There was a time when Melati van Java (1853 – 1927) was a well-known and much-liked name in the Netherlands. Especially around the turn of the century the general public was familiar with her... Show moreThere was a time when Melati van Java (1853 – 1927) was a well-known and much-liked name in the Netherlands. Especially around the turn of the century the general public was familiar with her novels, which remained in circulation in various editions for at least a quarter of a century; people read her contributions to newspapers and magazines or knew that she was active in the Roman Catholic women’s movement. Literary critics reacted with mixed feelings to her novels, from favourable to sympathetic, to disapproving and cynical, but her novels practically always got attention. In short, Melati van Java (pseudonym of Marie Sloot) was an important factor in the cultural society of the day in the Netherlands. The status she enjoyed at the time contrasts sharply with the regard she has today. Show less
This thesis provides insights in characteristics of newly introduced echocardiographic parameters in healthy children and their use in follow-up of patients with a congenital heart defect (CHD)... Show moreThis thesis provides insights in characteristics of newly introduced echocardiographic parameters in healthy children and their use in follow-up of patients with a congenital heart defect (CHD) after surgery. In healthy children, reference values and characteristics of two echocardiographic techniques, tissue Doppler imaging (TDI) and speckle-tracking strain imaging, are described. TDI-derived velocity parameters are reproducible and feasible in children. Yet use of age or growth-dependent reference values is recommended, especially in neonates. Speckle-tracking strain-derived global peak strain parameters have a good reproducibility, are age-independent and remain unchanged during periods of significant growth, such as the neonatal period. We encourage use of these parameters. In contrast, the limited reproducibility of parameters describing intraventricular time-differences is worrying. Our follow-up studies in CHD patients undergoing corrective surgery with cardiopulmonary bypass, describe a significant decrease in biventricular performance immediately postoperatively. Subsequently, left ventricular performance recovered to control values. In contrast, right ventricular performance remained impaired in most subgroups of CHD patients up to one year postoperatively. Considering the prognostic value of right ventricular performance parameters, these studies underline the need for careful evaluation of both left and right ventricular performance postoperatively. Furthermore, a longer-lasting negative influence of cardiopulmonary bypass on ventricular performance was suggested. Show less
Osteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic... Show moreOsteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic or chemotherapy-resistant disease have a poor outcome. Thus, novel targeted therapies are needed that combine potent and specific anti-cancer activity with limited toxicity toward normal tissues. The thesis is introduced by an outline of the biological properties of osteosarcoma and Ewing sarcoma, followed by an overview of cancer immunology and immunotherapy with the primary focus on innate immunity of human natural killer (NK) cells and macrophages. In the research chapters, cellular interactions of NK cells and macrophages with bone tumor cells are characterized in order to achieve favorable effects on anti-cancer immune cell functions. It is demonstrated that the anti-cancer potential of especially NK cells but also macrophages can be enhanced and directed to the bone tumor cells. It is discussed that the modulation of tumor__immune cell interactions may help to design novel immunotherapeutic approaches to harness anti-cancer functions of innate immune cells against osteosarcoma and Ewing sarcoma. Show less
In this thesis I describe the developmental role of the Y-family polymerases Pol Eta, Pol Kappa and Rev1 in protection against exogenous and endogenous damage in C. elegans. Furthermore I identify... Show moreIn this thesis I describe the developmental role of the Y-family polymerases Pol Eta, Pol Kappa and Rev1 in protection against exogenous and endogenous damage in C. elegans. Furthermore I identify a new role for the A-family Polymerase Pol Theta in repair of replication-associated breaks. Show less
This thesis may be regarded as a concept work, to see how feasible drug discovery approaches still are. For this, a strain collection was built up consisting of actinomycetes from soil in the... Show moreThis thesis may be regarded as a concept work, to see how feasible drug discovery approaches still are. For this, a strain collection was built up consisting of actinomycetes from soil in the Qinling and Himalaya mountains, which were subsequently tested for antibiotic production against multi-drug resistant clinical isolates. This resulted in close to 100 strains that showed strong antimicrobial activity, which were then analyzed in more detail. Two of the strains were subjected to extensive NMR-based metabolomics assisted by mass spectrometry, and several known and also novel antimicrobial compounds were elucidated. Finally, we also focused on the antibiotic activity of volatile organic compounds (VOCs) Show less
This dissertation explores the effects of the Treaty of Lisbon (ToL) on the coherence of the external representation of the European Union (EU) in the field of Common Foreign and Security Policy ... Show moreThis dissertation explores the effects of the Treaty of Lisbon (ToL) on the coherence of the external representation of the European Union (EU) in the field of Common Foreign and Security Policy (CFSP) at two main UN bodies, i.e., the UN General Assembly (UNGA) and the Security Council (UNSC). It theorizes EU representation into a principal-agent relationship and assesses the developments of the EU delegation relationship since the adoption of the ToL. In both contexts the EU and its entire membership are considered a collective principal while the actors that play the role of the agent(s) have been different through different historical periods. A mixed approach is adopted to combine both quantitative and qualitative methods to detect the pre- and post-Lisbon coherence variation in EU representation. At the UNGA, EU representation coherence is measured in terms of EU voting cohesion. At the UNSC, some descriptive statistics are first presented to describe and summarize the voting behaviour of the EU member states sitting on the UNSC, based on which the cases of Iraq and Libya are selected for further investigation. Subsequently, the coherence of the EU__s representation during these two conflicts __ both horizontal and vertical __ is examined and compared by looking at the coordination mechanisms and articulation consistency of the EU and its member states. The empirical evidence suggests that EU representation coherence, in general, has increased in parallel with the developments of the CFSP over time. The reformed delegation structure introduced by the ToL, however, has not yet contributed to greater EU representation coherence at the UN. Whereas the ToL offers an opportunity to strengthen agent capabilities and control mechanisms, coherent EU representation appears to be unlikely in the near future, if the remaining agency problems are left unaddressed. Especially it depends on the genuine willingness of EU member states to overcome diverging preferences and support common EU positions. Only until their declaratory commitments lead to real cooperation can the Union truly stand united and speak coherently on foreign affairs. Of equal importance is the demand for closer coordination among different EU institutions for the sake of consistent and complementary representation. Time is still needed for EU representatives, namely the President of the European Council, the Commission President and the refashioned High Representative __ the External Action Service under her authority as well __ to develop into fully-fledged agents with more autonomy and clearer delimitation of representation competences. Show less
The port-city of Izmir (old Smyrna) plays a crucial role in modern world history. From the 1570s, that city became subjected to European mercantile interests and quickly developed into the main... Show moreThe port-city of Izmir (old Smyrna) plays a crucial role in modern world history. From the 1570s, that city became subjected to European mercantile interests and quickly developed into the main conductor of an irreversible European takeover of the Ottoman economy – the structural basis of a centuries-long decline of the once-mighty Ottoman Empire. Or, so the historical consensus dictates. The problem is that this consensus has been constructed over a conspicuous shortage of sources by an overreliance on grand theories paired with a fundamental misunderstanding of the Ottoman (political, legal, economic and social) system and its solutions to the challenges of the times. This study wants to uncover and question the teleological (mostly Eurocentric, oftentimes triumphalist) historiography of city, empire and world systems that have resulted. In its stead, it lays the foundations of a historiography that restores 17th-century Izmir (and perhaps early-modern Ottoman civilization) to the role of an active and autonomous participant-alternative to Europe’s expanding world system. Show less
M.A. Nicolaie focuses in this thesis on inference in survival models for survival data with competing risks. The author introduces a new approach to competing risks data, called vertical modeling.... Show moreM.A. Nicolaie focuses in this thesis on inference in survival models for survival data with competing risks. The author introduces a new approach to competing risks data, called vertical modeling. It is built on natural observable quantities in competing risks, that is, it quantifies 1. the chance that a failure occurs, irrespective of its cause and 2. conditionally that a failure occurred, it quantifies the risk that the event of failure is ascertained to a certain type of failure. Another appealing feature of vertical modeling which is discussed is that it deals with competing risks when missing causes of failure occur. Next, the author tackles the topic of dynamic prediction in competing risks, a topical subject nowadays. She uses two different approaches, one which is based on modeling the cause-specific hazards and one which is based on modeling the dynamic pseudo-observations associated to the cumulative incidence functions. The results presented in this thesis provide key messages on the use of competing risks methods in different fields such as epidemiology, medicine, demography.M.A. Nicolaie focuses in this thesis on inference in survival models for survival data with competing risks. The author introduces a new approach to competing risks data, called vertical modeling. It is built on natural observable quantities in competing risks, that is, it quantifies 1. the chance that a failure occurs, irrespective of its cause and 2. conditionally that a failure occurred, it quantifies the risk that the event of failure is ascertained to a certain type of failure. Another appealing feature of vertical modeling which is discussed is that it deals with competing risks when missing causes of failure occur. Next, the author tackles the topic of dynamic prediction in competing risks, a topical subject nowadays. She uses two different approaches, one which is based on modeling the cause-specific hazards and one which is based on modeling the dynamic pseudo-observations associated to the cumulative incidence functions. The results presented in this thesis provide key messages on the use of competing risks methods in different fields such as epidemiology, medicine, demography. Show less
Vein graft surgery to treat occlusive arterial disease is a common applied procedure. Each year more than two million vein graft surgeries are performed worldwide. The major drawback of vein... Show moreVein graft surgery to treat occlusive arterial disease is a common applied procedure. Each year more than two million vein graft surgeries are performed worldwide. The major drawback of vein grafting is that within 10 years after vein graft surgery 50-60 % of the vein grafts suffer from patency loss due to thrombosis, intimal hyperplasia formation, accelerated atherosclerosis and rupture. Endogenous factors orchestrate the development and failure of vein grafts. Investigating the role of endogenous constituents on vein graft remodeling can enhance our basic knowledge of the involvement of these factors in vein graft remodeling. By interfering in the function of endogenous factors, as we showed in this thesis, vein graft remodeling can be negatively or positively influenced depending on the factor and strategy used. New therapeutic strategies can be developed based on this knowledge. In this thesis we investigate the role of innate immune components, complement system factors, toll like receptors, mast cells and NK cells and the role of Annexin A5 in vein graft remodeling. Furthermore we explored the role of plaque stability, plaque neovascularization and extracellular matrix remodeling in a hypercholersterolemic mouse vein graft model. Show less
The Feature Co-occurrence Constraint theory proposed in this dissertation provides a means to capture the development of the language-learning child's segment inventory. It does this by combining a... Show moreThe Feature Co-occurrence Constraint theory proposed in this dissertation provides a means to capture the development of the language-learning child's segment inventory. It does this by combining a growing set of features with constraints that are automatically activated as soon as these features are acquired. Representation and derivation go hand in hand, and develop together during acquisition. The Feature Co-occurrence Constraint theory builds on a minimal view of phonology, where the inventory is seen as epiphenomenal rather than a mentally ‘real’ object, features are few and monovalent, and the constraint set is limited to no more than two types. The theoretical consequences of the proposal for both feature theory and constraint theory are worked out in detail and a thorough discussion of phonological acquisition is provided, making this book of interest to both theoretical phonologists as acquisitionists. Show less
