Aim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI.... Show moreAim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI. Furthermore, this thesis focused on optimization of antimicrobial treatment of febrile UTI. The main results are: 1. Recent hospitalization, indwelling urinary catheter and especially individual fluoroquinolone (FQ) use are independent risk factors for a FQ-resistant Escherichia coli febrile UTI. 2. Women with febrile UTI, including postmenopausal women and those with comorbidities, can be safely and successfully treated with a 7-day course of oral ciprofloxacin. In men, however, treatment duration should be at least 14 days. 3. Diabetes mellitus does not affect the clinical presentation and course of febrile UTI; concurrent illnesses and higher age of the diabetic population attribute to a more complicated course. 4. MR-proADM more accurately predicts a complicated course of disease than currently available inflammatory biomarkers. Importantly, biomarkers derived directly from host defense mechanisms are not suitable to distinguish between febrile UTI patients with and without bacteremia. 5. MP-TF activity is related to disease severity and bacteraemia in febrile E. coli UTI and may contribute to the prothrombotic state in gram-negative sepsis. Show less
In this thesis, senescence is measured in human populations according to its definition of an increase in the risks of dysfunction, disease, and death with chronological age. Part I of this thesis... Show moreIn this thesis, senescence is measured in human populations according to its definition of an increase in the risks of dysfunction, disease, and death with chronological age. Part I of this thesis investigates how a population__s senescence rate can be measured through the increase in mortality rate with age. Part II of this thesis investigates how senescence can be measured through the increase in morbidity - with a focus on cardiovascular disease - in a non-western population and thus be compared with the senescence process in western populations. Show less
Endothelial injury and repair are most important concepts for our understanding of renal disease and allograft injury. The concept that injury to the endothelium may precede renal fibrosis strongly... Show moreEndothelial injury and repair are most important concepts for our understanding of renal disease and allograft injury. The concept that injury to the endothelium may precede renal fibrosis strongly suggests that interventions to maintain vascular integrity are of major importance for renal function. This thesis focuses on the mechanisms involved in the process of endothelial damage and repair in renal disease, (early) diabetes mellitus (DM) and renal ischemia-reperfusion (I/R) injury. Furthermore, microvascular alterations were assessed, using sidestream darkfield (SDF) imaging and measurement of endothelial dysfunction markers (including angiopoietins), in chronic kidney disease (CKD) and DM patients before and after (pancreas) kidney transplantation. The results of this thesis demonstrate an important role for endothelial damage and repair in renal disease and after transplantation. Both renal I/R and DM induced systemic capillary damage reflected by increased capillary tortuosity by SDF imaging and a dysbalance in angiopoietins. In addition, patients with CKD and allograft rejection after renal transplantation also had systemic microvascular derangements. Transplantation was effective in reversing the systemic microvascular alterations. Complementary use of SDF imaging to measure microvascular tortuosity and the assessment of endothelial dysfunction markers may be useful diagnostic tool for monitoring the microvasculature before and after transplantation. Show less
Model based approaches, integrating physiological parameters or linking exposure with response, are powerful tools to quantify and evaluate the impact of genetic differences that are reflected as... Show moreModel based approaches, integrating physiological parameters or linking exposure with response, are powerful tools to quantify and evaluate the impact of genetic differences that are reflected as variability of drug exposure and/or clinical response(s). This thesis __Pharmacogenomics in Drug Development: Implementation and Application of PKPD Model Based Approaches__ focused on genotype differences in explaining inter-individual variability in drug metabolism and clinical response. Population pharmacokinetic and pharmacodynamic models were developed to evaluate the relationship between exposure differences resulting from UGT2B15 genotype and their effects on both fasting plasma glucose and glycosylated haemoglobin for the type 2 diabetes drug, Sipoglitazar__. The model was used to quantify the optimal dose and regime (Single treatment/genotyped-based or titrated based upon response) for future clinical trials. Evaluating the potential impact of genetic differences early during development is important to appropriately design future clinical studies and to ensure that exposure response relationships for efficacy and safety can be identifed for all genetic subgroups. Ultimately, these model-based approaches can be used to determine if covariate-based dose individualization would be advantageous/beneficial to normalize exposure and minimize variability in clinical outcomes across heterogeneous clinical populations. Show less
