Nature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes... Show moreNature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes them more stable against degradation as compared to other natural materials such as oligonucleotides. Peptides adopt a secondary structure which is determined by their amino acid sequence resulting in a structure with a specific fold like a beta sheet, a helix or a random coil conformation.These secondary structures can govern the supra-molecular structure of the macromolecule to achieve specific function. Peptides can be short, such as dipeptides or as long as a small protein, which are able to selfassemble into a designed nanostructure and thus providing a wide choice of biomaterials for a chemical biologist. In last decade, peptides have been shown to have great versatility and inherent high affinity for their target to carry out various functions which is the scope of this thesis presented here. Show less
The studies performed in this thesis show that type 1 diabetes mellitus is characterized not only by insulin deficiency, but also by insulin resistance. Both hepatic and peripheral insulin... Show moreThe studies performed in this thesis show that type 1 diabetes mellitus is characterized not only by insulin deficiency, but also by insulin resistance. Both hepatic and peripheral insulin sensitivity were decreased in patients with type 1 diabetes mellitus, as well as inhibition of lipolysis. However, insulin resistance is not a fixed pathophysiological condition in type 1 diabetes. We demonstrated that a single night of partial sleep deprivation decreased insulin sensitivity by 14-20% in patients with type 1 diabetes and by 20-25% in healthy controls. These effects of partial sleep restriction could not be explained by a reduction of total slow wave sleep in patients with type 1 diabetes. Sleep duration is a determinant of insulin sensitivity, also in patients with diabetes. In addition, various aspects of diabetes could be linked to increased prevalence of sleep disturbances. Impaired sleep and type 1 diabetes might potentiate each other in some patients, thereby creating a negative vicious circle. Optimizing sleep duration and sleep quality could therefore be considered as a potential therapeutic target to improve metabolic control in patients with type 1 diabetes. Show less
Dit proefschrift onderzoekt de invloed van pro-inflammatoire cytokinen op de gevoeligheid van de mens voor mycobacteri_le infecties. Infecties met niet-tuberculeuze mycobacteri_n (NTM) komen zelden... Show moreDit proefschrift onderzoekt de invloed van pro-inflammatoire cytokinen op de gevoeligheid van de mens voor mycobacteri_le infecties. Infecties met niet-tuberculeuze mycobacteri_n (NTM) komen zelden voor. Omdat NTM sommige mensen ernstig en ook bij herhaling ziek maken, hebben wetenschappers zich lang afgevraagd of genetische afwijkingen daarbij een rol spelen. In de laatste vijftien jaar is dit vermoeden bevestigd. Wereldwijd zijn ruim 360 pati_nten met Mendelian Susceptibility to Mycobacterial Disease (MSMD) bekend. In dit proefschrift wordt NEMO defici_ntie voor het eerst aangemerkt als MSMD. Vervolgens legden wij het verband tussen het v__rkomen van mycobacteri_le infecties in jonge kinderen en variaties in IFNG en IL10. Ook onderzochten wij Cryopyrin Associated Periodic Syndrome (CAPS) waarbij een te hoge cytokine productie tot ontsteking leidt. Deze pati_nten bleken hun cytokine productie onvoldoende te kunnen verhogen na activatie van hun cellen. Dit bleek onafhankelijk van de IL-1_ antagonist Anakinra, een zeer effectief medicijn tegen deze ziekte, en daarom van IL-1_. Een zich steeds verder ontwikkelende medische wetenschap en toenemende hygi_ne zorgen ervoor dat immuundefici_nties slechts in gematigde vorm tot uiting komen. Tegelijkertijd blijven de meest ernstig zieke pati_nten nu veelal wel in leven. Deze pati_nten zijn een belangrijke bron van informatie over de werking van ons immuunsysteem. Show less
In my dissertation I dig into the constituent elements of River Plate tango in order to decode how specific musical materials were organized and combined by four outstanding musicians: Osvaldo... Show moreIn my dissertation I dig into the constituent elements of River Plate tango in order to decode how specific musical materials were organized and combined by four outstanding musicians: Osvaldo Pugliese, Horacio Salgán, Astor Piazzolla and Gustavo Beytelmann. For this purpose, I have analysed a select number of representative pieces through a study of their scores and recordings. This led to the definition of certain artistic processes and innovations within the genre, theoretical foundations for such processes, and, in all, a deeper understanding of the art of creating tango music, in addition to an overall, chronological view of its development and techniques. The articulation of this (partly) embodied knowledge has resulted in an original contribution to the field, providing new insights with which both I and the greater artistic community can enrich our skills in arranging, composing and performing tango music. The formulation of hypothesis and conclusions, and the translation of the findings into my own production through empiric methods and experimentation were executed alongside the analytical part of the work. The continuous exchange between the practical and theoretical aspects of this research project was fundamental, always strengthening and feeding back each other. Show less
Glycosidases are a large, evolutionary conserved enzyme family that catalyze the hydrolysis of glycosidic linkages of glycopolymers. These enzymes are involved in many (patho)physiological... Show moreGlycosidases are a large, evolutionary conserved enzyme family that catalyze the hydrolysis of glycosidic linkages of glycopolymers. These enzymes are involved in many (patho)physiological processes and they are applied in the glycopolymer assembly and biotechnological industry. The research described in this Thesis aims to develop inhibitors (mechanism-based and competitive) and activity-based probes for glycosidases using the naturally occurring molecule cyclophellitol as template. Different cyclophellitol derivatives have been synthesized and they could be used to study the role of glycosidases in different (patho)physiological and biotechnological processes. Show less
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is primarily characterized by the formation of thousands of kidney cysts, is caused by mutations in the PKD1 or PKD2 gene, and affects 0.1% of... Show moreAutosomal Dominant Polycystic Kidney Disease (ADPKD) is primarily characterized by the formation of thousands of kidney cysts, is caused by mutations in the PKD1 or PKD2 gene, and affects 0.1% of the population. However, also cyst formation in liver and pancreas can occur and there is a higher chance of developing aneurisms. No safe and effective therapy exists to treat ADPKD patients. In this thesis we generated a conditional Pkd1 knock-out mouse model in which we specifically can follow the disease progression in the kidney in more detail. This led to a further characterization of the mechanism behind cyst formation. In addition we report two different therapeutic strategies that effectively inhibited cyst formation in mice. The results in this thesis therefore have led to an improved understanding of cyst formation and to an improved understanding in how to inhibit this process, which ultimately might contribute to finding a clinically relevant therapy for patients. Show less
Het doel van dit proefschrift was om onderzoek te verrichten naar (het voorkomen van) plotse hartdood bij dialysepati_nten. Een groot deel van deze promotie is opgebouwd rondom de Implantable... Show moreHet doel van dit proefschrift was om onderzoek te verrichten naar (het voorkomen van) plotse hartdood bij dialysepati_nten. Een groot deel van deze promotie is opgebouwd rondom de Implantable Cardioverter Defibrillators in Dialysis patients (ICD2) studie. Dit studieprotocol werd opgezet om onderzoek te doen naar de mogelijke voordelen van profylactische implantatie van ICD__s bij dialysepati_nten. Verschillende aspecten van plotse dood bij deze pati_ntenpopulatie werden geanalyseerd. Verder werd onderzoek verricht naar de incidentie en behandeling van complicaties van deze therapie, met daarbij in het bijzonder aandacht voor pati_nten met nierfalen. Op basis van dit proefschrift kan gesteld worden dat er verscheidene onderzoeksmiddelen zijn, zoals bijvoorbeeld het electrocardiogram, waarmee pati_nten met een verhoogd risico op (plots) overlijden ge_dentificeerd kunnen worden. In de toekomst zal onderzocht kunnen worden of er behandelstrategie_n zijn die voor deze pati_nten een overlevingsvoordeel kunnen bieden. De rol van profylactische ICD implantatie bij dialysepati_nten, wordt momenteel nog onderzocht in de ICD2 studie. Hoewel ICD__s mogelijk in pati_nten met nierfalen een overlevingsvoordeel zouden kunnen bieden, moet wel in het achterhoofd gehouden worden dat er een belangrijke incidentie van complicaties is en dat mogelijk, met name, pati_nten met nierfalen potentieel levensbedreigende complicaties kunnen ervaren Show less
Duchenne spierdystrofie (Duchenne MD) en Becker spierdystrofie (Becker MD) zijn progressieve spierziekten die beide veroorzaakt worden door een genetische afwijking op het X-chromosoom. Omdat het... Show moreDuchenne spierdystrofie (Duchenne MD) en Becker spierdystrofie (Becker MD) zijn progressieve spierziekten die beide veroorzaakt worden door een genetische afwijking op het X-chromosoom. Omdat het eiwit dystrofine ontbreekt in de spieren hebben jongens met Duchenne MD vanaf de kleuterleeftijd progressief spierzwakte en worden zij rolstoelafhankelijk. Pati_nten met Becker MD hebben een milder beloop omdat zij in de spieren wel een afwijkend, partieel functionerend, eiwit kunnen maken waardoor het klinisch beloop milder is en de debuutleeftijd later. Het proefschrift focust op heterogene klinische kenmerken. Het IQ en de leerprestaties kunnen sterk verschillen tussen jongens met Duchenne MD. Met MRI onderzoek van de hersenen hebben wij gevonden dat het volume van de hersenen en van de grijze stof bij jongens met Duchenne MD kleiner is ten opzichte van controles. Dit komt het duidelijkst naar voren in een subgroep van pati_nten met een bepaalde lokalisatie van de genetische mutatie. Bij pati_nten met Becker MD kan juist het klachtenpatroon vari_ren tussen pati_nten van zeer mild tot ernstige spierzwakte. Deze heterogeniteit kan het diagnosticeren van de ziekte bemoeilijken. Bij complexe pati_nten met (een verdenking op) een erfelijke spierdystrofie is het essentieel dat de clinicus overlegt met de moleculair geneticus over de mogelijke diagnostische testen Show less
Breast cancer is the most frequently diagnosed type of cancer among women, both in developed and developing regions. The majority of patients is postmenopausal at diagnosis and has hormone... Show moreBreast cancer is the most frequently diagnosed type of cancer among women, both in developed and developing regions. The majority of patients is postmenopausal at diagnosis and has hormone sensitive tumours, implying that patients may benefit from endocrine therapy, both in curative and in metastatic setting. In the last twenty-five years, the treatment of patients with hormone-sensitive early breast cancer has largely changed as more treatment options became available, while over the last decade more tailored treatment was aimed at. This has resulted in an improved prognosis.2-4 Nevertheless, part of breast cancer patients will develop recurrent disease, especially late recurrences can occur in hormone sensitive disease while the various therapies may be associated with side effects which can affect quality of life. The research described in this thesis was designed to gain further insight in optimal treatment of early breast cancer patients, especially in postmenopausal women with hormone sensitive tumours. Show less
Does society need armed forces? If so, what form should they take and what position should they hold in a democratic society? Critical conscripts, conscientious objectors, professional soldiers,... Show moreDoes society need armed forces? If so, what form should they take and what position should they hold in a democratic society? Critical conscripts, conscientious objectors, professional soldiers, civilians and antimilitarists posed these questions during the Cold War. This study investigates their criticism of and protest against the armed forces and national security and defense policy in the Netherlands between 1945 and 1989. It first examines how and why the critics of the armed forces questioned its form and existence. Secondly, this study looks into the Ministry of Defense's reaction to these critics. It explores how the ministry interpreted and responded to criticism and protest. The main question of this study is to what extent did the ministry believe that the criticism undermined the armed forces' legitimacy? Show less
In this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic... Show moreIn this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic surgical procedure Roux-en-Y gastric bypass. Moreover, we found differences between NGT and T2DM subjects at baseline, which enable us to better be able to dissect the subsequent effects of the procedures. To our surprise, and in contrast to previous studies, we observed no additional effect of the RYGB as compared to calorie restriction, on our main outcome parameters: postprandial glucose, insulin and the gut peptide levels three weeks after surgery. Furthermore, both restrictive and RYGB induced weight loss resulted in comparable effects on the lipidome, circulating thyroid hormone levels and the autonomic nervous system. For these outcome parameters, it seems that calorie restriction is the common denominator of the effect of the different weight loss strategies on the short term. Clearly distinct effects of RYGB, however, were seen on bile salt, FGF21 and glucagon levels in response to food intake. Although neither the exact mechanisms, nor the eventual metabolic effect are as yet clear, the gut-liver-pancreas axis may be an important mediator of the effect of the RYGB Show less
This thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In... Show moreThis thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In the first part, we describe evidence for enhanced glucose metabolism in long-lived families. Middle-aged individuals predisposed to longevity were characterized by enhande insulin action at the level of the skeletal muscle, lower accumulation of intramyocellular lipids and lower nocturnal glucose levels. These results have provided the biological basis upon which health-promoting intervention in older age may be funded. In the second part, we have shonw that an internet-based intervention is effective at increasing physical activity and improving health in an older population. Furthermore, increasing total daily physical activity in sedentary elderly was shown to lead to better metabolic health. Show less
The subject of this thesis is the study of the function and behavior of CD8+ T cells that have exited the circulation and entered a tissue in order to get rid of an infection. In particular, the... Show moreThe subject of this thesis is the study of the function and behavior of CD8+ T cells that have exited the circulation and entered a tissue in order to get rid of an infection. In particular, the research focus on 1- how effector CD8+ T cells can localize infected cells within a tissue. 2-how, once the infection has been cleared, effector CD8+ T cells become memory T cells that take up permanent residence in the tissue; also, how the patrolling behavior that these cells acquire in the tissue allows quick control of local secondary infections. 3-how tissue-resident memory CD8+ T cells that have re-encountered a specific antigen can induce an increased level of local immune protection against infections. Show less
Newborn infants requiring intensive care treatment are at risk of cerebellar injury. This can have important consequences for long-term neurodevelopmental outcome. The aim of this thesis was to... Show moreNewborn infants requiring intensive care treatment are at risk of cerebellar injury. This can have important consequences for long-term neurodevelopmental outcome. The aim of this thesis was to study the incidence and characteristics of cerebellar injury, and to investigate the role of different neuroimaging techniques (cranial ultrasound (CUS) with additional mastoid fontanelle (MF) views and MRI) for its detection in both preterm and high-risk term infants. Part I describes the standard CUS procedure and supplementary imaging techniques to optimize its performance, including the use of additional acoustic windows. Part II focuses on the detection, risk factors and prognostic implications of cerebellar injury in preterm infants. Part III focuses on CUS and MRI findings of posterior fossa abnormalities in full-term infants with various neonatal disorders. Part VI reviews the main findings and conclusions of this thesis, and discusses future perspectives and proposals for further research. Based on the findings of this thesis, we conclude that in both preterm and critically ill full-term infants CUS protocols should include MF views. This enables early detection of most major and clinically relevant posterior fossa abnormalities. Routine MRI for the detection of small hemorrhagic lesions is not warranted, as these lesions have a favorable prognosis Show less
The analysis of the relationship between legitimacy and reform is complex. This is because 'political reform' consists of an array of institutional reforms.The general question guiding this project... Show moreThe analysis of the relationship between legitimacy and reform is complex. This is because 'political reform' consists of an array of institutional reforms.The general question guiding this project is whether the introduction of reform helps boost the legitimacy of the democratic system: does the impact of reform on legitimacy vary with the type of reform, or with the process of reform. To answer these questions, this study also seeks to establish how many reforms have taken place, what types of reform have been introduced and under what circumstances these reforms occur. Show less
Mapping Moving Media is an inquiry into the specificity of film and video. In this study, I argue that mapping the specificity of these two media is indispensable in analyzing and understanding... Show moreMapping Moving Media is an inquiry into the specificity of film and video. In this study, I argue that mapping the specificity of these two media is indispensable in analyzing and understanding contemporary intermedial objects in which film and video are mixed or combined. Our understanding of the meanings and effects of moving images in contemporary society will increase when combinations of film- and video elements within moving image objects are taken into account. Contemporary (new) media theory offers a wide range of terms by which interrelations between media can be defined and conceptualized. However, although I take the wide variety of notions such as remediation and hypermediacy as helpful tools in analyzing the relationships between media, I argue that the starting point of an investigation into intermedial interactions should be the concept of medium specificity instead of the many notions which define forms of intermediality. This does not mean that we should return to some of essentialist ideas on medium specificity which have been attached to the concept. However, the rightful conclusion that essentialist ideas on medium specificity are rendered untenable by today’s mixed, multi-, and intermedia, too often overshadows the question of what is being mixed, expanded, remediated, refashioned, converged or combined. In this study I ask the questions “what is meant by video?” and “what is meant by film?” How are these two media (to be) understood? Can film and video be defined as distinct, specific media, and if so, how? I hold that in this era of mixed moving media, it is vital to ask these questions precisely and especially on the media of video and film. Show less
Pain management in the ICU can be difficult due to lack of patient self report. This thesis describes pain management, including procedural pain in patients in the ICU after cardiac surgery.... Show morePain management in the ICU can be difficult due to lack of patient self report. This thesis describes pain management, including procedural pain in patients in the ICU after cardiac surgery. Chronic pain one year after cardiac surgery is also evaluated and risk factors for the development of chronic pain are identified. Recommendations for the management of acute and procedural pain in patients in the ICU and for the follow-up of chronic pain after cardiac surgery are provided. Show less
This thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of... Show moreThis thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of circulating adiponectin can predict radiographic progression in patients with early RA. In contrast, in patients with hand OA, this association appears protective. Therefore, to obtain insight into the mechanisms underlying these associations, we investigated the high-molecular-weight isoform of adiponectin (hmwAPN), which is one of the most biologically active isoforms of adiponectin. We show that the associations of total adiponectin with radiographic progression are not mediated by hmwAPN, in either RA or HOA. In the second part, we present the immunological characterization of the infrapatellar fat pad (IFP), a joint associated adipose tissue, in patients with advanced knee OA. We observed profound differences in secreted inflammatory factors and immune cell composition between the IFP and paired subcutaneous adipose tissue samples. Interestingly, we observed obesity-related changes in the IFP phenotype, and in macrophages and adipocytes, Therefore, we investigated the modulatory effects of adipocytes on the phenotype of human macrophages in vitro and we observed that adipocyte-derived lipids can mediate the obesity-related changes in the phenotype of adipose tissue macrophages in humans Show less
The analysis of the complex role of the inhibiting receptor for the Fc part of IgG, Fc__RIIb, was performed in various autoimmune diseases in murine models: Systemic Lupus Erythematosus (SLE),... Show moreThe analysis of the complex role of the inhibiting receptor for the Fc part of IgG, Fc__RIIb, was performed in various autoimmune diseases in murine models: Systemic Lupus Erythematosus (SLE), Goodpasture__s Syndrome (GPS), and arthritis.The crucial question is whether FcgRIIb plays a role in the maintenance of immunological tolerance. The important role of Fc__RIIb in the negative regulation of activating Fc receptors on myeloid effector cells and in a negative feedback mechanism in B cells, regulating antibody production, was confirmed by the immune hyperactive phenotype of Fc__RIIB KO mice. We demonstrate that Fc__RIIB-/- mice generated by gene targeting in B6-derived ES cells (Fc__RIIBB6 -/-), lacking the 129 derived flanking Sle16 region, exhibit a hyperactive phenotype, but fail to develop lupus. This fact indicates that in Fc__RIIB129 -/- mice, not the deficiency of Fc__RIIB, but the presence of the 129-derived fc__r2b flanking region, causes loss of tolerance. The contribution to the autoimmune-disease development by the resulting auto-reactive B cells is magnified by the Fc__RIIB absence, culminating in lethal lupus. We confirmed that Fc__RIIb deficiency renders B6 mice susceptible to CIA. Fc_RIIb on myeloid cells, but not B cells, manifests a dominant role in the predisposition to CIA. Regarding the role of Fc__R2b in autoimmune disease, all observations along the different autoimmune disease models (NTN, GPS, SLE, CIA) indicate towards the same direction: Fc__R2b possesses a minor function, if any, in the maintenance of the immunological tolerance. Show less
Legal actors typically decide case by case and rely on their own knowledge and experience to make legal decisions. However, an overview of what is happening in the legal system as a whole is... Show moreLegal actors typically decide case by case and rely on their own knowledge and experience to make legal decisions. However, an overview of what is happening in the legal system as a whole is often lacking. While many sentences are imposed by legal actors, much remains unknown about the determinants and consequences of sentencing at the aggregate level. How can legal actors impose deliberate and effective sentences? The Dutch Penal Code and the Code of Criminal Procedure obviously give some guidance, but also leave judges with high levels of discretion. This study zooms in on offender characteristics as determinants of sentencing decisions and addresses questions about the consequences of certain sentences on criminal behavior with a specific focus on the incapacitation effect and recidivism after specific sanctions. By focusing on the determinants of decisions at different points in the sentencing process, and on the effects of sentences, this study creates a better understanding of the different facets of the criminal justice system. This study reveals offender based disparities in contemporary sentencing practices and points out that certain intended future benefits in terms of crime reduction through punishment do not appear to be achieved. Show less
