 1978-
(författare)
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Genetic Risk Factors for Systemic Lupus Erythematosus : From Candidate Genes to Functional Variants
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis has been to identify genetic variants that increase the susceptibility for Systemic Lupus Erythematosus (SLE), an autoimmune disease caused by a complex interplay between various genetic and environmental factors. Five different candidate genes were selected through different strategies, and were analysed for association with SLE in an attempt to distinguish some of the underlying mechanisms of this disease. Two of these genes, PD-L1 and PD-L2, appeared not to contain any major risk factors for SLE in the analysed European and Latin American populations. In two other genes, CD24 and STAT4, there appeared to be population-specific effects. The A57V amino acid substitution in the CD24 gene, previously implicated with multiple sclerosis, was associated in a Spanish cohort, with a weak trend in German samples, and no association in Swedish. The previously reported and highly convincing association of the STAT4 transcription factor gene was confirmed in all our cohorts. Interestingly, the results indicate the presence of at least two independent risk variants: the first, represented by a previously reported SNP, was the strongest in individuals of Northern European ancestry, and the second was more pronounced in individuals from Southern Europe and Latin America. We also report the identification of a novel susceptibility gene. The BANK1 gene, encoding a scaffold protein involved in B-cell activation, contains functional variants affecting important domains, which are associated in all investigated cohorts from Europe and Latin America. These results confirm the existence of replicable associations between genetic variants and SLE, which are common and present in many populations. The results also illustrate a certain degree of heterogeneity, where some risk factors could have variable effect in different populations.
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| 14. |
- Abelson, Klas, 1976-
(författare)
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Acetylcholine in Spinal Pain Modulation : An in vivo Study in the Rat
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The spinal cord is an important component in the processing and modulation of painful stimuli. Nerve signals from the periphery are relayed and further conducted to the brain (nociception) in the spinal cord, and the most essential modulation of painful information (antinociception) occurs here. Several neurotransmitters are involved in spinal pain modulation, among them acetylcholine. However, the role of acetylcholine has previously been little investigated. In the present thesis, the acetylcholine release in the spinal cord was studied in vivo. By using spinal microdialysis on anaesthetised rats, the effects on the intraspinal acetylcholine release of various receptor ligands and analgesic agents were examined. This, together with pain behavioural tests and in vitro pharmacological assays, was used to evaluate the role of acetylcholine in spinal pain modulation. The four studies in this thesis resulted in the following conclusions: An increased release of spinal acetylcholine is associated with an elevated pain threshold, while a decreased acetylcholine release is associated with hyperalgesia, as seen after systemic treatment with a muscarinic agonist and an antagonist. Lidocaine is a potent analgesic when given systemically. It was found to produce an increase of intraspinal acetylcholine after intravenous injection of analgesic doses. This effect was attenuated after muscarinic, and abolished after nicotinic, receptor blockade. Various a2-adrenergic ligands, associated with nociceptive or antinociceptive effects, were found to affect intraspinal acetylcholine release via action on nicotinic receptors. Finally, the involvement of spinal acetylcholine in the analgesic effects of aspirin and paracetamol was examined. It was found that spinal acetylcholine could participate in the analgesic effects of aspirin, but not of paracetamol. The present thesis provides data that clearly demonstrate a relationship between intraspinal acetylcholine and antinociception, and elucidate interactions between acetylcholine and other mechanisms that mediate antinociception in the spinal cord.
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| 15. |
- Abrahamsson, Niclas, 1976-
(författare)
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On the Impact of Bariatric Surgery on Glucose Homeostasis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity has grown to epidemic proportions, and in lack of efficient life-style and medical treatments, the bariatric surgeries are performed in rising numbers. The most common surgery is the Gastric Bypass (GBP) surgery, with the Biliopancreatic diversion with duodenal switch (DS) as an option for the most extreme cases with a BMI>50 kg/m2.In paper I 20 GBP-patients were examined during the first post-operative year regarding the natriuretic peptide, NT-ProBNP, which is secreted from the cardiac ventricles. Levels of NT-ProBNP quickly increased during the first post-surgery week, and later established itself on a higher level than pre-surgery.In paper II we report of 5 patient-cases after GBP-surgery with severe problems with postprandial hypoglycaemia that were successfully treated with GLP-1-analogs. The effect of treatment could be observed both symptomatically and in some cases using continuous glucose measuring systems (CGMS).In paper III three groups of subjects; 15 post-GBP patients, 15 post-DS, and 15 obese controls were examined for three days using CGMS during everyday life. The post-GBP group had high glucose variability as measured by MAGE and CONGA, whereas the post-DS group had low variability. Both post-operative groups exhibited significant time in hypoglycaemia, about 40 and 80 minutes per day <3.3mmol/l and 20 and 40 minutes < 2.8mmol/l, respectively, longer time for DS-group. Remarkably, only about 20% of these hypoglycaemic episodes were accompanied with symptoms.In Paper IV the hypoglycaemia counter regulatory system was investigated; 12 patients were examined before and after GBP-surgery with a stepped hypoglycaemic hyperinsulinemic clamp. The results show a downregulation of symptoms, counter regulatory hormones (glucagon, cortisol, epinephrine, norepinephrine, growth hormone), incretin hormones (GLP-1 and GIP), and sympathetic nervous response.In conclusion patients post bariatric surgery exhibit a downregulated counter regulatory response to hypoglycaemia, accompanied by frequent asymptomatic hypoglycaemic episodes in everyday life. Patients suffering from severe hypoglycaemic episodes can often be treated successfully with GLP-1-analogues.
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| 16. |
- Abramenkovs, Andris, 1989-
(författare)
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Induction and repair of clustered DNA damage sites after exposure to ionizing radiation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mechanisms that maintain genomic stability safeguard cells from constant DNA damage produced by endogenous and external stressors. Therefore, this thesis aimed to specifically address questions regarding the requirement and involvement of DNA repair proteins in the repair of various types of radiation-induced DNA damage.The first aim was to determine whether the phosphorylation of DNA-PKcs, a major kinase involved in non-homologous end joining pathway, can be utilized to score the DNA double-strand break (DSB) content in cells. DNA-PKcs phosphorylated (pDNA-PKcs) at T2609 was more sensitive to the cellular DSB content than ɣH2AX, as analyzed by flow cytometry. Further, pDNA-PKcs at T2609 could discriminate between DSB repair-compromised and normal cells, confirming that the pDNA-PKcs can be used as a DSB repair marker. In paper II, the DSB repair was assessed in cells with reduced levels of DNA-PKcs. The reduction in DNA-PKcs resulted in decreased cell survival and unaffected DSB repair. These results clearly indicate that DNA-PKcs plays an additional role in promoting cell survival in addition to its function in DSB repair.The second part of the thesis focused on the characterization of complex DNA damage. DNA damage was investigated after exposure to α-particles originating from Ra-223. The Ra-223 treatment induced a nonrandom DSB distribution consistent with damage induced by high-linear energy transfer radiation. The exposure to Ra-223 significantly reduced cell survival in monolayers and 3D cell structures. The last paper unraveled the fate of heat-sensitive clustered DNA damage site (HSCS) repair in cells. HSCS repair was independent of DSB repair, and these lesions did not contribute to the generation of additional DSBs during repair. Prolonged heating of DNA at relatively low temperatures induced structural changes in the DNA that contributed to the production of DNA artifacts.In conclusion, these results demonstrate that DNA-PKcs can be used to monitor DSB repair in cells after exposure to ionizing radiation. However, the functions of DNA-PKcs are not limited to DSB repair, as it can promote cell survival through other mechanisms. The complexity of the DNA damage produced by high-LET radiation is a major contributor to cell death. However, not all clusters produced in irradiated cells are converted into DSBs during repair.
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| 17. |
- Abu Hamdeh, Sami, 1982-
(författare)
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Clinical Consequences of Axonal Injury in Traumatic Brain Injury
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Traumatic brain injury (TBI), mainly caused by road-traffic accidents and falls, is a leading cause of mortality. Survivors often display debilitating motor, sensory and cognitive symptoms, leading to reduced quality of life and a profound economic burden to society. Additionally, TBI is a risk factor for future neurodegenerative disorders including Alzheimer’s disease (AD). Commonly, TBI is categorized into focal and diffuse injuries, and based on symptom severity into mild, moderate and severe TBI. Diffuse axonal injury (DAI), biomechanically caused by rotational acceleration-deceleration forces at impact, is characterized by widespread axonal injury in superficial and deep white substance. DAI comprises a clinical challenge due to its variable course and unreliable prognostic methods. Furthermore, axonal injury may convey the link to neurodegeneration since molecules associated with neurodegenerative events aggregate in injured axons.The aim of this thesis was to study clinical consequences of axonal injury, its detection and pathological features, and potential link to neurodegeneration in severe TBI patients treated at the neurointensive care unit at Uppsala University Hospital. In paper I and IV DAI patients were studied for the relation of elevated intracranial pressure (ICP) and poor outcome to axonal injury on magnetic resonance imaging. In paper II, soluble amyloid-beta aggregates (oligomers and protofibrils), characteristic of AD pathology, were investigated in surgically resected brain tissue from severe TBI patients, using highly-selective Enzyme-Linked ImmunoSorbent Assays. In paper III, brain tissue biopsy samples from TBI patients with either focal injury or DAI were examined for differential proteome profiles using mass spectrometry-based proteomics.The results provide evidence that axonal injury, located in the central brain stem, in substantia nigra and the mesencephalic tegmentum, is particularly related to poor outcome and increased ICP during neurointensive care of DAI patients. A novel classification system for prognostication after DAI is proposed. Furthermore, the thesis shows that severe TBI induces rapid accumulation of neurotoxic soluble amyloid-beta oligomers and protofibrils. In addition, DAI initiates unique proteome profiles different from that of focal TBI in structurally normal-appearing brain. These findings have implication for the clinical management of DAI patients, and provide new insight in the neuropathological consequences of axonal injury.
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| 18. |
- Abu Sabaa, Amal
(författare)
-
Clinical and Molecular Studies of Diffuse Large B-cell Lymphoma
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim of this thesis was to study the prognostic clinical and biological markers of Diffuse Large B-cell Lymphoma (DLBCL).Paper I: Utilizing population-based data for patients with DLBCL in Sweden, the study aimed to establish whether event free survival at 24 months (EFS24) was a reproducible milestone. The disease-free survival for lymphoma patients was compared with that of age and sex matched Swedish general population. We demonstrated that overall survival was similar to age and sex matched general population only for younger patients (<60 years of age) achieving ES24. Patients older than that had worse prognosis. Death was mainly linked to cardiovascular disease and secondary malignancies.Paper II: Plasma samples collected via the bio bank U-CAN were analyzed using multiplex extension assay (PEA) utilizing preselected protein panels to examine the possibility of distinguishing lymphomas, leukemias and controls. The study confirmed that PEA technology could be used not only to effectively screen for large number of plasma protein biomarkers in low plasma sample volumes (1 µL), but even to discriminate between controls and different haematological malignancies. Paper III: Plasma protein pattern evolution in DLBCL patients was highlighted by PEA analysis of plasma proteins at different time points under treatment with Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Significant distinctions in protein patterns at diagnosis compared to controls and striking differences in protein levels before and after treatment in patient who responded to treatment were evident. The three top proteins were TCL1A, CXCL13 and IL2RA. Paper IV: An interesting protein that emerged from the above studies was TCL1A. This plasma protein was analyzed in plasma samples by PEA. Validation by plasma enzyme immunosorbent assay (ELISA) was attempted. The cytoplasm and nucleus bound form of TCL1A were analyzed with the help of immunohistochemistry in tissue microarray samples. The study included 178 patients of which 125 received R-CHOP. Clinical risk factor analysis showed no significant correlation with tissue IHC. Significantly higher levels of plasma TCL1A were seen in male patients (measured by ELISA and PEA) and in patients with Ann Arbor stages II-IV (measured by PEA). Survival analysis showed no statistical significance.
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| 19. |
- Acosta Ruiz, Vanessa, 1987-
(författare)
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CT Guided Ablation of T1 Renal Tumors
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The widespread use of medical imaging contributes to the increased detection of incidentally detected small renal tumors, a majority which are often indolent masses found in elderly patients with preexisting chronic kidney disease. In Sweden, partial nephrectomy with minimal invasive surgical approach is the current standard for removing these tumors, although another option is percutaneous image-guided tumor ablation that allows treatment of elderly patients with comorbidities for who surgery is a risk. Due to the lack of long-term follow-up studies and prospective randomized trials, ablation is still considered an alternative option to surgery in Sweden. The aim of this thesis was to evaluate treatment of T1 renal tumors with CT guided radiofrequency (RFA) and microwave ablation (MWA).Factors affecting the efficacy rate of complete tumor ablation with RFA after a single session were evaluated (Paper I). Optimal electrode placement and a long tumor distance to the collecting system were associated with an increased primary efficacy. Renal tumor RFA was compared with laparoscopic partial nephrectomy (LPN: Papers II-III): both methods had comparable secondary efficacy rates, but RFA involved several treatment sessions. Total session times and hospitalization times were shorter and complications less frequent for RFA than for LPN (Paper II). After treatment, renal function impact was assessed by evaluation of both renal function quantity and quality through determination of the split renal function (SRF: Paper III). Standard renal function measurements were assessed and both RFA and LPN were nephron sparing when treating small renal tumors and did not affect creatinine or GFR. However, LPN involved greater SRF reduction in the affected kidney than RFA. Initial experience with microwave ablation was evaluated and this new ablation technique demonstrated high efficacy rates with fewer complications, and was comparable with the mid-term results of now established ablation techniques (Paper IV).In conclusion, CT guided RFA and MWA are safe and effective treatments for the removal of T1 renal tumors. This thesis provides further insights into the field of thermal ablation of small renal masses, which can aid future treatment selection and patient management.
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| 20. |
- Adamsson, Viola
(författare)
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A Healthy Nordic Diet and Cardiometabolic Risk Factors : Intervention Studies with Special Emphasis on Plasma Lipoproteins
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A healthy diet is important in the prevention of cardiovascular disease (CVD). Several risk factors, modifiable by diet, are involved in the development of CVD, e.g. hyperlipidaemia, hyperglycaemia, insulin resistance, obesity and hypertension. Little data however exist on diets composed of foods originating from the Nordic countries, and their potential to reduce CVD risk.This thesis aimed to investigate whether an ad libitum healthy Nordic diet (ND), either provided as a whole diet, or as a prudent breakfast (PB) alone, could influence CVD risk factors in healthy, mildly hypercholesterolemic men and women. Another aim was to describe the nutrient and food composition of the ND, both by using self-reported data and serum biomarkers of dietary fat quality.The primary clinical outcome measure was LDL-cholesterol, and other cardiometabolic risk factors were secondary outcomes.Two parallel, randomised, controlled intervention studies were conducted in free-living subjects. Clinical and dietary assessments were performed at baseline and at the end of dietary interventions. All foods were provided to subjects randomised to ND, whereas only breakfast items were supplied to subjects randomised to PB. Control groups followed their habitual diet/breakfast.Compared with controls, ND reduced body weight and improved several CVD risk factors including LDL-cholesterol, insulin sensitivity and blood pressure. Several, but not all effects were probably partly mediated by diet-induced weight loss. ND accorded with Nordic nutrition recommendations and was defined as “a plant-based diet, where animal products are used sparingly as side dishes”. Compared with average Swedish diet, ND was high in dietary fibre, but low in sodium, meat, high-fat dairy products, sweets and alcohol. A decreased intake of saturated fat and increased intake of n-3 PUFA during ND was partly reflected in serum lipids. Eating a PB without other dietary changes did not improve lipid or glucose metabolism, but decreased markers of visceral fat and inflammation, without influencing body weight.This thesis suggests that a whole ND, but not PB alone, promotes weight loss and improves multiple CVD risk factors in healthy subjects after 6 weeks. These results suggest that ND could have a potential role in the prevention of cardiometabolic diseases.
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| 21. |
- Adde, Magdalena, 1960-
(författare)
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Aggressive B-cell Lymphomas : Studies of Treatment, FDG-PET Evaluation and Prognostic Factors
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- To improve outcome in young, high-risk lymphoma patients, treatment was intensified, adding etoposide and rituximab to standard CHOP treatment. Granulocyte-colony stimulating factor (G-CSF) enabled treatment bi-weekly. Results were promising: overall (OS) and event-free survival (EFS) 79% and 60% respectively, median follow up 27 months. Single infusion Ara-C, contrary to expectations, did not prevent relapse in CNS. DLBCL were classified as germinal center (GC) or non-GC derived, using immunohistochemical markers, CD10, BCL6 and MUM1. We investigated the outcome for both phenotypes after adding rituximab to chemotherapy. For 106 patients treated with CHOP alone, the GC phenotype displayed significantly better OS and EFS. In contrast, GC phenotype did not predict outcome in 95 patients treated with immunochemotherapy . Thus, addition of rituximab seems to eliminate the prognostic value of immunohistochemically defined GC phenotypes in DLBCL. To improve evaluation and find non-responders, mid-treatment FDG-PET CT was incorporated into clinical routine for patients with high-risk aggressive lymphoma. For those with positive PET, biopsy followed by treatment intensification was recommended. Twenty-five patients were examined, five with positive PET. Two of these had lymphoma in the biopsy. Two had a negative biopsy, and one had a false positive investigation. Seven patients had increased uptake of uncertain significance. Two patients with uncertain PET, and two with negative PET have relapsed, giving a negative predictive value of 85%. In case of relapse of aggressive lymphoma or if not obtaining CR, high dose chemotherapy with autologous stem cell support (HDT) is standard treatment. HDT outcome for 38 patients with transformed follicular lymphoma was compared to outcome for 79 patients with de novo B-cell lymphoma. At median follow-up of 11.5 years both OS and EFS were superior in the transformed group, OS 67% and 33%, EFS 55% and 27% respectively. Treatment related mortality was less than reported in other studies.
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| 22. |
- Adler, Anna
(författare)
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Initiation of alternative pathway of complement, and development of novel liposomal coatings
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The complement system is a central part of the innate immune system, and is an essential part in recognizing and clearing non/altered-self surfaces in the body. This thesis comprises of projects in which the initiation of the alternative pathway (AP) of complement in the fluid phase as well on various artificial and lipid surfaces has been studied. We have also synthesized and evaluated polymer-lipids as liposome coatings to suppress innate immune activation with focus on complement regulation.In paper I we investigated how “C3b-like” C3(H2O) is in regards to form an initial fluid phase AP C3 convertase. Even though C3(H2O) could form a C3 convertase, it was much slower in comparison to the convertase generated by C3b. In paper II the contact activation of C3 on various artificial and lipid surfaces as a potential targeted AP activation pathway was explored. C3 bound selectively to lipid surfaces with negatively charged phospholipids and cholesterol, activated platelets and apoptotic cells. Thus, AP was initiated without prior proteolytic cleavage of C3 nor by preformed C3(H2O) on specific surfaces in a selective manner.In paper III and IV, synthetic phosphatidylcholine inspired polymer-lipids consisting of poly(2-methacryloyloxyethyl phosphorylcholine)-conjugated lipids (PMPC-lipids) with different degrees of MPC polymerization were synthesized. The protein adsorption, with focus on complement proteins onto the PMPC-lipids were evaluated, indicating that PMPC-lipids with a longer polymer chain are better to suppress protein adsorption. In paper V fragmented heparin-conjugated (fHep) lipids were investigated for their potential ability to recruit complement regulators to a lipid bilayer surface for complement regulation. This study indicated that fHep-liposomes could recruit the main fluid phase regulator of the AP, factor H, as well as the coagulation regulator antithrombin from human plasma. To conclude, the results from this thesis indicates that C3(H2O) in the fluid phase is a poor initiator of the AP, however contact activated C3 could be targeting activation pathway for the AP. We could also successfully synthesize PMPC-lipids and fHep-lipids for protein suppression and potential complement regulation on coated liposomes.
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| 23. |
- Adler, Marlen, 1984-
(författare)
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Mechanisms and Dynamics of Carbapenem Resistance in Escherichia coli
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The emergence of extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae worldwide has led to an increased use of carbapenems and may drive the development of carbapenem resistance. Existing mechanisms are mainly due to acquired carbapenemases or the combination of ESBL-production and reduced outer membrane permeability. The focus of this thesis was to study the development of carbapenem resistance in Escherichia coli in the presence and absence of acquired β-lactamases. To this end we used the resistance plasmid pUUH239.2 that caused the first major outbreak of ESBL-producing Enterobacteriaceae in Scandinavia.Spontaneous carbapenem resistance was strongly favoured by the presence of the ESBL-encoding plasmid and different mutational spectra and resistance levels arose for different carbapenems. Mainly, loss of function mutations in the regulators of porin expression caused reduced influx of antibiotic into the cell and in combination with amplification of β-lactamase genes on the plasmid this led to high resistance levels. We further used a pharmacokinetic model, mimicking antibiotic concentrations found in patients during treatment, to test whether ertapenem resistant populations could be selected even at these concentrations. We found that resistant mutants only arose for the ESBL-producing strain and that an increased dosage of ertapenem could not prevent selection of these resistant subpopulations. In another study we saw that carbapenem resistance can even develop in the absence of ESBL-production. We found mutants in export pumps and the antibiotic targets to give high level resistance albeit with high fitness costs in the absence of antibiotics. In the last study, we used selective amplification of β-lactamases on the pUUH239.2 plasmid by carbapenems to determine the cost and stability of gene amplifications. Using mathematical modelling we determined the likelihood of evolution of new gene functions in this region. The high cost and instability of the amplified state makes de novo evolution very improbable, but constant selection of the amplified state may balance these factors until rare mutations can establish a new function.In my studies I observed the influence of β-lactamases on carbapenem resistance and saw that amplification of these genes would further contribute to resistance. The rapid disappearance of amplified arrays of resistance genes in the absence of antibiotic selection may lead to the underestimation of gene amplification as clinical resistance mechanism. Amplification of β-lactamase genes is an important stepping-stone and might lead to the evolution of new resistance genes.
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| 24. |
- Affatato, Oreste
(författare)
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Beating of hammers
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- I've been investigating the connection between migraine and depression—two debilitating disorders with high comorbidity. My overarching goal is to unravel their pathophysiology and pinpoint associated risk factors to pave the way for more effective therapeutic interventions. The fruits of my labor is discussed in the introductory part of the thesis and comprises four first-author publications in international peer-reviewed journals.In the first two projects, I worked mostly on the comorbid aspects of migraine and depression. I conducted a meta-analysis on the efficacy of onabotulinumtoxinA injections as a treatment for those grappling with both migraine and depression. The findings were promising, showing not only the treatment's safety and effectiveness but also hinting at a shared pathophysiology between the two conditions. The second project delved into the structural brain anatomy, utilizing voxel-based magnetic resonance imaging measures to explore subcortical volumes in migraine and depression patients. The distinct patterns observed suggest a nuanced relationship at the subcortical level.Expanding beyond comorbidity, my research ventured into the occupational determinants of migraine, scrutinizing the impact of job-related factors on migraine prevalence. Leveraging data from the UK Biobank, the third project identified strong associations between migraine and specific job categories, setting the stage for future interventions and policies to enhance workers' well-being. Additionally, my exploration into the role of the cerebellum and brainstem in migraine pathophysiology, using the UK Biobank data, unveiled larger gray matter volumes in multiple cerebellar regions in individuals with migraines. This sheds light on potential mechanisms underlying migraine attacks, contributing significantly to our understanding and potential treatments for these challenging disorders.
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| 25. |
- Afshari, Kevin
(författare)
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Surgical Aspects and Prognostic Factors in the Management of Rectal Cancer
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Survival among patients with stage IV rectal cancer is poor and surgical treatment for this disease is associated with morbidities such as small bowel obstruction, complications with a diverting loop ileostomy, and functional bowel disturbances. The overall aim of this thesis was to assess risk factors and morbidity after surgery for rectal cancer and to evaluate factors affecting survival in patients with stage IV rectal cancer.Paper I a prospective study on patients with rectal cancer with loop ileostomy who underwent stoma closure in a 23-hour hospital stay setting. Results were compared with a group who underwent standard in-hospital stoma closure prior to the start of the study, selected retrospectively as controls. No differences were found in the number of complications or the frequency of re-hospitalization or re-operation, indicating that ileostomy closure in a 23-hour hospital stay setting in these selected patients was feasible and safe with high patient satisfaction.Paper II a population-based study with data gathered prospectively. In total, 11% of the patients developed small bowel obstruction (SBO), mostly during the first year after rectal cancer surgery. Surgical treatment for SBO was performed in 4.2% of the patients, and the mechanism was stoma-related in one-fourth. Rectal resection without anastomoses, age, morbidity, and previous radiotherapy (RT) was not associated with admission to the hospital or surgery for SBO. Re-laparotomy due to complications after rectal cancer surgery was an independent risk factor for admission for treating SBO.Paper III a population-based study with data gathered prospectively on bowel function at 1 year after anterior resection or stoma reversal. No associations were found between any defecatory dysfunction and the part of the colon used for anastomosis, the level of the vascular tie, or gender. An association was observed between higher anastomotic level and a lower risk of incontinence and clustering. At 1 year after loop ileostomy closure, the risks of incontinence, clustering, and urgency increased by up to fourfold.Paper IV a case-control study aiming to identify patient-, tumor-, and treatment-related prognostic factors for 5-year survival in patients with rectal cancer with synchronous stage IV disease. Patient-related factors did not differ between groups. Among the tumor-related factors, multiple site metastases, bilobar liver metastases, and increasing numbers of liver metastases were associated with poor survival. Prognostic treatment-related factors were preoperative RT, metastasectomy, and radical resection of the primary tumor. The most important prognostic factor for long-term survival was metastasectomy.
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| 26. |
- Aftab, Obaid, 1984-
(författare)
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Towards High-Throughput Phenotypic and Systemic Profiling of in vitro Growing Cell Populations using Label-Free Microscopy and Spectroscopy : Applications in Cancer Pharmacology
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Modern techniques like automated microscopy and spectroscopy now make it possible to study quantitatively, across multiple phenotypic and molecular parameters, how cell populations are affected by different treatments and/or environmental disturbances. As the technology development at the instrument level often is ahead of the data analytical tools and the scientific questions, there is a large and growing need for computational algorithms enabling desired data analysis. These algorithms must have capacity to extract and process quantitative dynamic information about how the cell population is affected by different stimuli with the final goal to transform this information into development of new powerful therapeutic strategies. In particular, there is a great need for automated systems that can facilitate the analysis of massive data streams for label-free methods such as phase contrast microscopy (PCM) imaging and spectroscopy (NMR). Therefore, in this thesis, algorithms for quantitative high-throughput phenotypic and systemic profiling of in vitro growing cell populations via label-free microscopy and spectroscopy are developed and evaluated. First a two-dimensional filter approach for high-throughput screening for drugs inducing autophagy and apoptosis from phase contrast time-lapse microscopy images is studied. Then new methods and applications are presented for label-free extraction and comparison of time-evolving morphological features in phase-contrast time-lapse microscopy images recorded from in vitro growing cell populations. Finally, the use of dynamic morphology and NMR/MS spectra for implementation of a reference database of drug induced changes, analogous to the outstanding mRNA gene expression based Connectivity Map database, is explored. In conclusion, relatively simple computational methods are useful for extraction of very valuable biological and pharmacological information from time-lapse microscopy images and NMR spectroscopy data offering great potential for biomedical applications in general and cancer pharmacology in particular.
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| 27. |
- Agarwal, Prasoon
(författare)
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Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts : Integrative Bioinformatic and Experimental Approaches
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology.In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM.In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted.In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.
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| 28. |
- Agnarsdóttir, Margrét, 1970-
(författare)
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Biomarker Discovery in Cutaneous Malignant Melanoma : A Study Based on Tissue Microarrays and Immunohistochemistry
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The incidence of cutaneous malignant melanoma has increased dramatically in Caucasians the last few decades, an increase that is partly explained by altered sun exposure habits. For the individual patient, with a localized disease, the tumor thickness of the excised lesion is the most important prognostic factor. However, there is a need to identify characteristics that can place patients in certain risk groups. In this study, the protein expression of multiple proteins in malignant melanoma tumors was studied, with the aim of identifying potential new candidate biomarkers. Representative samples from melanoma tissues were assembled in a tissue microarray format and protein expression was detected using immunohistochemistry. Multiple cohorts were used and for a subset of proteins the expression was also analyzed in melanocytes in normal skin and in benign nevi. The immunohistochemical staining was evaluated manually and for part of the proteins also with an automated algorithm. The protein expression of STX7 was described for the first time in tumors of the melanocytic lineage. Stronger expression of STX7 and SOX10 was seen in superficial spreading melanomas compared with nodular malignant melanomas. An inverse relationship between STX7 expression and T-stage was seen and between SOX10 expression and T-stage and Ki-67, respectively. In a population-based cohort the expression of MITF was analyzed and found to be associated with prognosis. Twenty-one potential biomarkers were analyzed using bioinformatics tools and a protein signature was identified which had a prognostic value independent of T-stage. The protein driving this signature was RBM3, a protein not previously described in malignant melanoma. Other markers included in the signature were MITF, SOX10 and Ki-67. In conclusion, the protein expression of numerous potential biomarkers was extensively studied and a new prognostic protein panel was identified which can be of value for risk stratification.
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| 29. |
- Agrasada, Grace V., 1956-
(författare)
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Postnatal Peer Counseling on Exclusive Breastfeeding of Low-birthweight Filipino Infants : Results of a Randomized Controlled Trial
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In a Manila hospital, 204 mothers were randomized into three groups: two intervention groups receiving home-based counseling visits, one of them (n=68) by counselors trained to use a locally developed, two-tiered program of breastfeeding counseling, and the other by counselors trained in general childcare (n=67), were compared with a control group of mothers (n=69) who did not receive any counseling. All infants were scheduled for seven visits to the hospital for follow-up. During hospital visits, maternal and infant body measurements were made and an independent interviewer asked the mothers individually to recall how the infant had been fed. One study physician, blind to participant groups, was consulted at all scheduled and unscheduled infant visits.At six months, 44% of the breastfeeding-counseled mothers, 7% of the childcare-counseled mothers and none of the mothers in the control group were exclusively breastfeeding. Twenty- four mothers breastfed exclusively during the first six months, of whom 22 received breastfeeding counseling and 2 had no breastfeeding counseling. Among 24 infants who were exclusively breastfed from birth to six months there were no episodes of diarrhea. All infants had gained in weight, length and head circumference. Mean maternal weight loss at six months was similar whether her breastfeeding was exclusive or partial.The reasons why mothers without breastfeeding counseling introduced non-breast milk feeding before six months reflected lack of knowledge and support. Breastfeeding support during the first six months focusing on how to prevent and solve breastfeeding problems, particularly during the first two weeks, will enable mothers to choose to breastfeed exclusively up to six months. This study has provided fundamental evidence of successful intervention by breastfeeding counseling to achieve six months of exclusive breastfeeding among term, low-birthweight infants. The locally developed training program in breastfeeding counseling, which successfully prepared volunteers to counsel mothers at home, could be incorporated into primary health care in the Philippines. Mothers who received breastfeeding counseling appreciated how this helped them to achieve their breastfeeding goals for the first six months. Improved breastfeeding practices as a result of breastfeeding counseling provided infants with protection from diarrhea and respiratory infections, contributing to their health and development.
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| 30. |
- Aguda, Adeleke H., 1969-
(författare)
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Structural Study of the WH2 Family and Filamin: Implications for Actin Cytoskeleton Regulation
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cellular processes like motility, chemotaxis, phagocytosis and morphogenesis are dependent on the dynamic regulation of the actin cytoskeleton. This cytoskeleton system is tightly controlled by a number of diverse actin-binding proteins (ABPs) by various mechanisms described as nucleation, polymerization, capping, severing, depolymerization and sequestration. The ABPs are grouped based on sequence identity as in the Wiskott-Aldrich Syndrome protein homology domain 2 (WH2), and the calponin homology domain (CH) containing proteins.In this work, we elucidate the crystal structures of hybrids of gelsolin domain 1 with thymosin β4, ciboulot domain 2, and the second WH2 domain of N-WASP each bound to actin. We show that the single WH2 motif containing protein thymosin β4 in part sequesters actin by binding its pointed end via a C-terminal helix. This interaction prevents the addition of bound actin protomers to the barbed end of the filament. We propose that sequence variations in some WH2 motifs conferred F-actin binding ability to multiple repeat-containing proteins. These F-actin binding domains interact with the barbed end of a filament and the adjacent WH2 motifs are then freed to add their bound actin to the growing filament end. We demonstrate the binding of ciboulot domains 2 and 3 to both G- and F-actin and that full length ciboulot is capable of binding two actin monomers simultaneously. We have also cloned, expressed, purified and crystallized rod domains 14-16 from the actin crosslinking protein a-filamin. Preliminary X-ray crystallography data gives us hope that we shall be able to solve the structure of this triple domain repeat.
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| 31. |
- Ahlberg, Mats Steinholtz, 1979-
(författare)
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Surveillance and follow-up of early prostate cancer
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Active surveillance (AS) for prostate cancer was introduced to address overtreatment resulting from prostate-specific antigen (PSA) testing. Despite advancements such as Magnetic Resonance Imaging (MRI) and targeted biopsies, PSA remains crucial in prostate cancer diagnostics, leading to ongoing challenges of overdiagnosis and overtreatment. This thesis aimed to investigate different aspects of AS and follow-up of early prostate cancer and provide new insights to reduce overtreatment and enhance surveillance and follow-up. In Paper I, the rationale and methodology of a randomized controlled trial, the Prostate Cancer Active Surveillance Trigger trial/Scandinavian Prostate Cancer Group study no. 17 (PCASTt/SPCG17), were outlined. This trial's objective is to evaluate the safety of an AS protocol based on MRI and standardized triggers for repeat biopsies and transition to radical treatment. Patient recruitment is anticipated to conclude in 2024. Paper II investigated the risks of biochemical recurrence, metastatic disease, and prostate cancer-related death in patients following radical prostatectomy. The analysis was conditioned on time after radical prostatectomy without biochemical recurrence. For patients with favourable histopathology in prostatectomy specimens and no biochemical recurrence five years post-prostatectomy, the probability of developing metastatic disease or dying from prostate cancer within 20 years after surgery was very low. This suggests shorter follow-up for selected patients. Paper III compared outcomes of AS for men from different healthcare regions in Sweden with varying traditions of AS. Regions with lower uptake in AS demonstrated a higher probability of transitioning from AS to radical treatment, but no difference in AS failure. The results suggest overtreatment in regions with low uptake in AS. Paper IV explored the associations between potential triggers for transitioning from AS to radical treatment and the transition to treatment. We analysed how this association changed with the introduction of prostate MRI. We found an increasingly strong association between triggers, particularly histopathological progression, and transition. However, most treated men had not experienced histopathological progression. The introduction of MRI did not contribute much to the change. In conclusion, this thesis outlines an ongoing study on defined triggers for transitioning from AS to radical treatment, suggests shorter follow-up after radical prostatectomy for selected patients, reveals overtreatment in regions with low uptake in AS, and shows an increasing use of histopathological progression as a trigger for transition to radical treatment.
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| 32. |
- Ahlford, Annika, 1980-
(författare)
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Applications of Four-Colour Fluorescent Primer Extension Technology for SNP Analysis and Discovery
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Studies on genetic variation can reveal effects on traits and disease, both in humans and in model organisms. Good technology for the analysis of DNA sequence variations is critical. Currently the development towards assays for large-scale and parallel DNA sequencing and genotyping is progressing rapidly. Single base primer extension (SBE) is a robust reaction principle based on four-colour fluorescent terminating nucleotides to interrogate all four DNA nucleotides in a single reaction. In this thesis, SBE methods were applied to the analysis and discovery of single nucleotide polymorphism (SNP) in the model organism Drosophila melanogaster and in humans. The tag-array minisequencing system in a microarray format is convenient for intermediate sized genotyping projects. The system is scalable and flexible to adapt to specialized and novel applications. In Study I of the thesis a tool was established to automate quality control of clustered genotype data. By calculating “Silhouette scores”, the SNP genotype assignment can be evaluated by a single numeric measure. Silhouette scores were then applied in Study I to compare the performance of four DNA polymerases and in Study III to evaluate freeze-dried reagents in the tag-array minisequencing system. The characteristics of the tag-array minisequencing system makes it suitable for inexpensive genome-wide gene mapping in the fruit fly. In Study II a high-resolution SNP map, and 293 genotyping assays, were established across the X, 2nd and 3rd chromosomes to distinguish commonly used Drosophila strains. A database of the SNP markers and a program for automatic allele calling and identification of map positions of mutants was also developed. The utility of the system was demonstrated by rapid mapping of 14 genes that disrupt embryonic muscle patterning. In Study III the tag-array minisequencing system was adapted to a lab-on-a-chip format for diagnostic testing for mutations in the TP53 gene. Freeze-drying was evaluated for storing reagents, including thermo-sensitive enzymes, on the microchip to reduce the complexity of the integrated test. Correct genotyping results were obtained using freeze-dried reagents in each reaction step of the genotyping protocol, both in test tubes and in single polymer test chambers. The results showed the potential of the approach to be implemented in fully integrated systems. The four-colour chemistry of SBE has been developed further to allow massively parallel sequencing (MPS) of short DNA fragments as in the Genome Analyzer system (Solexa/Illumina). In Study IV MPS was used to compare Nimblegen arrays and the SureSelect solution-based system for targeted enrichment of 56 continuous human candidate-gene regions totalling 3.1 Mb in size. Both methods detected known SNPs and discovered novel SNPs in the target regions, demonstrating the feasibility for complexity reduction of sequencing libraries by hybridization methods.
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| 33. |
- Ahlgren, Kerstin M.
(författare)
-
Immunological Studies using Human and Canine Model Disorders
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The studies presented in this thesis focus on human and canine models for autoimmune disease, with the main aim to gain new knowledge about disease mechanisms and to further evaluate the dog as a model for autoimmune disease. Autoimmune Polyendocrine Syndrome type 1 (APS-1) is a hereditary human multiorgan disease caused by mutations in the autoimmune regulator (AIRE) gene. Hallmarks of APS-1 are chronic mucocutaneous candidiasis caused by Candida albicans, together with the autoimmune endocrine disorders hypoparathyroidism and adrenocortical failure. Many human diseases have an equivalent disease in dogs. Because humans share environment, and in part life style with the dogs they provide an interesting model for further genetic studies. Immune responses to Candida albicans in APS-1 patients displayed an increased secretion of the proinflammatory cytokine IL-17A and similar results were also found in AIRE deficient mice. Anticytokine autoantibodies to IL-17A, IL-17F and IL-22 were detected in APS-1 patients, and a radioligand binding assay for measuring these autoantibodies was developed and evaluated. In the canine studies we investigated whether canine diabetes mellitus could serve as a model for human autoimmune diabetes mellitus. Furthermore, we investigated type I IFN responses in Nova Scotia duck tolling retriever dogs with a systemic autoimmune disease resembling human SLE. Four assays were used in search for signs of humoral autoimmunity in diabetic dogs. However, no evidence for a type 1 diabetes-like phenotype in dogs was found. Sera from Nova Scotia duck tolling retrievers suffering from steroid-responsive meningitis arteritis elicited an increased expression of IFN-inducible genes in the canine MDCK cell line. This suggests that these dogs have an IFN signature, as seen in human SLE.
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| 34. |
- Ahlgren, Sara, 1979-
(författare)
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Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules : Preparation and Preclinical Evaluation
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours. Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection. Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial. Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule. It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.
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| 35. |
- Ahlin, Cecilia, 1966-
(författare)
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Cyclin A and cyclin E as prognostic factors in early breast cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is one of the most common malignancies in women. Due to early detection and the use of screening programs approximately 60% of all new cases lack lymph node involvement. Today, a substantial proportion of these women will be offered adjuvant systemic chemotherapy. However, better proliferation markers are needed to predict patient outcome and to avoid overtreatment. Cyclin A, cyclin E and Ki-67 are all markers for proliferation and involved in the regulation of the cell cycle. Overexpression has been associated with disease recurrence in several studies, but the results have not been consistent. However, none of these studies has investigated aberrant expression of cyclin E (the expression of cyclin E during phases of the cell cycle other than late G1 and early S-phase). Studies have shown that aberrant cyclin E might provide additional prognostic information compared to cyclin E alone.The aims of this thesis were 1.to investigate the prognostic value of cyclin A, cyclin E and aberrant cyclin E in early breast cancer. 2.to validate the tissue microarray (TMA) technique for cyclin A and 3.to define the most optimal cut-off values for cyclin A and Ki-67.We found that the agreement of TMA and large section results was good with kappa values 0.62-0.75 and that the reproducibility of the two readers’ results was good or even very good, with kappa values 0.71 – 0.87. The optimal cut-off value for cyclin A average was 8% and for cyclin A maximum value 11%. The corresponding values for Ki-67 were 15 and 22%. Neither cyclin E nor aberrant cyclin E was a prognostic factor in low-risk node negative breast cancer patients. Finally, we conclude that cyclin A is a prognostic factor in node negative breast cancer (univariate analysis average value OR=2.9 95% CI 1.8-4.6; maximum value OR=3.7 95% CI 2.3-5.9).
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| 36. |
- Ahlsson, Fredrik, 1967-
(författare)
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Being Born Large for Gestational Age : Metabolic and Epidemiological Studies
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is a major health problem in the Western world. Mean birth weight has increased during the last 25 years. One explanation is that the proportion of large for gestational age (LGA) infants has increased. Such infants risk developing obesity, cardiovascular disease and diabetes later in life. Despite the risk of neonatal hypoglycemia, their postnatal metabolic adaptation has not been investigated. Our data, obtained with stable isotope labeled compounds, demonstrate that newborn LGA infants have increased lipolysis and decreased insulin sensitivity. After administration of glucagon, the plasma levels of glucose and the rate of glucose production increased. The simultaneous increase in insulin correlated with the decrease in lipolysis, indicating an antilipolytic effect of insulin in these infants.We also demonstrated an intergenerational effect of being born LGA, since women born LGA, were at higher risk of giving birth to LGA infants than women not born LGA. Further, the LGA infants formed three subgroups: born long only, born heavy only, and born both long and heavy. Infants born LGA of women with high birth weight or adult obesity were at higher risk of being LGA concerning weight alone, predisposing to overweight and obesity at childbearing age. In addition we found that pregnant women with gestational diabetes were at increased risk of giving birth to infants that were heavy alone. This could explain the risk of both perinatal complications and later metabolic disease in infants of this group of women.To identify determinants of fetal growth, 20 pregnant women with a wide range of fetal weights were investigated at 36 weeks of gestation. Maternal fat mass was strongly associated with insulin resistance. Insulin resistance was related to glucose production, which correlated positively with fetal size. The variation in resting energy expenditure, which was closely related to fetal weight, was largely explained by BMI, insulin resistance, and glucose production. Lipolysis was not rate limiting for fetal growth in this group of women. Consequently, high maternal glucose production due to a high fat mass may result in excessive fetal growth.
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| 37. |
- Ahlstedt, Carina, 1969-
(författare)
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Registered nurses' work motivation and intention to stay at the workplace
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is currently a shortage of registered nurses (RNs) and high turnover of RNs, both nationally and internationally. Work motivation is an important part of a healthy work environment and something we need to know more about from an RN perspective.The overarching aim of this thesis was to enhance our understanding of the organisational and social workplace factors that contribute to an attractive environment for RNs, by exploring factors associated with work motivation. Four research questions were posed. (i) What factors create the conditions for motivation in RNs’ daily work? (ii) What role does social support in the workplace play in RNs’ work motivation? (iii) What role does the opportunity to work with relevant tasks play in RNs’ work motivation? (iv) Are there differences between healthcare settings regarding RNs’ social support, illegitimate tasks, and associations with work motivation? Four empirical studies were performed to answer these questions. Two were qualitative studies based on an ethnographic approach and two were quantitative cross-sectional studies based on a stratified national sample of RNs. The results of the qualitative studies indicate that crucial factors for RNs' work motivation include a friendly and permissive atmosphere in daily work. Visible progress and receiving feedback from the work itself also positively contributed to motivation. Additionally, RNs' opportunities to learn and support each other through ongoing communication during daily work tended to have a positive impact on work motivation. Effective collaboration between physicians and RNs with mutual respect, understanding of each other's competencies, and creating an environment where RNs could seek clarification were also central to work motivation. The quantitative studies revealed that the opportunity for social support from the immediate manager or co-workers was significant for dimensions related to RNs’ work motivation and the willingness to stay in the workplace. The associations differed in strength between healthcare settings. Furthermore, the results indicated that a factor in RNs' work motivation was the ability to work with tasks perceived as relevant, not illegitimate. However, the results highlighted that a significant portion of RNs performed illegitimate tasks, and that illegitimate tasks were more prevalent for RNs in home healthcare than those in primary care and hospitals. This is something to consider as more complex care is being conducted outside of hospitals. The thesis adds new knowledge that can be useful to the development of attractive workplaces, which could contribute to more RNs choosing to remain in their position for a longer period.
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| 38. |
- Ahlström, Björn
(författare)
-
The epidemiology of risk factors and short- and long-term outcome in the Swedish intensive care cohort
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The sepsis syndrome is present in ¼ to ⅓ of patients in intensive care units (ICUs) worldwide. The short-term prognosis is grim, with a 30-day mortality of 30–35%; however, the long- term outcomes are now being explored, as multi-professional follow-up after ICU care is increasingly being implemented. In 2020 the first and second waves of another severe infection, the Coronavirus disease 2019 (Covid-19) hit Sweden. The number of ICU beds were scaled up by several hundred percent while we simultaneously tried to understand the disease. Reports on risk factors for adverse outcomes in Covid-19 started to appear, but we needed to know more. Thus, we initiated this project aiming at assessing sepsis as an independent risk factor for later morbidity and mortality. Subsequently, with the onset of the pandemic, our focus shifted to identifying risk factors for adverse outcomes in Covid-19 and describing the functional recovery after severe Covid-19. We used the Swedish Intensive Care Registry and several governmental registries to this end.In Cox regression, we compared one-year ICU sepsis survivors without previous dementia with ICU patients without sepsis, finding no increased risk of dementia during follow- up. In a similar cohort, we assessed the impact of sepsis on long-term mortality and causes of death in a series of Cox and multinomial models. We found a surprisingly small overall association between sepsis and mortality and a persistently increased risk of infectious causes of death in sepsis patients. We compared the prevalence of several common comorbidities and medications as risk factors for ICU admission and mortality in ICU patients with Covid-19 with that of age- and sex-matched population controls and in patients discharged alive with those that were deceased at discharge. We found associations between several comorbidities and medications with these adverse outcomes. To better understand the meaning of these comorbidities as risk factors for short-term mortality, we compared them in logistic regression models on patients with Covid-19, sepsis and acute respiratory distress syndrome (ARDS). We found very similar impacts from the comorbidities; however, greater age was more associated with mortality in Covid-19 than in either sepsis or ARDS. Finally, we investigated the long-term functional recovery in ICU patients with Covid-19 compared to hospital-admitted patients with Covid-19 and population controls matched to the ICU group. The ICU patients had a markedly impeded recovery that was not explained by demographics or comorbidities in statistical models.
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| 39. |
- Ahmed, Fozia
(författare)
-
Estrogen and its receptors in adipose tissue from women and men : Associations with age, adiposity and type 2 diabetes
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity and its complications, such as insulin resistance and type 2 diabetes (T2D), are leading causes of morbidity and mortality globally. Adipose tissue is important for whole-body homeostasis, functioning as an energy storage reservoir and an endocrine organ. Estrogens mediate their effects through estrogen receptor alpha (ESR1) and beta (ESR2) and contribute to sex and menopause-related differences in body fat distribution. Moreover, estrogens can be produced from androgens in the adipose tissue by the enzyme aromatase. The overall aim of this thesis was to investigate the role of estrogen and estrogen signalling in human adipose tissue and their association with age, adiposity, and insulin resistance. In Paper I, we assessed ESR1 and ESR2 gene expression in subcutaneous adipose tissue (SAT) from pre- and postmenopausal women, and investigated the effects of estradiol on adipocyte glucose uptake. We found that ESR2 gene expression was higher in postmenopausal women than premenopausal women. Moreover, in late, but not pre- or early postmenopausal women, estradiol incubation reduced basal and insulin-stimulated glucose uptake, which corresponded to an increase in ESR2 gene expression levels. The inhibiting effect of estradiol on adipocyte glucose uptake was prevented using an ESR2 antagonist. Subsequently, in Paper II we assessed the role of ESR2 in SAT lipid and glucose metabolism and preadipocyte differentiation. ESR2 expression in SAT was inversely correlated with markers of central adiposity and positively correlated with markers of lipid accumulation. Moreover, ESR2 knockdown impaired subcutaneous preadipocyte differentiation and glucose utilization. In Paper III, we focused on adipocyte lipolysis in women, which is regulated, in part, by catecholamines. OCT3, which mediates catecholamine transport into adipocytes, where they can be degraded, was increased in SAT with age, and higher in postmenopausal women than premenopausal women. Moreover, its expression was negatively associated with markers of insulin resistance and ex vivo lipolysis. Estradiol incubation of SAT downregulated OCT3 gene expression, which may explain lower OCT3 gene expression in premenopausal compared to postmenopausal women. In Paper IV, we focused on the role of aromatase and estradiol in SAT from men. We found that aromatase expression was higher in SAT from men with obesity and T2D compared to subjects without obesity and T2D, respectively, and was positively associated with markers of central obesity and markers of insulin resistance. Contrastingly, ESR1 expression in SAT was lower in men with obesity and T2D compared to subjects without obesity and T2D, respectively, and negatively associated with markers of obesity and insulin resistance. ESR2 expression was higher in SAT from men with T2D compared to men without T2D. Estradiol reduced insulin-stimulated glucose uptake, however, neither testosterone, nor aromatase inhibition, altered adipocyte glucose uptake. In this thesis, we found that estrogen has important metabolic effects in adipose tissue, including regulating lipid accumulation, glucose uptake capacity, and catecholamine transport. Overall, our findings suggest that estrogen and estrogen receptors may have an important role in age-, menopausal- and sex-dependent differences in body fat distribution, and may serve as potential targets for the prevention and treatment obesity and insulin resistance.
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| 40. |
- Akaberi, Dario, 1989-
(författare)
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Identification of protease inhibitors against Flaviviruses and Coronaviruses
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vector-borne flaviviruses and coronaviruses of zoonotic origins are important human pathogens and represent a serious threat to public health worldwide. Flaviviruses can be found on all continents, apart from Antarctica, where they are transmitted by arthropod vectors causing millions of infections every year. While most of the infections are mild or asymptomatic, flaviviruses like dengue and yellow fever viruses can cause potentially lethal hemorrhagic fever and shock syndrome. Neurotropic flaviviruses like West Nile, Japanese encephalitis, and Tick-borne encephalitis (TBEV) can cause meningoencephalitis with long-term symptoms. Coronaviruses, and in particular betacoronaviruses of zoonotic origin like SARS (2003) and MERS (2012), have been periodically emerging since the early 2000s causing outbreaks of severe respiratory syndrome. The latest example is SARS-CoV-2 that after causing a cluster of infection in the Chinese city of Wuhan, spread all over the world causing at present over 6.9 million deaths. Although vaccines are essential in preventing infections or severe disease and hospitalization in the case of SARS-CoV-2, antivirals represent an extremely valuable tool for treatment and prevention of current and future flavivirus and coronavirus infections. In the work presented in this thesis we have used a combination of in silico and in vitro techniques to identify and test the activity of potential inhibitors of viral proteases. In our first study (paper 1) we unexpectedly identified an HIV protease inhibitor with in vitro activity against ZIKV NS2B-NS3 protease. The inhibitor was identified by virtual screening of a library of known protease inhibitors, evaluated by molecular dynamics simulation and finally tested against recombinant ZIKV protease using a FRET-based enzymatic assay. The same combination of molecular docking and molecular dynamics simulations were also used to correctly predict the activity of a known pan-Flavivirus protease inhibitor against TBEV protease (paper 2). As a result, we were the first to report peptide-based compounds with in vitro activity against TBEV. After the outbreak of the COVID-19 we switched our attention to SARS-CoV-2. We first tested the inhibitory effect of the broad-spectrum antiviral nitric oxide (NO) and found that the NO-releasing compound SNAP had a dose dependent inhibitory effect on SARS-CoV-2 replication in cell-based assays (paper 3). We speculated that SNAP could inhibit SARS-COV-2 protease by trans-nitration of the catalytic Cys145 of SARS-CoV-2 main protease and found that SNAP had a dose dependent inhibitory effect on recombinant SARS-CoV-2 Mpro protease activity in an in vitro enzymatic assay. In our last study (paper 4) we identified a new class of potent SARS-CoV-2 protease inhibitors through the affinity screening of DNA-encoded-chemical libraries containing 4.2 billion compounds. The identified compounds inhibited recombinant SARS-CoV-2 protease with IC50 as low as 25 nM and had a dose dependent antiviral effect in the low micromolar range in infected Calu-3 and Caco-2 cell lines.
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| 41. |
- Akhter, Tansim, 1967-
(författare)
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Carotid Artery Wall Layer Dimensions during and after Pre-eclampsia : An investigation using non-invasive high-frequency ultrasound
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pre-eclampsia is associated with increased risk of cardiovascular disease (CVD) later in life. The ‘gold standard’ for estimating cardiovascular risk - ultrasound assessment of the common carotid artery intima-media thickness (CCA-IMT) - does not convincingly demonstrate this increased risk. The aim of this thesis was to examine whether high-frequency (22 MHz) ultrasound assessment of the individual CCA intima and media layers and calculation of the intima/media (I/M) ratio - can indicate the increased cardiovascular risk after pre-eclampsia. After validation of the method in premenopausal women with systemic lupus erythematosus (SLE) who have a recognized increased risk of CVD, women during and after normal and preeclamptic pregnancies were investigated.Assessment of the individual artery wall layers reliably demonstrated the increased cardiovascular risk in premenopausal women with SLE, while CCA-IMT did not. The artery wall layer dimensions in women with SLE were comparable to those of postmenopausal women without SLE and were 30 years older.Among the women with normal pregnancies negative changes to the artery wall later on in the pregnancy were seen in those with lower serum estradiol, older age, higher body mass index or higher blood pressure early in the pregnancy. About one year postpartum, both the mean intima thickness and the I/M ratio had improved, compared to values during pregnancy. These findings support the theory that normal pregnancy is a stress on the vascular system.Women who developed pre-eclampsia (mean age 31 years) had thicker intima layers, thinner media layers and higher I/M ratios, both at diagnosis and one year postpartum, than women with normal pregnancies, indicating increased cardiovascular risk.Women with a history of severe pre-eclampsia (mean age 44 years; mean 11 years since the last delivery) had thicker intima layers and higher I/M ratios than women with a history of normal pregnancies, indicating long-standing negative vascular effects.Assessment of individual CCA wall layers, but not of CCA-IMT, provided clear evidence of the well-known increased cardiovascular risk in women with SLE or pre-eclampsia. The method has the potential to become an important tool in reducing cardiovascular morbidity and mortality in these women through early diagnosis and intervention.
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| 42. |
- Al-Adhami, Maissa, 1972-
(författare)
-
Health of refugee migrants in the early post-migration phase in Sweden : The role of health resources and health promotion
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the early post-migration phase, the health and well-being of newly settled refugee migrants is negatively affected by structural factors such as restrictive immigration policies, hostile political discourse and limited housing and work opportunities. There is a need for a better understanding of how individual health resources and health promotion can mitigate the impact of these ongoing stressors. The thesis aimed to explore, assess, and further the understanding of the role of health promotion and individual health resources for health and well-being of newly settled refugee migrants in Sweden.In Study I, six focus group discussions were conducted with 32 newly settled refugees, exploring their perceptions of a Swedish Civic Orientation (CO) course with added health communication. The results showed that the course inspired them to focus on their health, promoted independence and empowerment, and gave new social contacts. However, the course is needed earlier in the post-migration phase and should be adjusted to better fit refugee migrants’ varying pre-existing knowledge. Study II was a cross-sectional study, exploring how individual resources of newly settled refugee migrants (n=787) were associated with self-rated health and psychological well-being. Logistical regression analysis showed that limited health literacy, lack of emotional support, and low self-efficacy were consistently associated with poor health outcomes. In Study III, interviews with 10 civic communicators were performed to explore their perceptions of an in-depth training course on mental health in relation to observed psychological needs among newly settled refugee migrants. The overall result was that the attainment of new knowledge and new tools enabled them to lead reflective conversations about mental health with participants. Mental health needs were perceived to be related to pre- and post-migration experiences. Barriers included stigma and lack of arenas to address mental health needs of refugee migrants.In Study IV, the effectiveness of a regular and an extended CO course was compared in a quasi-experimental study design among newly settled refugee migrants (n=173 and 143 respectively). Linear mixed models and Chi-square analyses showed that the extended course led to a small, but significant increase in health literacy. No significant differences were observed regarding other outcomes (emotional and practical support, general self-rated health, or psychological well-being).The thesis illustrates the potential of early health promotion initiatives focusing on individual health resources to enhance health. However, overarching structural barriers related to living conditions, work opportunities and inclusion must also be addressed.
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| 43. |
- Al-Amin, Abdullah, PhD student, 1983-
(författare)
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Molecular Approaches to Explore Drug-Target Interactions
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Improved means to assess the clinical potential of drug candidates can critically influence development of new therapeutic entities, a central aim in medical life science. Drug discovery and development relies on construction and selection of small organic compounds or biological agents that bind targets of interest. This thesis includes new methodology to investigate target engagement - that is the tendency for these drugs and drug candidates to bind their intended target molecules versus any off-targets. This is a matter of great importance and current strong interest in the pharmaceutical industry as well as academically and an important aim for precision medicine. Paper I describes the target engagement-mediated amplification (TEMA) technique, an accurate, selective and physiological relevant techniques to monitor target binding by DNA-conjugated low molecular weight drug molecules. The DNA conjugated forms of the drugs are uniquely suited to accurately and sensitively reveal the binding characteristics of drugs directly in relevant tissues. Paper II describes the evaluation of cellular thermal shift assays (CETSA) by multiplex proximity extension assays (PEA), to sensitively measure binding of drugs to their proper targets and off-targets in minimal samples of cells and tissues, and for many targets and samples in parallel. The technique provides valuable advantages during drug development, and potentially also in clinical care. Paper III describes a high-throughput approach to use in situ proximity ligation assays to investigate protein interactions or modifications along with phenotypic responses to drugs or cytokines. The technique allows responses by large numbers of cells to be evaluated by automated microscopy and computer-based analysis. Our approach expands the scope for combined molecular and morphological profiling, offering an information-rich means to profile cellular responses to drugs and other agents at the single cell level.
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| 44. |
- Al-Mashhadi, Ammar Nadhom Farman
(författare)
-
High Blood Pressure in Children with Hydronephrosis
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The most common cause of secondary hypertension is intrinsic renal disease, but little is known about the influence of hydronephrosis on blood pressure. In this thesis, the risk of development of hypertension in children with hydronephrosis was studied.Experimental and clinical studies were combined in order to investigate the risk of developing elevated blood pressure following conservative treatment of hydronephrosis, and to further explore underlying mechanisms. We started with a clinical study in children (study I), which in agreement with previous experimental studies, showed that blood pressure was lowered by surgical management of hydronephrosis. In parallel, an experimental study was conducted (study II) to investigate the involvement of renal sympathetic nerve activity in development of hypertension following induction of hydronephrosis caused by pelvo-ureteric junction obstruction. Renal denervation of the obstructed kidney attenuated hypertension and restored the renal excretion pattern, effects that were associated with reduced activity of both renal NADPH oxidase derived oxidative stress and components of the renin-angiotensin-aldosterone system.Based on the findings in studies I and II, we continued our studies in children with hydronephrosis, and including two control groups as comparisons with the hydronephrotic group (study III). In the same study, we further investigated potential mechanism(s) of hypertension by analyzing markers of oxidative stress and nitric oxide homeostasis in both urine and blood samples. We demonstrated increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which was restored to normal levels by surgical correction of the obstruction. Finally, in a retrospective cohort study, blood pressure of adult patients undergoing surgical management of hydronephrosis due to pelvo-ureteric junction obstruction was assessed (study IV). Similar to that demonstrated in the pediatric hydronephrotic population, blood pressure was significantly reduced by relief of the obstruction. In addition, blood pressure was increased again if the hydronephrosis recurred, and was reduced again following re-operation.It is concluded that conservative management of hydronephrosis in children is associated with a risk for development of high blood pressure, which can be reduced or even normalized by relief of the obstruction. The mechanism(s), at least in part, is coupled to increased oxidative stress.
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| 45. |
- Al-Saffar, Anas Kh. 1969-
(författare)
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Gastrointestinal Permeability and Motility in Inflammatory Bowel Disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Synchronized motility, permeability and secretory (hormones and enzymes) events are integral to normal physiology. Smooth muscle syncytium operates with enteric nervous system (ENS) and endocrine signalling to accommodate, mix and control passage of ingested materials. The intestinal epithelial cells (IECs) drive digestion and absorption while repelling harmful compounds.This thesis investigated GI barrier function (permeability, mucosal integrity), motility and hormonal patterns in inflammatory bowel disease (IBD) by: 1) assessing GI motility using a wireless motility capsule (WMC, SmartPill®) and video capsule endoscopy (VCE, Pillcam®), 2) investigation of intestinal fatty acid binding protein (I-FABP) as a biomarker of Crohn’s disease (CD) disease activity, 3) evaluation of small intestinal permeability in IBD, 4) investigating meal-related WMC motility and simultaneous hormonal (e.g., Ghrelin, GLP-1, GIP, PYY) patterns in IBD. Reference WMC motility values for transit times for gastric emptying, small bowel, orocecal, small+large bowel, colon and whole gut were established. Software-generated estimates and visually determined values were nearly identical. Compared with VCE estimates (represents fasting conditions), the WMC records longer GET and SBTT. Variations in intra-subject reproducibility must be considered in clinical investigations. This data was then used to investigate IBD patients. I-FABP was primarily expressed in the epithelium of the small bowel and to lesser extent also in the colon and stomach. Circulating I-FABP was elevated in active CD with a magnitude comparable to TNFα. I-FABP lowers and rises again in parallel with TNFα and HBI during infliximab treatment. I-FABP can be used as a jejunum and ileum selective prognostic biomarker for monitoring disease activity. Increased small intestine mucosal barrier permeability to lactulose in both CD and UC was found. Sucralose can serve a dual purpose in quantifying small and large intestinal permeability. Small intestinal hyper-permeability was not revealed as a transporter dependent nutrient (riboflavin) malabsorption. Using the WMC, consistent motility disturbances in IBD were limited, as were differences in pH. However, disturbances within many individuals were found. As part of the investigation, defects in gut peptide and metabolic hormone meal responses were found, typically higher plasma levels. No clear associations between hormones and motility were found. Effects on hunger/satiety signaling in IBD are anticipated.The present thesis shows the utility of the WMC and gut barrier tests in monitoring IBD patients.
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| 46. |
- Alaie, Iman
(författare)
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Adulthood Outcomes of Child and Adolescent Depression : From Mental Health to Social Functioning
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Depression is a common mental disorder affecting people across the lifespan, with first onset frequently occurring in the teenage years. The disorder is costly to society and constitutes one of the leading causes of disability in youths and adults worldwide. Research demonstrates that depression in childhood or adolescence is linked to adverse adult consequences, including mental health problems, physical health issues, various social difficulties, and economic hardships. While the specific factors and mechanisms associated with these long-term adversities are not well understood, previous studies point to the relevance of considering the heterogeneity in early-life depression.The overarching aim of this doctoral thesis was to shed more light on long-term outcomes of childhood and adolescent depression across multiple life domains. This work made use of extensive follow-up data gathered in Sweden and USA, as part of two community-based longitudinal cohort studies of depressed and nondepressed youths prospectively followed into adulthood. In the Uppsala Longitudinal Adolescent Depression Study, participants were interviewed around age 16 (n=631) and age 31 (n=409). Using linkage to nationwide population-based registries, participants were followed up around age 40 (n=576). In the Great Smoky Mountains Study, participants were interviewed at repeated occasions in childhood and adolescence (n=1,420), and at further follow-ups in adulthood extending up to age 30 (n=1,336).Findings from this work suggest that childhood/adolescent depression can have long-lasting associations with a broad spectrum of adverse outcomes. First, the risk of adult depression is known to be elevated among those exposed to depression in early life; however, depressed youths experiencing major conflicts with parents may be at an additionally increased risk of subsequent depression recurrence. Second, early-life depression was found to be associated with higher levels of adult psychiatric disorders, and also with worse health, criminal, and social functioning, even when accounting for a multitude of potential confounders. Third, early-life depression was predictive of poor labor market outcomes, especially for those with persistent depression. This link was partially mediated by the course of depression. Fourth, the welfare burden associated with early depression amounted to considerable public expenditures in adulthood, particularly for those with persistent depression or comorbid psychiatric conditions such as anxiety and disruptive behavior disorders.The adverse long-term consequences in the wake of early-life depression underscore the importance of prevention and treatment approaches that are both efficacious and cost-effective. Such targeted efforts may have the potential to avert later ill-health, impairment, and possibly also economic disadvantage.
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| 47. |
- Alassaad, Anna, 1977-
(författare)
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Improving the Quality and Safety of Drug Use in Hospitalized Elderly : Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization.
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| 48. |
- Albrecht, Lisa M.
(författare)
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Antibiotic Resistance : Selection in the Presence of Metals and Antimicrobials
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The external environment is complex: Antibiotics, metals and antimicrobials do not exist in isolation but in mixtures. Human activities such as animal husbandry, fertilization of agricultural fields and human medicine release high amounts these compounds into the environment. The work in this thesis contributes to our understanding of how the selection of bacterial antibiotic resistance can be facilitated by the pollution by metals and antimicrobials. We show that low levels of antibiotics, metals and combinations thereof can lead to the selection of chromosomally encoded antibiotic resistance genes as well as a multidrug resistance plasmid. The underlying genetic and cellular mechanisms of selection identified relate to mutational changes in a plasmid-encoded metal resistance operon, and metal-associated increases in cellular membrane permeability. We further show that exposure to quaternary ammonium compounds can result in cross-resistance to antibiotics following genetic changes in genes related to efflux, membrane synthesis and transcription/translation. Taken together, the work in this thesis suggests that the stewardship of antibiotics should include prudent use of metals and antimicrobials.
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| 49. |
- Alenkvist, Ida
(författare)
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Epac2 signaling at the β-cell plasma membrane
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Secretion of appropriate amounts of insulin from pancreatic β-cells is crucial for glucose homeostasis. The β-cells release insulin in response to glucose and other nutrients, hormones and neurotransmitters, which trigger intracellular signaling cascades, that result in exocytotic fusion of insulin-containing vesicles with the plasma membrane. Increases of the intracellular concentration of calcium ions ([Ca2+]i) trigger exocytosis, whereas the messenger cyclic adenosine monophosphate (cAMP) amplifies various steps of the secretion process. The protein Epac2 mediates some effects of cAMP, but little is known about its regulation in β-cells. In this study, the spatio-temporal dynamics of Epac2 was investigated in insulin-secreting MIN6-cells and primary β-cells using various cell signaling biosensors and live-cell fluorescence microscopy approaches. Increases in the cAMP concentration triggered translocation of Epac2 from the cytoplasm to the plasma membrane. Oscillations of cAMP induced by glucose and the insulin-releasing hormone GLP-1 were associated with cyclic translocation of Epac2. Analyses of Epac2 mutants showed that the high-affinity cyclic nucleotide-binding domain and Ras-association domains were crucial for the translocation, whereas neither the DEP domain, nor the low-affinity cAMP-binding domain were required for membrane binding. However, the latter domain targeted Epac2 to insulin granules at the plasma membrane, which promoted their priming for exocytosis. Depolarization-induced elevations of [Ca2+]i also stimulated Epac2 translocation, but the effects were complex and in the presence of high cAMP concentrations, [Ca2+]i increases often reduced membrane binding. The stimulatory effect of Ca2+ was mediated by increased Ras activity, while the inhibitory effect reflected reduced concentrations of the membrane phospholipid PtdIns(4,5)P2. Anti-diabetic drugs of the sulfonylurea class, suggested to directly activate Epac2, induced translocation indirectly by depolarizing β-cells to increase [Ca2+]i. Epac2 is an activator of Rap GTPases, and its translocation increased Rap activity at the plasma membrane. It is concluded that the subcellular localization of Epac2 is controlled by a complex interplay between cAMP, Ca2+ and PtdIns(4,5)P2 and that the protein controls insulin release by binding to the exocytosis machinery. These results provide new insights into the regulation of β-cell function and may facilitate the development of new anti-diabetic drugs that amplify insulin secretion.
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| 50. |
- Alfonsson, Sven
(författare)
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Treatment Adherence in Internet-Based CBT : The Effects of Presentation, Support and Motivation
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Homework assignments that patient work with between sessions is a key component in both face-to-face and Internet-based Cognitive Behavior Therapy (CBT). However, adherence to assignments is often low and it is largely unclear what factors predict or affect treatment adherence, and in the end, treatment outcomes. The overall aim of this thesis was to investigate if treatment presentation and therapist support can affect adherence and treatment outcome in internet-based CBT, whether adherence can be predicted by motivation variables and to compare differences in face-to-face and online conditions in this regard.A randomized controlled trial with a brief online relaxation program for people with stress and anxiety symptoms was conducted (n = 162). Participants in the enhanced support conditions completed a larger proportion of the online treatment but adherence was not affected by enhanced treatment presentation (Study I). Participants reported reduced symptoms of stress and anxiety after the relaxation program but there were no significant additional effects of enhanced presentation or support (Study II). Participants who adhered to the prescribed assignments reported lower symptom levels at study end, regardless of treatment conditions. Adherence to the online treatment was predicted by subject factors such as treatment credibility prior to the treatment and intrinsic motivation during the treatment (Study III). To further elucidate how motivation may affect adherence, an experiment with a one-session psychotherapy model was subsequently conducted (n = 100). Participants who were randomized to the face-to-face condition reported higher motivation for the assignment and completed significantly more of the homework compared to participants in the online condition (Study IV). Self-reported intrinsic motivation could predict adherence in both conditions while new motivational variables were identified specifically for the online condition.The results from these studies confirm that adherence to assignments in Internet-based CBT is difficult to affect with treatment features but can be predicted early in treatment by subject factors such as treatment credibility and motivation. How such motivational variables can be affected to improve treatments is still unclear.
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