Molecular imaging plays a vital role in current medical diagnostics. There is a constant need for new and improved molecular imaging agents in terms of resolution, specificity, stability, safety... Show moreMolecular imaging plays a vital role in current medical diagnostics. There is a constant need for new and improved molecular imaging agents in terms of resolution, specificity, stability, safety and cost. The research described in this thesis deals with the development of activatable luminescence lifetime imaging agents as well as with the use of supramolecular chemistry to introduce cell surface modifications to living cells. Show less
BAV morphology and especially the presence and extent of a raphe is of clinical importance, as a complete raphe predisposes to more valvular dysfunction and aortopathy. Regarding variations in... Show moreBAV morphology and especially the presence and extent of a raphe is of clinical importance, as a complete raphe predisposes to more valvular dysfunction and aortopathy. Regarding variations in coronary anatomy, it turns out that patients with left-right BAVs without raphe and patients with BAV and CoA more often have a left dominant coronary artery system. Patients with left-right BAVs without raphe also seem more at risk of developing significant coronary artery disease. In addition, separate ostia of the LAD and LCX are more common in these patients. Patients with Turner syndrome and BAV do not show significant differences in coronary dominance as compared to patients with Turner syndrome with TAV and to patients with isolated BAV. However, patients with TS and BAV show more separate ostia of the LAD and LCX as compared to patients with isolated BAV. In BAV with associated complex congenital heart disease, a high take-off of the coronary arteries, occurred more frequently than reported in structurally normal hearts and in hearts with isolated BAV. Finally, there should be awareness of possible bilateral semilunar valvular disease, which is associated with strictly bicuspid BAVs and in many cases related to chromosomal abnormalities. Show less
Kidney transplantation is the preferred treatment of patients with end stage renal disease, as it provides longer patient survival and better quality of life compared to dialysis. Prediction of... Show moreKidney transplantation is the preferred treatment of patients with end stage renal disease, as it provides longer patient survival and better quality of life compared to dialysis. Prediction of DGF, response to steroid resistant rejection and long-term graft outcome remain difficult when using merely clinical parameters. Numerous studies have reported on the predictive value of molecular markers for AR and worse graft outcome. However, the heterogeneity of AR and the variation among transplant centers leads to controversial results and preclude a more general clinical application. In the first part of this thesis, we aimed to investigate the molecular markers of steroid resistance and long-term graft survival on the basis of acute rejection biopsies. In the second part, we focused on genetic variants associated with acute rejection in kidney transplantation. In the final part we described the possible immune regulatory effect of S100 calcium binding proteins. Show less
Is de geboden cardiologische zorg `sufficiently safe' ? Dit proefschrift richtte zich op de vraag hoe je kwaliteit van zorg kan meten om te kijken of de geboden zorg voor de behandeling van acuut... Show moreIs de geboden cardiologische zorg `sufficiently safe' ? Dit proefschrift richtte zich op de vraag hoe je kwaliteit van zorg kan meten om te kijken of de geboden zorg voor de behandeling van acuut coronair syndroom sufficiently safe is en deed dit middels twee methoden: lokaal dossieronderzoek ten aanzien van patiëntveiligheid (Deel 1) en nationaal declaratie data-registratie voor kwaliteit-van-zorg onderzoek (Deel 2). Waar declaratiedata in detail moet inleveren, levert dossieronderzoek in op de efficiëntie. De twee verschillende methodes vullen elkaar aan en dienen een verschillend doel: veiligheid en kwaliteit van zorg. De geboden zorg lijkt veilig, maar toch ervaart 13% zorggerelateerde schade bij de behandeling van een acuut coronair syndroom. Welk onderzoek is hiervoor nodig? Dossieronderzoek is zeer arbeidsintensief, zelfs een onderzoek binnen het heldere MISSION!-protocol leidt nog tot heterogene antwoorden op causale relaties van zorggerelateerde schade. Real-time monitoring van afwijkende processen met reeds geregistreerde data biedt meer inzicht in zorggerelateerde schade. De geboden zorg lijkt volgens de richtlijnen te gaan, maar toch krijgt slechts 49% zijn preventieve medicatie. Ook hier is ruimte voor verbetering. Toekomstige analyses met declaratiedata, gecombineerd met klinische data en andere databronnen, kan meer inzicht geven om zo de kwaliteit van zorg continu te blijven verbeteren. Show less
Quality and safety improvement is a relatively novel discipline in healthcare practice and research that solidified in the early 21st century. Since then, various systems have been installed to... Show moreQuality and safety improvement is a relatively novel discipline in healthcare practice and research that solidified in the early 21st century. Since then, various systems have been installed to collect information on various types of adverse outcomes, such as adverse events, incidents and patient complaints. Data from these systems can be used to evaluate care delivered to individual cases as well as to study aggregated data for patterns, trends and other insights. More research is warranted to assess whether these systems actually meet the objective of continuous, systemwide learning and improvement. It was expected that existing practices could benefit from individual optimization as well as better integration, because most of this intelligence is currently stored and used in isolation. The research in this PhD thesis focused on how we can learn most effectively from various types of adverse outcomes in healthcare, in order to continuously improve the care delivered to patients. Specific research questions included how we can learn from: i) case discussions at morbidity and mortality conferences ; ii) integrating available information sources (e.g., incidents, patient experiences); iii) the context of everyday practice that produces both adverse and desired outcomes. Show less
HPV has evolved mechanisms to resist immune attack. I showed that HPV impaired necroptosis induced by IFNγ and TNFα by down-regulation of RIPK3 expression. Methyltransferase inhibitor DZNeP... Show moreHPV has evolved mechanisms to resist immune attack. I showed that HPV impaired necroptosis induced by IFNγ and TNFα by down-regulation of RIPK3 expression. Methyltransferase inhibitor DZNeP restored the expression of RIPK3 in HPV+ keratinocytes, and increased the necroptosis in HPV+ keratinocytes. Simultaneously, hrHPV effectively inhibited IFNγ/TNFα-mediated arrest of cell growth by down-regulating IFITM1. Then I studied HPV associated oropharyngeal squamous cell cancer (OPSCC). The OPSCC infiltrating HPV specific CD4+ Tcells produce cytokines such as IFNγ and TNFα. I found that HPV16-positive tumor cells lacked expression of RIPK3, which were not sensitive to the necroptosis induced by IFNγ /TNFα. I also showed that a combination of IFNγ and TNFα with cisplatin synergized in killing tumor cells. Last but not least I showed that combination of the clinically applied EGFR inhibitor Cetuximab and IFNγ/TNFα increased gene expression of multiple cytokines, including CXCL9, CXCL10 and CCL5, which may attract more lymphocytes to the tumor site. By using the inhibitors of the targets downstream of EGFR, I found that JNK and MEK1 played major role in mediating the suppression of CCL5, CXCL9 and CXCL10 expression. Show less
The effect of donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation is difficult to determine and currently unknown. The thesis describes different statistical methods the... Show moreThe effect of donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation is difficult to determine and currently unknown. The thesis describes different statistical methods the determine the effect of DLI after T-cell depleted allogeneic stem cell transplantation for ALL, AML, MDS, relapse AML and multiple myeloma. The effect on bone marrow disease appears strong as compared to extramudullary disease. Show less
The aim of this dissertation is to explore what adaptations are needed to improve the fit of a parenting intervention for use in multi-ethnic disadvantaged neighborhoods. A bottom-up approach is... Show moreThe aim of this dissertation is to explore what adaptations are needed to improve the fit of a parenting intervention for use in multi-ethnic disadvantaged neighborhoods. A bottom-up approach is used to assess parents’ perspectives regarding their parenting experiences, and to identify their needs and stressors. Data is collected among parents with an ethnic minority and low socioeconomic status background. Each chapter is a part of a stepwise approach that led to the selection of an intervention, and its adaptation for and evaluation in a multi-ethnic disadvantaged neighbourhood. It was found that a focus on coping strategies to handle stress and unhelpful emotions is not a standard theme in parenting interventions, while this would be beneficial for ethnic minority and low SES parents. The intervention module ‘Coping with stress and unhelpful emotions’ was developed to be incorporated into an existing parenting intervention to assist parents in handling their emotions and decreasing the impact of stress, and simultaneously regulating their parenting behavior. An evaluation study showed the relevance of this in-built module for parents living in multi-ethnic disadvantaged neighborhoods and also yielded recommendations to further improve the module. Show less
The striatum plays a central role in the limbic system and the cholinergic system, which are both affected in AD. Therefore the striatum can be considered a key candidate structure to be affected... Show moreThe striatum plays a central role in the limbic system and the cholinergic system, which are both affected in AD. Therefore the striatum can be considered a key candidate structure to be affected early in the disease. Part one of this thesis bundled the results of several volumetric and morphometric structural MRI studies of the striatum in older people and especially in patients with AD. Identifying pathological (focal) brain atrophy is, however, complex and a simple estimation of brain structure volumes of an individual patient does not lead to a diagnosis but needs to be assessed relative to group volumes and premorbid brain size. Therefore, in part two of this thesis two large population studies were included that focused on improving our understanding of the physiologic variability of brain structure and degeneration. Show less
This thesis focus on the quality assurance in the surgical treatment of gastric cancer. This has been investigated using data of the CRITICS trial. In this randomized clinical patients underwent... Show moreThis thesis focus on the quality assurance in the surgical treatment of gastric cancer. This has been investigated using data of the CRITICS trial. In this randomized clinical patients underwent preoperative chemotherapy, followed by surgery, followed by adjuvant chemotherapy or chemoradiotherapy. Surgical quality in the CRITICS trial was investigated and was excellent (PART I). Furthermore, the influence of hospital volume on surgical quality and survival was analyzed using data of the CRITICS trial (PART II). Surgery performed in hospitals with high hospital volume was associated with better surgical quality and better survival. In part III of this thesis analyses were performed to analyze treatment strategy and survival in patients with resectable gastric cancer and in patients with metastatic gastric cancer. Show less
Cardiac arrhythmias are one of the major causes of morbidity and mortality in the world. The clinical management of cardiac arrhythmias relies on several anti-arrhythmic therapies, e.g. drugs,... Show moreCardiac arrhythmias are one of the major causes of morbidity and mortality in the world. The clinical management of cardiac arrhythmias relies on several anti-arrhythmic therapies, e.g. drugs, ablation, and device implantation that, unfortunately, are often unspecific, irreversible and/or traumatizing, respectively. Recently, to overcome these side effects, gene therapy has been introduced as an alternative option to treat cardiac arrhythmias by specifically targeting the biological defect. However, gene therapy alone is lacking the possibility to gain precise spatiotemporal and quantitative control over a certain target. Interestingly, more recently, such precise control could be achieved with an innovative strategy, called optogenetics. Here, gene therapy is combined with optics allowing expression of light-activatable proteins that are specifically activate and deactivate by simply turning light on and off, respectively. This now opens new and unique possibilities for cardiac arrhythmias research based on optical modulation of excitability with superb spatiotemporal resolution. Therefore, in the studies presented in this thesis, the unique features of optogenetics were employed for investigating the underlying mechanism of arrhythmia initiation, maintenance, and termination in order to identify novel biological anti-arrhythmic strategies. Show less
This thesis has provided more knowledge on the disease course and its determinants of outcome in hand osteoarthritis. The role of joint-specific factors and coping styles on disability, the... Show moreThis thesis has provided more knowledge on the disease course and its determinants of outcome in hand osteoarthritis. The role of joint-specific factors and coping styles on disability, the prevelance of aesthetic dissatisfaction, its impact on daily life and their determinants were evaluated. Additionally, the association between MR Imaging features with hand pain and the association of MR Imaging features with radiographic progression were investigated. Another part of the thesis focused on the association between osteoarthritis and mortality. Show less
This thesis evaluates two total hip implant designs used in the younger aged patient population; (1) a cementless THR with a conventional cobalt on polyethylene (CoP) bearing and (2) a THR with a... Show moreThis thesis evaluates two total hip implant designs used in the younger aged patient population; (1) a cementless THR with a conventional cobalt on polyethylene (CoP) bearing and (2) a THR with a MoM bearing. An analysis into outcome and failure mechanisms on both designs was performed with focus on: The clinical outcome and survival of a conventional MoP THA cohort with the 24-year follow-up and an analysis into factors associated with clinical and radiographic outcome. The clinical evaluation of a large head MoM THA cohort. Analysis of failure of the MoM THA in relation to anatomical reconstruction of the hip. The failure mechanisms of the MoM THA as visualised at MRI images. The reproducibility of the histological scoring system of peri-articulair tissue reactions of failed MoM THA. Show less
In een cross-sectioneel onderzoek is nagegaan hoe het op de lange duur met CVA patiënten gaat die in het Haaglanden Medisch Centrum te Den Haag opgenomen zijn geweest vanwege een beroerte. Er is... Show moreIn een cross-sectioneel onderzoek is nagegaan hoe het op de lange duur met CVA patiënten gaat die in het Haaglanden Medisch Centrum te Den Haag opgenomen zijn geweest vanwege een beroerte. Er is gekeken naar verschillende aspecten zoals handfunctie, werkhervatting, stemmingsproblemen en zorggebruik. Het blijkt dat, ondanks alle behandelingen die gegeven worden, een grote groep van deze mensen restbeperkingen ervaart. Hun partners voelen zich fors belast, vooral als er sprake is van stemmingsproblemen en als werkhervatting niet lukt. Ook jaren later geeft de meerderheid van CVA patiënten aan nog steeds zorgvragen te hebben die niet beantwoord zijn. Ze lijken beter hun weg te vinden in de eerstelijn voor hun fysieke problemen dan voor hun mentale problemen. Er is gekeken naar de mate waarin eerstelijns behandelaars zich hebben georganiseerd met betrekking tot chronische behandeling en begeleiding van CVA patiënten. Een goed georganiseerd netwerk, met een visie op kwaliteitsaspecten en scholing, is maar op enkele plaatsen in het land beschikbaar. Er zijn aanbevelingen geformuleerd om de ontwikkeling van eerstelijns netwerken voor CVA patiënten te stimuleren. Show less
This thesis aimed to investigate the link between cardiac biomarkers, cognitive impairment and functional decline in older subjects with a focus on non-invasive markers that are routinely... Show moreThis thesis aimed to investigate the link between cardiac biomarkers, cognitive impairment and functional decline in older subjects with a focus on non-invasive markers that are routinely available in clinical practice. The findings of this thesis show that markers of subclinical cardiac dysfunction are linked with accelerated cognitive decline and a higher risk of functional decline. In addition, we provide preliminary findings on the potential role of centrally acting natriuretic peptides in relation to cognitive impairment. Collectively, these findings highlight a complex pathophysiological heart-brain coupling that might extend beyond vascular and hemodynamic factors. Future studies are needed to investigate whether such link warrants mutual screening of the heart and the brain functions, and whether such practice could improve early diagnosis of dementia. Show less
This thesis explores clinical phenotypes and the pathophysiology of rare monogenic models of migraine with the ultimate goal to identify novel treatment targets for these disorders, as well as for... Show moreThis thesis explores clinical phenotypes and the pathophysiology of rare monogenic models of migraine with the ultimate goal to identify novel treatment targets for these disorders, as well as for the common types of migraine. The research is divided in two parts: part one describes studies on hemiplegic migraine (HM), a monogenic form of migraine, part two describes studies on Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S), a monogenic vascular syndrome hypothesised to be associated with migraine. Show less
Adolescents with delinquency and cannabis abuse, primarily boys, are predisposed to a variety of comorbid psychiatric psychopathology and form an intricate subgroup which is difficult to treat ... Show more Adolescents with delinquency and cannabis abuse, primarily boys, are predisposed to a variety of comorbid psychiatric psychopathology and form an intricate subgroup which is difficult to treat (Merikangas et al., 2010; Zahn-Waxler, Shirtcliff, & Marceau, 2008). Systemic treatments are considered the type of treatment which renders the most promising results in addressing the complex taxonomy of adolescents’ problem behaviours (Carr, 2009; Von Sydow, Retzlaff, Beher, Haun, & Schweitzer,2013; Waldron & Turner, 2008). Clinicians working with this group of adolescents have to deal, on a daily basis, with serious issues and have to make difficult decisions, impacting the adolescent, his/her family, and society as a whole. For the forensic research field, comprehending and grasping the complexity of these adolescents, which could generate insights and practical advises leading to improvement of care, is a tough and demanding task. This dissertation tries to inform clinical and research practice by providing insight and knowledge concerning: the common elements of systemic treatment, the effectiveness of Multidimensional Family Therapy (MDFT), and the predictive value on treatment outcome of baseline characteristics of the adolescent. This to better understand systemic treatments and to be better able to match a treatment with the individual adolescent’s psycho-social make-up. Show less
Cell culture models play an important role in biomedical research and will continue to do so given the growing opposition to vivisection and the limited predictive value of animal models for... Show moreCell culture models play an important role in biomedical research and will continue to do so given the growing opposition to vivisection and the limited predictive value of animal models for human disease. Moreover, cell culture models can be easily established to mimic physiological or pathological processes, which is difficult to accomplish using in silico models. While non-cellular in vitro models are highly suitable for studying simple biochemical processes, cell culture models recapitulate many of the complex regulatory circuits governing protein activity in vivo and hence allow investigation of diverse physiological processes. Also, cell culture models offer the possibility to address fundamental research questions in a much more simplified, specific and controllable manner than can be achieved using in vivo models. Show less
For rodent malaria parasites the availability of a variety transgenic parasite lines expressing different reporter proteins under the control of stage-specific or constitutive promoters have been... Show moreFor rodent malaria parasites the availability of a variety transgenic parasite lines expressing different reporter proteins under the control of stage-specific or constitutive promoters have been of great benefit to studies to reveal parasite gene function and to studies focussed on the evaluation of novel drugs and vaccines. The availability of similar transgenic P. falciparum reporter lines would also help to advance gene-function studies and studies aiming at development of new therapies for P. falciparum parasites. In this thesis, we describe a set of studies performed in P. falciparum to develop novel CRISPR/Cas9 methodologies to improve P. falciparum transgenesis and to create novel transgenic parasites that can be used to analyse host-pathogen interactions and for anti-malarial drug and vaccine research. We describe studies aiming at improving CRISPR/Cas9 genetic modification for introduction of transgenes into the genome of P. falciparum using a ‘neutral’ locus, a disruption of the P230p gene using CRISPR/Cas9 showed that P230p like P230 and P48/45, has a vital role in P. falciparum male fertility and zygote formation and the creation of two chimeric P. falciparum parasites (Pf-PvCSP), where the gene encoding circumsporozoite protein (CSP), was replaced by two csp gene variants (VK210 and VK247) showing that species-specific features of CSP govern full sporozoite development. Show less
It is increasingly recognized that in order to gain further insights into human disorders and develop new therapeutic strategies and diagnostic tools, it is critical to have a comprehensive... Show moreIt is increasingly recognized that in order to gain further insights into human disorders and develop new therapeutic strategies and diagnostic tools, it is critical to have a comprehensive overview of immune cell subsets resident in tissues under physiological and pathological conditions. Flow cytometry has been the golden standard for analyzing immune cell subsets, and with a typical experiment, dozens of immune subsets can be discriminated. Due to the lack of spectrally-resolvable fluorochromes, mass cytometry utilizing metal-conjugated antibodies has shown to be a powerful tool for dissecting the immune landscape even further. Inflammatory intestinal diseases can only be understood by studying specialized cell types within the tissue niche itself. In this thesis, we applied mass cytometry and data-driven, automated analysis approaches to investigate the complex compositions of heterogeneous cell subsets, such as those encountered in intestinal biopsies. These types of data have the potential to greatly improve our understanding of human disease. In concert with clinical data, mass cytometry could enable a finer classification of patients and might aid in the development of improved diagnostics, prognostics and personalized therapeutic regimens. Show less
