This thesis describes clinical and immunological aspects of immunoablative therapy followed by reinfusion of T-cell depleted autologous stem cells in patients with progressive refractory Juvenile... Show moreThis thesis describes clinical and immunological aspects of immunoablative therapy followed by reinfusion of T-cell depleted autologous stem cells in patients with progressive refractory Juvenile Idiopathic Arthritis (JIA). After an intensive immunoablative therapy in order to eradicate auto-agressive T cells, autologous hematopoietic stem cells of bone marrow, purged of potentially autoreactive mature T lymphocytes, were reinfused as rescue to reduce the aplastic phase after autologous stem cell transplantation (ASCT). Chapter 1 addresses the background and rationale leading to this study. Chapter 2 describes the safety, efficacy, complications and long term clinical outcome after ASCT in 22 patients with JIA, who were refractory to conventional medication. In chapter 3 the efficacy and safety of ASCT in 34 JIA patients transplanted in 9 different centers in Europe were evaluated. In chapter 4 the immunological effects of the conditioning on cellular infiltrates and expression of cytokines in the synovial tissue of two JIA patients were studied before and 6 months after ASCT. The subject of chapter 5 of this thesis is macrophage activation syndrome in systemic JIA patients. The actual effect of conditioning in vivo and graft manipulation ex vivo on the intended elimination of the adaptive (auto)immunological memory after ASCT was studied in 19 JIA/systemic lupus erythematodes (SLE) and 10 multiple sclerosis (MS) patients (chapter 7). In order to obtain reference values for anti-rabies specific humoral and cellular immune responses after a single and booster vaccination, we conducted a study in 18 healthy controls as described in chapter 6. Show less
Congenital Human Parvovirus B19 (B19V) infection can lead to life threatening fetal complications as hydrops, fetal demise or severe fetal anaemia and thrombocytopenia. Maternal symptoms frequently... Show moreCongenital Human Parvovirus B19 (B19V) infection can lead to life threatening fetal complications as hydrops, fetal demise or severe fetal anaemia and thrombocytopenia. Maternal symptoms frequently pass unnoticed at the time of maternal infection and there was little information on the mechanism and time course of vertical transmission of B19V during gestation. Treatment consists of intrauterine fetal red blood cell and/ or platelet transfusion (IUT). The indication for treatment with IUT is set by performing fetal ultrasound screening for fetal anaemia and signs of fetal hydrops. The fetal middle cerebral artery peak systolic flow correlates well with the severity of fetal anaemia. The first two chapters of this thesis give an overview of the existing literature concerning fetal hydrops and congenital B19V infection. In the ensuing chapters we describe the course of maternal and fetal B19V infection by the B19V viral load and maternal immune response. We did not find a correlation between the fetal or maternal B19V viral load and the severity of fetal anaemia or thrombocytopenia. Thrombocytopenia is frequently encountered in congenital B19V infection, but fetal bleeding complications are not. The use of fetal platelet transfusion is therefore a matter of debate. The long- term neurodevelopment of affected fetus can be significantly delayed at a later age despite a technically correct IUT procedure. The possibility of cerebral damage due to congenital B19V infection is discussed. Parents should be counselled of these risks before the IUT procedure and long term follow -up following congenital B19V infection is advised Show less
In public debate and academic discussions about Islam in Western society, reference is often made to the role of the imam in processes of acculturation of Muslims. Throughout these debates, we come... Show moreIn public debate and academic discussions about Islam in Western society, reference is often made to the role of the imam in processes of acculturation of Muslims. Throughout these debates, we come across the important question of how imams transmit Islamic norms and values to Muslims living in secular, non-Islamic societies. This descriptive-exploratory research considers this question specifically looking at the role of the imam in the local mosque in the Netherlands. This dissertation describes and analyses the external perspective of the views circulating in the public debate on imams between 1993 and 2004. The internal perspective has been brought into focus empirically by describing and exploring his role, authority and influence in two mosque-communities and one Islamic student association. The internal perspective further divides into the perspective of the imam and the perspective of a group practising, mostly young and highly educated Muslims who grew up in the Netherlands. The imam finds himself in a field of tension between expectations from the majority society and expectations of the believers. The indicative findings from the internal perspective have been compared with the external views. The outcome of this comparison is used to clarify the ongoing public __imam-debate__. Show less
The studies in this thesis concentrate on memory for an emotional event, with a specific focus on completeness, consistency and accuracy of emotional memories and their predictors. In doing so,... Show moreThe studies in this thesis concentrate on memory for an emotional event, with a specific focus on completeness, consistency and accuracy of emotional memories and their predictors. In doing so, both field and laboratory studies were conducted. The results show that overall, memory for emotional events is fairly complete and consistent over time. Still, the human memory is sometimes incomplete and prone to inaccuracies and inconsistencies. Maybe an elephant never forgets, people occasionally do! Emotional state, psychiatric status and psychological variables, with the exception of (peri) traumatic dissociation, did not have a strong influence on completeness, consistency and accuracy of memory for emotional events. Show less
The formation of complex organic molecules that consist of more than four atoms in space is one of the main questions in the field of astrochemistry and star formation. Although the exact formation... Show moreThe formation of complex organic molecules that consist of more than four atoms in space is one of the main questions in the field of astrochemistry and star formation. Although the exact formation mechanisms are not yet known, they are expected to form in thin ice layers on the surfaces of small interstellar dust grains through successive addition of H, C, N or O atoms to CO (carbon monoxide). In this thesis the formation of these molecules is studied in two different ways: simulation of interstellar ices analogues in the laboratory and observations of the same molecules after evaporation toward star forming regions. The laboratory experiments are high and ultra high vacuum setups in which ices of e.g. CO, CO2, HCOOH and CH3CHO are frozen out on an inert surface. The spectroscopy and the thermal behavior of pure and layered ices have been studied. Furthermore, the ices have been bombarded with H-atoms to test reactions schemes relevant for astronomical environments. In the second part of this thesis the same molecules have been observed with the single dish submillimeter telescopes the __James Clerk Maxwell Telescope__ at Hawaii and the Institut de Radioastronomie Millim_trique in Spain toward a sample star forming regions as well as with interferometer the SubMillimeter Array at Hawaii toward two sources. The relative abundances of molecules in different star forming regions measured with the single dish telescopes as well as the spatial extent of the emission detected with the interferometer has been used to determine the chemical relations between complex organics that have also been studied in the laboratory. Show less
Caecilians, or Gymnophiona, constitute one of the three extant orders of the Recent Amphibia and are the least known, major living tetrapod clade. Compared to frogs and salamanders, caecilians have... Show moreCaecilians, or Gymnophiona, constitute one of the three extant orders of the Recent Amphibia and are the least known, major living tetrapod clade. Compared to frogs and salamanders, caecilians have an unusual skull morphology. Earlier reports of an unusually high number of individual skull ossifications in Hypogeophis rostratus are addressed and found to be erroneous. Changes in skull morphology and myology at metamorphoses are investigated in representatives of all taxa possessing free-living larvae. It is argued that caecilians are derived from gymno- or zygokrotaphic ancestors and that stegokrotaphy evolved within Recent caecilians. The influence of different life-histories on postembryonic skull development was studied in two direct-developing species. The direct-developing Boulengerula taitanus is characterized by very immature hatchlings, which is correlated with an extended period of post-hatching parental care in this species, during which juveniles feed on the modified skin of their mothers. Direct development in caecilians is characterized by ontogenetic repatterning and heterochronic shifts in certain developmental events. The ontogeny of Scolecomorphus kirkii was studied as a representative of a viviparous form. The emerging picture of available published information, together with observations presented here, suggest a previously unsuspected degree of developmental diversity among caecilians. It is further argued that caecilians are lissamphibians with temnospondyl affinities rather than closely related to lepospondyl microsaurs. Show less
Growth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder,... Show moreGrowth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder, disrupting the normal growth process. The growth hormone __ IGF-I axis plays a key role in regulating this growth process. This thesis focuses on growth disorders as a result of genetic defects in the GH-IGF-I axis. The aim of the thesis is to study the genotype-fenotype relationship in patients with a documented genetic defect in one of the components of the GH-IGF-I axis and to unravel the role of the GH-IGF-I axis in the complex process of growth and development throughout life. Two patients with a mutation in the GH releasing hormone receptor gene demonstrate that combined treatment of GH and gonadotropin-releasing hormone antagonists is very effective in increasing final height. The characteristics of the first male patient with a STAT5b mutation are described in detail. The fenotype of the first patient with an inactivating mutation of the IGF-I gene is described, as well as functional characteristics of the mutation. Finally the consequences of a genetic defect of the IGF-I receptor gene are discussed. Show less
This study analyses the economical and commercial development of Holland in the late Middle Ages, focusing on the fuel market and fuel trade. Energy was of vital importance to this society in which... Show moreThis study analyses the economical and commercial development of Holland in the late Middle Ages, focusing on the fuel market and fuel trade. Energy was of vital importance to this society in which industry, trade and export were expanding rapidly. The brisk commercial and industrial development of Holland between the 13th and 16th centuries coincided with demographic growth and increasing urbanisation. Fuel markets in Holland developed in the 15th and 16th century from local to regional and inter-regional markets. Transaction costs were low, partly as a result of a fairly well-developed justice system and partly because an excellent infrastructure minimised the transport costs of these high volume products. Fuels other than peat were preferred only because of certain technological requirements or superior properties. Fuel markets in 16th century Holland were well integrated due to the import and export processes and a well-developed transport infrastructure. Municipal autonomy in Holland had led to inefficiencies in measuring systems, trade restrictions and tax advantages for certain groups. However by the 16th century many such impediments were reduced or removed. Show less
This political biography analyzes the political influence of, and methods used by, P.W.A. Cort van der Linden (1846-1935), Dutch Prime-Minister from 1913 to 1918. While he was a Professor of... Show moreThis political biography analyzes the political influence of, and methods used by, P.W.A. Cort van der Linden (1846-1935), Dutch Prime-Minister from 1913 to 1918. While he was a Professor of Economics he developed a view of liberalism based on German idealism which also included a progressive use of Social Darwinism. This view was what he called “the theory of a higher sense of justice.” The application of this theory is evident in his legislation to protect children (1901) as well as in the constitutional revision of 1917. According to Van der Linden’s views, it was ‘a political necessity’ to introduce general male suffrage. He also made the future introduction of female suffrage possible, and, in spite of criticism from Kuyper, the leader of the Calvinistic antirevolutionary party, he made possible the equal treatment of private, denominational, and state schools. The non-partisan attitude of the Prime-Minister was also important for the maintenance of neutrality in the Netherlands during the First World War. Van der Linden stayed in close contact with Germany while Foreign Secretary Loudon spoke to the French. In addition to all these efforts, the Prime-Minister had to settle disputes within his cabinet, with commander-in-chief Snijders and with Queen Wilhelmina. Show less
The current classification of the Nephtheidae (Cnidaria, Octocorallia) is still based on colony morphology. In this family the Indo-Pacific genera Litophyton, Nephthea, Dendronephthya and... Show moreThe current classification of the Nephtheidae (Cnidaria, Octocorallia) is still based on colony morphology. In this family the Indo-Pacific genera Litophyton, Nephthea, Dendronephthya and Stereonephthya, and the Atlantic genus Neospongodes form a complex mix of closely related, poorly described species, which cannot be recognized using only colony morphology. Attempts with the more modern approach of comparing skeleton composition (sclerites) resulted in describing the genus Chromonephthea Ofwegen, 2005, introduced for several species previously assigned to Dendronephthya, Nephthea and Stereonephthya. In Chromonephthea 53 species were included, 34 of which were new to science. However, the true generic status of the majority of the nominal nephtheid species remained unresolved. In an attempt to clarify the phylogenetic relationships fourteen specimens have been used in molecular analyses. Two clades were supported, which were related to the shape of the sclerites present in the polyp stalks. One clade contained the specimens with characters for Stereonephthya along with a Chromonephthea specimen as a sister group. The other clade had a __true__ Nephthea and Litophyton together with the specimens that could not be placed in any particular genus using the old classification criteria. The consequences of these results for nephtheid classification are discussed. Show less
This dissertation studies trade and transport on the rivers Rhine, Waal and IJssel during the Late Middle Ages. These rivers were the main arteries connecting Holland, Flanders and Brabant on the... Show moreThis dissertation studies trade and transport on the rivers Rhine, Waal and IJssel during the Late Middle Ages. These rivers were the main arteries connecting Holland, Flanders and Brabant on the one hand with Guelders, Cleves, J_lich and Cologne on the other hand. The study tries to establish the nature and volume of river trade at three 'measuring' periods during the 14th, 15th and 16th centuries. It seeks to explain both short-term fluctuations and long-term changes in the river trade during those centuries. Short-term fluctuations were often the result of warfare or meteorological conditions and did not alter river trade structurally. Long-term changes were induced by large-scale economic developments within North-Western Europe, such as the rise of Antwerp and that of Holland and Zeeland. Merchants and skippers from territories along the rivers, such as Guelders, Oversticht and Cleves, who had found a place within the Hanseatic League from the early 14th century onwards, could not compete with their Holland neighbours. Instead they focussed on a role as full time skippers or tried to find a specialisation or niche on the large markets of Holland, Zeeland and Brabant, selling Rhine wine or lumber from the German hinterland. Show less
Synthetic peptide vaccines aiming at the induction of a protective CD8+ T-cell response against infectious or malignant diseases are widely used in the clinic but, despite their success in animal... Show moreSynthetic peptide vaccines aiming at the induction of a protective CD8+ T-cell response against infectious or malignant diseases are widely used in the clinic but, despite their success in animal models, they do not yet live up to their promise in humans. This thesis assesses the development of synthetic peptide vaccines, weighs it against the immunological concepts that have emerged, and identifies the key issues that play a role in the failure or success of a synthetic peptide vaccine. The current state-of-the-art peptide vaccine is a complete synthetic inflammatory product that is ingested by professional antigen-presenting cells and stimulates both CD4+ and CD8+ T cells. Show less
In the present thesis, a homogeneous upper middle class sample of firstborn girls and their mothers were followed from infancy (18 and 24 months) to middle childhood (89 months) using... Show moreIn the present thesis, a homogeneous upper middle class sample of firstborn girls and their mothers were followed from infancy (18 and 24 months) to middle childhood (89 months) using questionnaires and observations. The focus of the study was on three components of moral behavior, i.e. empathy, compliance and prosocial behavoir. The longitudinal development and stability of empathy and compliance from infancy to middle childhood was described, and their relation to prosocial behavior in middle childhood. Empathic concern towards mother increased from 18 to 24 months, but strongly decreased from 24 to 89 months. Empathic concern toward an unfamiliar person decreased from 18 to 89 months. Compliance increased from 18 to 89 months. Only empathy towards mother seems to be fertile ground for donating to charitable organizations like UNICEF. Also, the role of antecedent and concurrent sensitivity and attachment security in prosocial, externalizing, and internalizing behavior in middle childhood was investigated. Results showed that, controlling for concurrent influences, maternal sensitivity and attachment security in infancy predicted prosocial and externalizing behavior Show less
Sunlight has many beneficial effects. However, from a biological point of view, solar UV radiation has also detrimental effects, especially at high doses of exposure. Because of its genotoxic... Show moreSunlight has many beneficial effects. However, from a biological point of view, solar UV radiation has also detrimental effects, especially at high doses of exposure. Because of its genotoxic properties, UV radiation plays an important role in the induction of skin cancer. In the last decennia, the incidence of skin cancer is rapidly increasing. This can partly be explained by an ageing population. However, the rise in skin cancer incidence appears to be primarily due to a change in human lifestyle in which sunbathing has become very popular. Our skin is continuously challenged by UV radiation, which may lead to irreversible damage. In order to withstand sustained physical, chemical and biological damage from the environment, among which UV radiation, the skin is continuously renewed. The regenerative capacity of skin is conferred by stem cells, which persist throughout the organism__s lifetime. Because of their long residency and unlimited capacity to replicate, stem cells might accumulate DNA damage and generate the multiple genetic lesions necessary for tumour development, despite efficient cellular defence mechanisms against DNA damage. Thus, stem cells may play an important role in carcinogenesis. The aim of this study is to investigate the role of stem cells in skin carcinogenesis. Show less
This study analyses the relations between Siam and the League of Nations from 1920 to 1940. It identifies Siam’s policy towards the League as a cornerstone of Siam’s foreign policy and an important... Show moreThis study analyses the relations between Siam and the League of Nations from 1920 to 1940. It identifies Siam’s policy towards the League as a cornerstone of Siam’s foreign policy and an important element of Siam’s domestic modernization during the sixth, seventh and eighth reigns of the Chakri dynasty. In doing so, the study aims at adding a key multilateral dimension to the existing historical analysis of Thai foreign relations during the first half of the twentieth century. It argues that Siam’s League membership played an important role in modernizing the country, reaffirming elite rule and regaining full sovereignty. This study concentrates on the inter-war years and traces Siam’s League membership in the most significant areas of interaction among the wide range of multilateral policy fields. It draws on extensive primary sources which have so far not been studied; the bulk of these files are located at the Thai National Archives in Bangkok and at the League of Nations Archives at the United Nations European Headquarters in Geneva. Show less
The thesis is focused on the DNA-cleaving antibiotic bleomycin that is successfully used in the chemotherapy against several types of cancer like head and neck cancer or certain lymphomas and... Show moreThe thesis is focused on the DNA-cleaving antibiotic bleomycin that is successfully used in the chemotherapy against several types of cancer like head and neck cancer or certain lymphomas and testicular cancer. Although it has been in use for more than two decades, the mechanism of its action is not known. Thus the harmful side effects are difficult to eliminate. On the other hand the process of design or improvement of pharmaceuticals is extremely complex and expensive. Therefore a new trend within drug discovery is emerging with the application of clean chemistry, by performing molecular modeling of new compounds and by running virtual tests to assess their suitability before an expensive synthesis attempt is made. In the thesis, the contribution of different computational methods into this field is discussed, emphasizing the growing role played by quantum mechanical methods. Using state-of-the-art methods, an insight into the mechanism of bleomycin action was gained. The possible reaction pathways of the active bleomycin-Fe(III)-OOH complex with the deoxyribose sugar of DNA were investigated. The simulations show that a facile decaying process involves a homolytic O-O bond cleavage with an almost simultaneous hydrogen atom abstraction. The formation of a hydrogen bond appears to be crucial for the O-O bond cleavage in the Fe(III)-OOH species. The highly selective reaction between the bleomycin drug and the genetic material comes from the selectivity of the created hydrogen bond Show less
Sunwar is a Tibeto-Burman language spoken in eastern Nepal, in the districts of Okhaldhūgā and Rāmechāp, which are situated in an area called Kirant. The languages spoken in this region, also known... Show moreSunwar is a Tibeto-Burman language spoken in eastern Nepal, in the districts of Okhaldhūgā and Rāmechāp, which are situated in an area called Kirant. The languages spoken in this region, also known as Kiranti languages. The language commonly known as Sunwar in English and as Sunuvār in Nepali, is called Koĩc by its native speakers. This description of the Sunwar language is based on data collected during twelve months of field work and contains a chapter with background information on the Sunwar language, its speakers and their culture, followed by chapters on the phonology, the indigenous writing system and the nominal and verbal morphology of Sunwar. Final chapters contain verb paradigms, glossed texts, a Sunwar-English glossary and bibliographical references. Two of the new discoveries depicted in this grammar pertain to the phonology and to the verbal morphology. Sunwar has no implosives anymore, but the language once had at least one implosive // as can be shown by a comparison of phonetic realisa¬tions of the former implosive // in different dialects. At an earlier stage, Sunwar had a biactantial agreement system typical for Kiranti languages. A comparison of the suffix conjugations of modern Sunwar with the older biactantial agreement system shows a regular relationship between the two systems. Show less
Interaction patterns between plants and flower visitors in a Mediterranean flower visitation web can be explained surprisingly well by the combination of two simple mechanisms. Firstly, the size... Show moreInteraction patterns between plants and flower visitors in a Mediterranean flower visitation web can be explained surprisingly well by the combination of two simple mechanisms. Firstly, the size threshold that the nectar tube depth of flowers puts on the tongue length of potential flower visitors; and secondly, random interactions proportional to the frequency of tube depths and tongue lengths in the local species pool. Simulation models revealed that the combination of these factors can reproduce the observed variation in the number of interaction partners, the observed asymmetry of plant - flower visitor interactions, and the degree of morphological matching between tube depth and proboscis length. The study shows also that the frequency distributions of tongue lengths and tube depths have a profound influence on the interaction patterns. The shapes of the observed trait distributions resemble ubiquitous lognormal body size distributions. Knowledge about the structure of flower visitation webs and the underlying causes is essential for understanding the evolution of plants and their pollinators. It also provides an important tool for biodiversity conservation. Show less
