This thesis describes various studies during the long-term follow-up of patients after treatment for pituitary diseases. The focus of this thesis is acromegaly, growth hormone deficiency, sleep and... Show moreThis thesis describes various studies during the long-term follow-up of patients after treatment for pituitary diseases. The focus of this thesis is acromegaly, growth hormone deficiency, sleep and quality of life. Various aspects are described. Show less
Various non-invasive imaging techniques are available for the diagnosis of coronary artery disease (CAD). Multi-slice computed tomography (MSCT) is an upcoming technique that allows direct... Show moreVarious non-invasive imaging techniques are available for the diagnosis of coronary artery disease (CAD). Multi-slice computed tomography (MSCT) is an upcoming technique that allows direct visualization of the coronary arteries. Apart from the assessment of atherosclerosis, MSCT can also provide important information on the global and regional left ventricular (LV) function. However, it should be realized that the hemodynamic consequences of atherosclerosis can not be obtained by MSCT imaging, and that functional testing, with for example nuclear imaging, will remain necessary to determine therapeutic strategy. CAD is the most common cause of chronic heart failure. Recently, cardiac resynchronization therapy (CRT) has become implemented in the treatment of patients with severe heart failure. Although the improvement in systolic function after CRT implantation can be considerable, 20% to 30% of patients do not respond to CRT. It has been shown that the presence of LV dyssynchrony is an important predictor of response to CRT. Gated SPECT allows not only the assessment of myocardial perfusion (scar tissue and viable myocardium) but also the evaluation of LV dyssynchrony. As many patients with heart failure undergo nuclear imaging with SPECT, integrated assessment of LV dyssynchrony, viability and scar tissue may be an attractive option. Show less
The work presented in this thesis involves the development of new instrumental techniques and analysing tools, combining high spectral resolution with high spatial information, with the aim to... Show moreThe work presented in this thesis involves the development of new instrumental techniques and analysing tools, combining high spectral resolution with high spatial information, with the aim to increase our understanding of the formation and evolution of stars and planets. First, a novel instrumental concept is presented that aims to achieve high spatial and spectral resolution by combining existing Echelle spectrographs with existing optical interferometers. Subsequently, several studies combining high spatial and spectral resolution are presented. We investigate the immediate environment of the massive young stellar object MWC349A, using the VLT-interferometer. New methods are presented to analyse the Rossiter-McLaughlin effect during stellar eclipses. By using this effect it is possible to obtain spatial information on stellar surface scales, something difficult to achieve by other means. Using these new tools we show that the spin axes in both stars of in the DI Herculis system are strongly tilted with respect to the orbital angular momentum. This solves a 20-year-old riddle about the DI Herculis system, involving its apparently slow apsidal motion. In the final chapter of this thesis sodium measurements for the atmosphere of the extrasolar planet HD209458b using ground-based transmission spectroscopy are presented. Show less
In the 21st century, space activities increasingly affect global society, economy, technology, culture, and the environment. Many countries wish to develop space activities in order to obtain space... Show moreIn the 21st century, space activities increasingly affect global society, economy, technology, culture, and the environment. Many countries wish to develop space activities in order to obtain space benefits. However, a lot of them, especially developing countries, face huge obstacles such as lack of human and financial resources, technical support, inadequate information and sustainability of transferred technology. Developing countries believe they do not have equal access to space benefits. This may lead to international conflicts between developing and developed countries. Based on the concept of international cooperation this study examines the legal aspects and feasibility of the creation of a space organization in the Southeast Asian region. It aims at providing an instrument for ASEAN countries to ensure equitable access to outer space and to its benefits. On the basis of a comparison of existing space organizations, this study identifies the key elements needed for the creation of a model for ASEAN space cooperation. The study concludes that if ASEAN countries want to break the cycle of technological dependency, they should combine their efforts to promote sustainable space development by creating an ASEAN Space Organization. Show less
Over the past decades, life expectancy in patients with congenital heart disease has increased dramatically. However, serious complications may develop late after total repair in infancy. These... Show moreOver the past decades, life expectancy in patients with congenital heart disease has increased dramatically. However, serious complications may develop late after total repair in infancy. These complications are usually the result of longstanding pulmonary regurgitation which leads tot dilatation of the right ventricle and an increased risk for severe arrhythmias. Therefore lifelong follow-up in these patients is required. Cardiac magnetic resonance imaging is the current imaging tool of choice because it offers superior imaging quality and enables accurate quantification of functional parameters such as flow volumes and systolic and diastolic performance. Pulmonary valve replacement is often performed in Tetralogy of Fallot patients later in life due to pulmonary regurgitation with or without severe right ventricular failure. However, the optimal timing of pulmonary valve replacement has not yet been elucidated. Therefore, the current study focuses on the optimal timing of pulmonary valve replacement in patient late after total repair of Tetralogy of Fallot. Show less
The European natural gas market is in a state of flux. In order to better secure the public service obligations supply security, competitiveness and sustainability this market is currently being... Show moreThe European natural gas market is in a state of flux. In order to better secure the public service obligations supply security, competitiveness and sustainability this market is currently being liberalized. This requires significant structural and regulatory reform. This reform process is not yet finished; the European gas market finds itself in a transition phase from the traditional managed market structure towards an internal European gas market which is governed by competitive forces. In such a transition phase, problems and tensions are inevitable. This study assesses the adequacy of the current approach towards structural and regulatory reform of the European gas market in light of the changes that are taking place on this market. These changes create a new context for gas regulation. Given the vital role of investments in securing any of the public service obligations, the analysis is conducted from the perspective of ensuring sufficient investments. The theoretical part criticizes the current neoclassical approach towards reform and argues that the transaction cost perspective will result in better outcomes in terms of market behavior in the new regulatory context. The empirical part undertakes case studies on two recent amendments to gas regulation the possibility for certain investments to be exempted from the provisions to provide third party access, and the enlarged scope for concluding downstream long-term gas supply contracts in order to assess whether the theoretical critique is also valid in practice. Both case studies confirm the theoretical critique. The current regulatory approach appears to be stuck between the neoclassical and the transaction cost perspective. Recommendations are provided in order to better align current regulation with the insights provided by Transaction Cost Economics. Show less
Unfairness increases noise annoyance. Noise annoyance increases due to unfair sound management. Fair sound management reduces annoyance, however only when the sound pressure level is high,... Show moreUnfairness increases noise annoyance. Noise annoyance increases due to unfair sound management. Fair sound management reduces annoyance, however only when the sound pressure level is high, concludes Eveline Maris based on two laboratory experiments.Being exposed to man-made sound is more than mere exposure: it is a social experience, too: You expose Me. This social hypothesis of noise annoyance has been confirmed in two laboratory experiments. Participants were exposed to aircraft noise (sound pressure level (SPL): 50 or 70 dB A) and treated either in a neutral, fair, or unfair manner. The results show that besides SPL, also the fairness of the procedure determines the level of noise annoyance. The first experiment shows an interaction effect of procedural fairness and SPL: annoyance ratings are significantly lower in the fair than in the neutral condition, but the effect is found only when SPL is 70 dB. The second experiment shows a main effect of procedural unfairness on noise annoyance: annoyance ratings are significantly higher in the unfair than in the neutral conditions, regardless of SPL.The findings imply that, in addition to noise reduction engineering, application of knowledge on the social side of noise annoyance can help reduce future noise annoyance levels. Show less
Many decisions in the legal system are based on eyewitness evidence. It seems to be a matter of common sense that the level of confidence expressed by a witness can be used as a diagnostic tool to... Show moreMany decisions in the legal system are based on eyewitness evidence. It seems to be a matter of common sense that the level of confidence expressed by a witness can be used as a diagnostic tool to discriminate between accurate and inaccurate memories. Contrary to this general belief, the bulk of empirical evidence collected in laboratory and field experiments over the past 25 years indicates that the relationship between confidence and accuracy is far from perfect. The central focus of this dissertation is on the accuracy of eyewitness memory, and especially on the relationship between accuracy and confidence (i.e., the subjective judgment of accuracy). To enhance the ecological validity of the laboratory studies, we used a method that allowed us to determine accuracy and confidence scores for the recall of details of complex naturalistic events. The first three chapters are experiments from the laboratory testing the effect of repeated retrieval, retention interval and repeated misleading questioning. The fourth chapter is a case study in which real live witnesses of a robbery on a supermarket were interviewed. Our findings show a clear and consistent relationship between confidence judgements and the actual accuracy of memories. With some caution, confidence may be used as a partial indicator of accuracy, especially during the early stages of an investigation. Unfortunately, however, there always remain incorrect items that are given the maximum confidence score. That is the reason why no single witness statement can be accepted as certainly correct, based on confidence alone. Show less
Following allograft transplantation, the immune system is triggered to induce an immunogenic response against the non-self organ. To prevent the induction of this immunogenic response, recipients... Show moreFollowing allograft transplantation, the immune system is triggered to induce an immunogenic response against the non-self organ. To prevent the induction of this immunogenic response, recipients are treated with immunosuppressive medication. The majority of these medications target T cells, which play a key role in the rejection process, and thereby prevent acute rejection in most of the recipients. Non-specific targeting of these T cells not only prevents acute rejection, it also prevents responses against pathogens or tumor growth. In addition, long-term use of immunosuppressive agents may cause organ failure due to toxic effects on the organ [1]. Therefore, the ultimate goal is to develop a therapy, which targets alloreactive T cells, allowing a normal response against pathogens and tumors, in the absence of chronic use of immunosuppressive agents. Various strategies have been employed to induce such a donor-specific tolerance, amongst which treatment with immature DC [2]. These immature DC have, in contrast to mature DC, the capacity to induce tolerogenic responses and are therefore an attractive candidate for cellular therapy. The studies presented in this thesis demonstrate that in fully mismatched kidney transplantation models, administration of modulated donor-derived DC to recipient__s results in regulation of recipient__s immune response. Both the donor-specific hyporesponsiveness of recipient T cells and the reduced influx of CD8+ T cells into the graft of LPS-DexDC treated recipients indicate a positive effect of this treatment. However, optimization of this treatment is necessary, since no prolonged allograft survival was induced. Several mechanisms, which are not regulated by LPS-DexDC, may be responsible for the observed rejection, amongst which the preformed alloantibodies, increased levels of C3 in the graft and the increased influx of NK cells. Additional studies are required to explore the modulating effects of antibodies which block co-stimulation and/or short courses of immunosuppressive drugs as a co-treatment in these settings. Show less
The last decade has witnessed an increased occurrence of bacterial resistance against antibiotics. The first part of this thesis describes the discovery of a novel target, protein kinase B / Akt1,... Show moreThe last decade has witnessed an increased occurrence of bacterial resistance against antibiotics. The first part of this thesis describes the discovery of a novel target, protein kinase B / Akt1, that may be used to combat infection with pathogenic bacteria like Salmonella typhimurium. Inhibitors of this enzyme are currently being developed as anti-tumor agents. These molecules can now also be seen as potential antibiotics. The synthesis and biological evaluation of several series of new inhibitors of this enzyme are described. This resulted in the identification of a compound with sufficient potency and selectivity to allow in vivo inhibition of Salmonella outgrowth. The second part describes the optimization of an existing antibiotic, Gramicidin S. This is a naturally occurring decapeptide that disrupts the cellular membrane of bacteria. This results in leakage of intracellular contents and bacterial death. Unfortunately, Gramicidin S is toxic for red blood cells since their membrane is also destroyed. As part of an ongoing project to reduce the toxicity against red blood cells, part of the original decapeptide is replaced by synthetic molecules. One compound showed similar activity against bacteria and reduced toxicity against red blood cells. Further research is needed to further improve this antibiotic. Show less
Bacteria belonging to the genus Collimonas consist of soil bacteria that can grow at expense of living fungal hyphae i.e. they are mycophagous. This PhD studies deals with the ecology of... Show moreBacteria belonging to the genus Collimonas consist of soil bacteria that can grow at expense of living fungal hyphae i.e. they are mycophagous. This PhD studies deals with the ecology of mycophagous bacteria in soil using collimonads as model organisms. Collimonads were found to be widely distributed in different types of soils albeit at low densities. Highest numbers were present in fungal-rich grassland soils and lowest numbers in fungal-poor arable soils. Yet, no significant positive correlation between numbers of collimonads and fungal biomass densities was obtained when all soils were included in the analysis. Actual growth of indigenous collimonads in soils upon invasion by fungal hyphae was demonstrated using a newly, developed Collimonas-specific qPCR assay. The fungal-induced increase in numbers of collimonads was moderate and did not result in an increased turn-over of fungal biomass. In contrast to the effects on fungal-biomass turn-over, effects of presence of collimonads on soil fungal community composition were strong. This implies that collimonads can change the competitive relationships between soil fungal species. Hence, our conclusion is that a small component of the soil microbial community can have a huge impact on this community. Show less
The findings of the present thesis can be summarized in the following conclusions: 1. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of... Show moreThe findings of the present thesis can be summarized in the following conclusions: 1. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of one single SDHD mutation, the SDHD-c.274G>T (p.Asp92Tyr) mutation. 2. Patients with head-and-neck paragangliomas have a considerable impairment of quality of life. 3. Patients with head-and-neck paragangliomas have serious subjective sleep complaints. 4. Patients with SDHD-associated head-and-neck paragangliomas have an increased risk for development of pheochromocytomas and paragangliomas at other locations and life long, repetitive follow up with protocolized clinical, biochemical and radiological screening is therefore mandatory. 5. The use of [123I]-MIBG for detection of intra- and extra-adrenal paragangliomas combined, revealed a sensitivity and specificity of only 80% and 75%, respectively. The sensitivity is dependent on tumor localization and tumor behavior, with an increase in sensitivity to 92% if (intra-adrenal) pheochromocytomas are investigated separately. 6. The practical clinical implications of non-secreting intra-adrenal paragangliomas are currently uncertain. 7. Patients with SDHD mutations have malignant disease in at least ~2.5% of the cases. 8. Mediastinal paragangliomas are associated with mutations in the succinate dehydrogenase genes (either SDHB or SDHD) and aggressive behavior and might be more prevalent than hitherto appreciated. 9. Although the consequences of missing non-secreting and mediastinal paragangliomas in an SDHD-associated population are currently unclear, their possible presence should be taken into consideration in the development of future screening protocols. 10. In the future, [18F]-FDOPA and/or [18F]-FDA are expected to (at least partly) replace MIBG in diagnostic imaging for pheochromocytoma and paraganglioma. Show less
Replicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower... Show moreReplicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower replicative capacity of human fibroblasts from donors of higher chronological age, but these inverse relations have not been reported unequivocally. The relation between chronological age and fibroblast growth characteristics was assessed in nonagenarian subjects of the Leiden 85+ Study. A high remaining replicative capacity impressively showed that even in the very elderly a crucial number of cells with high mitotic capacity are left to give rise to fibroblast strains with the capacity for more than 100 population doublings. During the course of fibroblast growth in vitro, beta-galactosidase activity has been shown to be a reliable biomarker for replicative senescence. In myoblast cultures the relation between mixed cultures and clonal cultures was studied, showing marked heterogeneity between clonal cultures that all had a significantly lower replicative capacity when compared to mixed cultures, indicating heterogeneity of cells within one tissue compartment in their in vivo history. In a formal review on the replicative capacity of fibroblasts from patients suffering from accelerated ageing syndromes, age related diseases and donor age it was found that except for premature ageing syndromes, the replicative capacity of fibroblasts in vitro does not mirror key characteristics of human life histories. Show less
We study the shear flow of two-dimensional foams, i.e., a monolayer of bubbles floating on a soapy solution. We successfully connect local and global flow behaviour
The central focus of this thesis was to examine the role of self-regulation principles in predicting and changing self-care behaviors of diabetes type 2 patients. Overall, the results in this... Show moreThe central focus of this thesis was to examine the role of self-regulation principles in predicting and changing self-care behaviors of diabetes type 2 patients. Overall, the results in this thesis indicate that self-regulation cognitions and skills might be important intervention targets of future diabetes (weight) interventions. The studies in this thesis indicated that self-regulatory cognitions were related to diabetes behavior (weight regulating behavior), HbA1c and drop-out from a diabetes weight loss intervention. Show less
Het proefschrift beschrijft verschillende technische zaken die verbeterd of veranderd kunnen worden om betere metingen te kunnen doen met een AFM in biologisch onderzoek, zaken die kunnen leiden... Show moreHet proefschrift beschrijft verschillende technische zaken die verbeterd of veranderd kunnen worden om betere metingen te kunnen doen met een AFM in biologisch onderzoek, zaken die kunnen leiden tot een hogere gevoeligheid, een bredere toepassing of beter begrip en interpretatie van de metingen, en voorbeelden van de toepassing van dergelijke verbeteringen op verschillende systemen die in biologisch of biomedisch onderzoek in de belangstelling staan. Een voorbeeld van dergelijk onderzoek beschreven in het proefschrift is de rol van collageen-fibers in de mechanische sterkte van de vaatwand van de aorta en hun rol in het mogelijke falen van die vaatwand: dergelijke aneurysma's zijn meestal dodelijk. Show less
This study examines the mobilisation of South African women into trade union activities between the period 1973 and 2003. Firstly, it underscores the role of South African women in fighting for... Show moreThis study examines the mobilisation of South African women into trade union activities between the period 1973 and 2003. Firstly, it underscores the role of South African women in fighting for workers’ rights in the workplace and their contributions in the building of the labour movement at the national level. In explaining the mobilisation of women, this research focuses on their social biography. It explores women’s experiences in society, the family (or personal relationships), the workplace and trade unions. It is shown that women’s experiences within all these different social settings are interconnected and influence their consciousness. Based on these observations, I argue that the activism of South African women takes place at the level of race, class and gender. Secondly, the study focuses on the participation of women trade unionists in the South African transition. It argues that women the struggles of women in the trade unions and the workplace have contributed significantly to the proposals adopted by the Women’s National Coalition which were subsequently incorporated into political negotiation process during the transition and ultimately into the constitution. Show less
A number of chitosan derivatives were synthesized and compared to the previously synthesized derivatives for their permeation enhancing activity. Using these derivatives insulin nanoparticles were... Show moreA number of chitosan derivatives were synthesized and compared to the previously synthesized derivatives for their permeation enhancing activity. Using these derivatives insulin nanoparticles were prepared and their effect was compared to the free polymer and insulin in Caco-2 cells. The results suggested that the paracellular transport of insulin across the intestinal cells was more pronounced with the free soluble polymer due to the availability of more positive charge in free soluble polymer. A novel Gas Empowered Drug Delivery (GEDD) system was then designed using CO2 force to transport insulin, Polyethylene Oxide (PEO) as well as trimethyl chitosan (TMC) to the surface of the small intestine. PEO and TMC act as mucoadhesive polymer and permeation enhancer in the system, respectively. The GEDD system is enterically coated to protect the protein against the acidic environment of the stomach. The insulin transport across the intestinal membrane has been increased up to 9 times in the ex-vivo studies in sheep__s intestine using the GEDD system. Moreover, the in-vivo results showed a 5.5 fold enhancement in comparison to free insulin in rabbits as well as a relative bioavailability of 1.1 _0.4% in compare to the s.c. injection. The GEDD system is easy to manufacture and shows promising future for peroral delivery of peptide drugs. Show less
What is an effective and efficient enforcement policy for fire safety in the catering industry? When and why is an informal, cooperative enforcement style through warnings, persuasion and advice (a... Show moreWhat is an effective and efficient enforcement policy for fire safety in the catering industry? When and why is an informal, cooperative enforcement style through warnings, persuasion and advice (a so called compliance strategy) effective in inducing compliance with the fire safety regulation? The standard economic model of enforcement stresses the importance of immediately punishing individuals and firms for non-compliance (a deterrence strategy). Part I of this thesis analyzes the economic literature to discuss whether and when a compliance strategy can be beneficial. It discusses which enforcement method (private, administrative or criminal) is effective and efficient to enforce safety standards. Part II of this thesis analyzes the optimal enforcement policy for the case of fire safety in the catering industry in the Netherlands. Enforcement officials have been interviewed to examine the use of a compliance strategy in practice. The benefits and costs of the enforcement efforts of the past years are estimated to see whether these efforts have been a desirable investment. Also, the compensation of the victims of the Volendam disaster is investigated to analyze the incentive to take precautions. Finally, a simulation of different enforcement policies in a representative municipality examines which policy is efficient. Show less
