The aim of this thesis is to understand the epidemiology, treatment and outcomes of specialized burn care in The Netherlands. This thesis is mainly based on historical data of the burn... Show more The aim of this thesis is to understand the epidemiology, treatment and outcomes of specialized burn care in The Netherlands. This thesis is mainly based on historical data of the burn centre in Rotterdam from 1986, combined with historical data from the burn centres in Groningen and Beverwijk from 1995-2009 and the common Dutch Burns Registration (NBR) R3 from 2009. This dissertation consists of three parts: part 1: Epidemiology Part 2: Treatment part 3: Results Part 1 Epidemiology In two chapters trends in severe burns in the Netherlands and epidemiology of children admitted to the Dutch Burn Centres and changes in referral influence admittance rates in burn centres are described . Part 2 Treatment Chapter 4 describes the use of modern wound dressings (hydrofibres) where a reduction in the number of operations to be carried out was seen in comparison with the ointment treatment with silver sulfadiazine in second degree burns. Chapter 5 describes the results of bacteriological cultures at admission, which is used an extensive database from 1987. Part 3 Results In 3 chapters the predictive value of a scoring system and the mortality in burn centers in The Netherlands are described. Show less
DNA is arguably the most important molecule found in any organism, as it contains all information to perform cellular functions and enables continuity of species. It is continuously exposed... Show more DNA is arguably the most important molecule found in any organism, as it contains all information to perform cellular functions and enables continuity of species. It is continuously exposed to DNA-damaging agents both from endogenous and exogenous sources. To protect DNA against these sources of DNA damage various DNA-repair mechanisms have evolved. If not properly repaired, DNA damage can lead to mutations that may eventually lead to cell-death or tumorigenesis. One of the most dangerous types of DNA damage is a DNA double-stranded break (DSB), in which a DNA molecule is broken into two pieces. Cells are equipped with several DSB-repair mechanisms to deal with this type of damage. Some of these mechanisms repair DSBs in an error-free fashion, while others are error-prone and can lead to the accumulation of mutations. Although accumulating many mutations in cells can lead to severely reduced cellular fitness, perfect DNA repair is less desirable in the long term as mutations allow for speciation and evolution to take place. The key question addressed in my thesis is which DSB-repair mechanisms organisms use to protect their genome against DSBs and I find alternative end-joining of DNA breaks to play a major role in maintaining genome stability. Show less
Early identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for... Show moreEarly identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for risk stratification and optimizing individual prevention and treatment strategies in patients with metabolic syndrome. This thesis evaluates MR and CT imaging techniques for identifying risk factors and subclinical disease in metabolic syndrome. Show less
Prevalence of childhood obesity is increasing. Insulin resistance is a consequence of childhood obesity, and it has a keyrole in the development of cardiometabolic complications, such as... Show more Prevalence of childhood obesity is increasing. Insulin resistance is a consequence of childhood obesity, and it has a keyrole in the development of cardiometabolic complications, such as diabetes mellitus. In the first part of this thesis, the epidemiology of insulin resistance has been described. Since there is no clear definition for insulin resistance, the prevalence of IR remains unclear. In addition, the use of IR in the screening for diabetes mellitus in obese children was evaluated. In the second part of the thesis, treatment of obese children with insulin resistance is discussed. In a randomized controlled trial of 18 months, children were treated with either metformin or placebo in addition to lifestyle intervention. Body mass index in children treated with metformin remained stable during the 18 months, whereas placebo-treated children had an increase in body mass index. Finally, the treatment with metformin under the strict circumstances of the clinical trial was compared to treatment with metformin in daily practice during 18 months. Both groups showed similar results regarding body mass index during metformin treatment. Show less
Blood loss requiring transfusions, and, in some cases even surgical re-exploration, is relatively common after cardiac surgery. There are several factors associated with this blood loss that can... Show moreBlood loss requiring transfusions, and, in some cases even surgical re-exploration, is relatively common after cardiac surgery. There are several factors associated with this blood loss that can be separated into bleeding complications with a surgical origin (bleeding vessel, anastomosis or other suture line) and those related to ineffective hemostasis. The aim of this thesis is to improve our understanding of the development of (excessive) blood loss due to ineffective hemostasis during and after coronary artery bypass graft (CABG) surgery, in order to support the process of decision making concerning medication and blood product substitution, and to explore several preventative measures to reduce the risk of bleeding. Both processes of bleeding and hypercoagulation appear to define the peri-operative period in CABG surgery. Show less
This thesis has dealt with the role of endosonography in the diagnosis of sarcoidosis. The main conclusion is that endosonography with aspiration of mediastinal lymph nodes has superior... Show moreThis thesis has dealt with the role of endosonography in the diagnosis of sarcoidosis. The main conclusion is that endosonography with aspiration of mediastinal lymph nodes has superior diagnostic yield in comparison to conventional bronchoscopy with taking of peripheral (TBLB) and endobronchial (EBB) tissue (80% vs 53%). Guidelines advising to perform bronchoscopy (including TBLB and EBB) as a first choice procedure to detect granulomas should be revised. In case EUS or EBUS are not available, bronchoscopy may reach comparable sensitivity but only if cTBNA, TBLB and EBB are all performed. This will increase procedure time and likely also complications because of the number of needle and forceps samples. Secondly, we assessed morbidity and mortality rates of EBUS and EUS for pulmonary indications and found that both techniques are very safe. Fatalities have been described but are very rare with a mortality rate of 0.04% and mostly occurred in patients of fragile health. Serious adverse events happen occasionally (0.15%) and are mostly of infectious origin in patients undergoing needle aspiration of cysts, sarcoid of necrotic lymph nodes. Show less
Cancer immunotherapy has taken up its place in oncological practice and it is likely there to stay. Although the field has come from far, much is still to learn as oncologists observe that not... Show moreCancer immunotherapy has taken up its place in oncological practice and it is likely there to stay. Although the field has come from far, much is still to learn as oncologists observe that not all patients with the same disease type respond to cancer immunotherapy, Furthermore, in some cancer types, no clinical benefit is observed at all, despite the presence of an abundant local immune infiltrate, indicating that our understanding of cancer – immune interaction is still incomplete. The overall goal of this thesis is to help address these matters in three ways. First, we have retrospectively analyzed a cohort of melanoma patients treated with ipilimumab, an anti-CTLA-4 antibody, for markers of responsiveness and review the literature to explore the limitations and curative potential of treatment strategies currently used in the clinic or under development. Second, we have developed several technology platforms that allow us to characterize and compare different types of T-cell responses that are directed against tumor-specific antigens in patient tumor material. Third, we aim to increase our understanding of the potential of cancer immunotherapy in ovarian and colorectal cancer, by analysis of the tumor-reactive compartment within these diseases. Show less
Epidural analgesia provided superior analgesia to remifentanil PCA. Women randomised to epidural analgesia with a request for pain relief are more satisfied with their analgesia than women... Show more Epidural analgesia provided superior analgesia to remifentanil PCA. Women randomised to epidural analgesia with a request for pain relief are more satisfied with their analgesia than women randomised to remifentanil PCA. Costs of epidural analgesia and remifentanil PCA are not significantly different. From an economic perspective, there is no preferential pain treatment in labouring women. Epidural analgesia is associated with a greater incidence of fever and significantly higher temperature overall. Patient controlled remifentanil has an effect on maternal SpO2 with significantly lower mean SpO2 during the labour period. This shows that respiratory complications are a serious problem associated with remifentanil and that continuous monitoring by trained personnel is obligatory. Persistent postpartum pain affects many women. Of surveyed women, 6.1% complained of significant pain related to delivery. Since this was a retrospective follow up study this results might be explained by the study design and these findings have to be evaluated by further research. Show less
This thesis focuses on the relationship between smoking and macrophages in chronic obstructive pulmonary disease (COPD), and on treatment with inhaled corticosteroids (ICS). Macrophages play an... Show moreThis thesis focuses on the relationship between smoking and macrophages in chronic obstructive pulmonary disease (COPD), and on treatment with inhaled corticosteroids (ICS). Macrophages play an important role in COPD, and constitute a heterogeneous population with pro- (Mf1) and anti-inflammatory (Mf2) cells. This thesis evaluated YKL-40 and CD163 as markers for Mf1 and Mf2, respectively. Peripheral airways contained more CD163-positive Mf2 compared to central airways. Smoking cessation skewed the macrophage phenotype towards Mf2 in the peripheral airways, but did not influence YKL-40 levels in sputum. Whereas smoking can induce structural alterations in extracellular matrix (ECM) components in the airways, no differences in ECM components in bronchial biopsies were found between current and ex-smokers with COPD. ICS treatment attenuates lung function decline and decreases airway inflammation in a subgroup of COPD patients. However, long-term ICS treatment did not change YKL-40 levels in sputum and serum. ICS increased deposition of several ECM proteins in the airways, which was correlated with improved lung function, suggesting prevention of airway collapse. Withdrawal of ICS after long-term treatment induced a relapse in lung function decline and increased airway inflammation in bronchial biopsies and sputum, suggesting that benefits of ICS do not persist after discontinuation of ICS. Show less
In this thesis, we have addressed aspects of two main arms of the adaptive immune system; the B cell and antibody arm and the T cell arm. This led to a division in the presentation of the... Show more In this thesis, we have addressed aspects of two main arms of the adaptive immune system; the B cell and antibody arm and the T cell arm. This led to a division in the presentation of the results described in this thesis into two sections. In the first section, we present the results regarding the characterization of ACPA responses, B cells and ACPA secreting plasmablasts/-cells in RA as well as autoantibody responses and their regulation by an effective anti-rheumatic drug, abatacept, in the arthritis mouse model; Collagen Induced Arthritis (CIA). The second section is compiled of results obtained from studies examining the regulatory and other aspects of CD49b+CD4+ T cells on proinflammatory responses involved in the pathogenesis of arthritis. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation of the synovial membrane of the joints, culminating in destruction of cartilage and deformity of the joints if remains untreated. Infiltration of inflammatory immune cells such as B cells and T cells into the inflamed joints is a characteristic feature of RA. These immune cells are in continuous interaction with each other and create a viscous circle that sustains persistent synovitis and damage to articular cartilage. Show less
Measuring biomechanics of the knee with an acceptable degree of accuracy is difficult. When the in vivo knee joint motion is analyzed in all its six degrees-of-freedom without compromising on... Show moreMeasuring biomechanics of the knee with an acceptable degree of accuracy is difficult. When the in vivo knee joint motion is analyzed in all its six degrees-of-freedom without compromising on physiological loading conditions, the task becomes even more challenging. This thesis offers a brief overview of the development, validation and application of a non-invasive imaging methodology to capture the in vivo biomechanics of anterior cruciate ligament (ACL) deficient and posterior cruciate ligament (PCL) deficient knees. By combining dual fluoroscopy to capture the in vivo joint motion and magnetic resonance imaging to reconstruct the joint anatomy, we obtained a comprehensive insight in both tibiofemoral as well as patellofemoral kinematics and cartilage biomechanics of healthy knees under various loading conditions. These baseline measurements helped us comprehend the alterations in biomechanics seen in knees after injury of either ACL or PCL, which in turn generated clinically useful data for the improvement of our surgical reconstruction techniques. Show less
The research in this thesis was aimed at investigating the central hypothesis that susceptibility to SD determines both the susceptibility to migraine with aura and the susceptibility to... Show moreThe research in this thesis was aimed at investigating the central hypothesis that susceptibility to SD determines both the susceptibility to migraine with aura and the susceptibility to hypoxic/ischemic injury in the same direction. We envisage that factors that enhance the susceptibility to SD increase the likelihood of migraine with aura as well as ischemic stroke. To this end we assess to what extent genetic, hormonal and pharmacological modulators of SD susceptibility will influence the susceptible to ischemic injury. Thus we will unravel underlying mechanisms of SD susceptibility and susceptibility to ischemic injury. Central to this research is the use of two transgenic mouse models of migraine that carry migraine-relevant FHM1 gene mutations in voltage-gated CaV2.1 Ca2+ channels. Show less
Globally more than 200,000 people develop leprosy every year and 2-3 million people live with leprosy associated disabilities. Despite the availability of multi drug therapy, leprosy has continued... Show moreGlobally more than 200,000 people develop leprosy every year and 2-3 million people live with leprosy associated disabilities. Despite the availability of multi drug therapy, leprosy has continued affecting many individuals, including children because of the uninterrupted transmission in the population. Untreated multi bacillary cases as well as non-symptomatic M. leprae infected individuals in the population are believed to be the major sources of M. leprae infection and transmission. Leprosy reactions are also the major causes of disabilities. However, no tools are available to predict their occurrence. This thesis focuses on in vitro assessment of recombinant M. leprae proteins and synthetic peptides for their immunogenicity and specificity in populations with different genetic backgrounds by measuring cell mediated immunity and this has shown the presence of potential antigens. Further in depth analysis of the host immune responses against these unique antigens in leprosy patients, their household contacts and healthy endemic controls has led to identification of potential biomarkers with an immense importance in development of diagnostic tools for detection of M. leprae infection and early diagnosis of leprosy reactions. Currently, field friendly tests for early detection are developed at the LUMC using identified M. leprae antigens and host biomarkers with diagnostic potential. Show less
Fluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as... Show moreFluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as prolonged infusion. Many tissues throughout the body express thymidine phosphorylase. Dihydropyrimidine Dehydrogenase (DPD) is involved in the degradation of endogenous pyrimidine nucleosides, but also in the degradation of fluoropyrimidines. More than 80% of the amount of 5-FU administered is catabolized primarily in the liver where DPD is abundantly expressed. DPD is encoded by the DPYD gene for which 567 coding variants are known to date, some of them being pathogenic by reducing enzyme capacity. Interindividual variability in the activity of DPD influences 5-FU pharmacokinetics and a reduced DPD activity can lead to severe toxicity and even death following administration of 5-FU or capecitabine. Knowledge regarding the clinical impact of reduced DPD activity on the pharmacokinetics and pharmacodynamics of fluoropyrimidines may be useful to dose individualize therapy. In this thesis, an in depth overview is given of methods and their potential to optimize fluoropyrimidine dosing based on individual DPD enzyme activity. Furthermore an oral uracil loading dose as probe for DPD deficiency in cancer patients treated with fluoropyrimdines for this purpose is studied. Show less
Despite optimal medical treatment and advanced revascularization strategies, a growing number of patients suffer from severe coronary artery disease not amenable to conventional treatment... Show more Despite optimal medical treatment and advanced revascularization strategies, a growing number of patients suffer from severe coronary artery disease not amenable to conventional treatment options. Bone marrow cell injection has emerged as a new potential therapeutic option for these patients. As preclinical studies provided evidence for improvement in myocardial perfusion and function after transplantation of cells, cell therapy was introduced in the clinical setting. As initial studies demonstrated promising results, intramyocardial injection of autologous bone marrow-derived mononuclear cells emerged as a new therapeutic option for patients with severe coronary artery disease. Although studies demonstrated safety and feasibility of the approach, the overall effect of bone marrow cell treatment has shown moderately positive but variable effects. However, many questions remain whether there are certain factors, such as patient specific characteristics, that influence treatment outcome. Therefore, in the current thesis, the efficacy of bone marrow cell injection was investigated in a large refractory angina patient population with chronic myocardial ischemia to further evaluate treatment effect during short and long term follow-up. In addition, the safety and effect of autologous mesenchymal stem cells injection, a specific bone marrow-derived cell type, in patients shorty after acute myocardial infarction was evaluated. Show less
Adenoviral vectors (AdVs) constitute powerful gene delivery vehicles. However, so far, their potential for genome editing has not been extensively investigated. By tailoring AdVs as... Show more Adenoviral vectors (AdVs) constitute powerful gene delivery vehicles. However, so far, their potential for genome editing has not been extensively investigated. By tailoring AdVs as carriers of designer nucleases and donor DNA sequences, the research presented in this thesis expands the utility of the AdV platform to genome editing. In particular, in the first part of this thesis, AdVs are exploited for tackling two of the major bottlenecks of genome editing: (i) developing improved methods for delivering the sizable gene-editing tools, such as RNA-guided nuclease complexes, into target cells, and (ii) increasing the specificity and fidelity of the gene-editing procedures. In the second part of the thesis, the insights derived from these studies are further exploited for testing AdVs encoding nucleases as repairing agents of defective DMD alleles in muscle cell populations derived from patients with Duchenne muscular dystrophy (DMD). Finally, the application of AdVs as gene editing tools for repairing endogenous DMD alleles is discussed in the context of other viral vector-based DMD editing strategies. Taken together, the findings reported in this work are expected to aid in the designing and testing of new therapeutic interventions for tackling DMD and are anticipated to be applicable to other genetic disorders. Show less
Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories,... Show more Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories, morbidity and mortality. In the three parts of this thesis, we examined three interacting systems that have been identified as contributing to a slower pace of ageing, namely glucose/insulin metabolism (part I), the thyroid axis (part II), and the autonomic nervous system (part III). We found that familial longevity is associated with a stronger association of insulin parameters with microstructural brain parameters, and by higher TSH secretion, in the absence of differences in basal energy metabolism or differences in heart rate and its variability. Using specialized MRI techniques, we showed that subtle changes in microstructural brain parenchymal homogeneity in relation to insulin can be detected, even in brain tissue that appears normal on conventional MR imaging sequences. Insulin (rather than glucose), seemed to be a stronger indicator of micro- structural brain integrity in normo-glycemic older adults. Furthermore, intranasal application of insulin improved brain perfusion in parietal and occipital gray matter and in the thalamus of older adults. These results deepen our understanding of the physiological mechanisms and processes that underlie the ageing process. Show less
The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable... Show more The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable of detecting this tracers. In part one, the reader is introduced to the concept of fluorescence image-guided surgery and the evolution thereof. Furthermore the hybrid approach for image-guided surgical guidance is presented. Part two describes the clinical evaluation of the hybrid approach using the hybrid tracer indocyanine green-technetium 99m-nanocolloid. To further refine the hybrid approach for surgical guidance, part three of this thesis describes the development and evaluation of different types of (hybrid) imaging modalities. Show less
The objective of this dissertation was to establish the value of QCT to further enhance the clinical applicability and accuracy of coronary CTA. The automatic characterization of coronary... Show more The objective of this dissertation was to establish the value of QCT to further enhance the clinical applicability and accuracy of coronary CTA. The automatic characterization of coronary atherosclerosis with QCT is feasible and correlates well with IVUS VH. Secondly, novel CTA risk score was created incorporating detailed information on the location, severity and composition of atherosclerosis as assessed with QCT. This CTA risk score allows accurate risk stratification of patients with suspected CAD. A drawback of coronary CTA is the fact that the hemodynamic significance of a lesion cannot be evaluated. In this thesis it was demonstrated that QCT provided better correlation with the presence of myocardial ischemia on SPECT MPI as compared to current visual assessment of coronary CTA. With regards to the specific setting of high risk diabetic patients without chest pain syndrome several conclusion can be derived from this thesis. First, if treated with optimal medical therapy, very few patients present with progression of myocardial ischemia. Second, the prognosis of these patients is good; the overall long-term event-rate is limited. Especially diabetic patients without CAD on coronary CTA have an excellent prognosis. Show less
The field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the... Show moreThe field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the phase of Clinically Suspect Arthralgia (CSA). Patients with arthralgia that were considered by the rheumatologist to have an increased risk to progress to RA (CSA) had indeed an increased risk of RA. In addition, subclinical MRI-inflammation preceded clinical arthritis with a few months. Future research will shed more light on processes underlying progression from CSA to RA and effectiveness of treatment initiation in the CSA phase. The severity of the course of RA is variable between patients and this cannot be yet accurately predicted. In this thesis, we performed studies that contributed to the understanding of these differences in severity. Three genetic risk factors for more severe joint damage progression (two non-HLA and one HLA variation) and one for arthritis persistence were identified. Further research on functional implications of the identified variants and whether they might be useful as biomarkers to guide treatment decisions is needed. Show less
