Cerebral small vessel disease (cSVD) is frequently seen on FLAIR MRI of older adults. White matter hyperintensities (WMH), lacunes of presumed vascular origin (lacunes), microbleeds and (sub)cortical atrophy are the well known ‘traditional cSVD makers’. cSVD is very common in persons aged above 60 years, it’s incidence increases non-linearly with age, and its progression is thought to be related to baseline cSVD load and vascular risk factors. The clinical spectrum and the prognosis of cSVD is highly heterogeneous and ranges from very mild symptoms to full blown stages of dementia and even death. With the aid of conventional MRI it has proven to be very difficult to predict which patients with cSVD are at highest risk to develop these sever..
Opportunity identification by employees Opportunities and their identification are of significant importance for competitiveness in today’s complex and turbulent business environment because they serve as a key influencing factor for new value-creation. Opportunity identification (OI) is interesting not only from the perspective of new business start-ups, but also from the perspective of employees in existing organisations. Each entrepreneurial process starts with an imagined, rudimentary idea in the mind of an individual. The further exploration and development of such opportunities by employees can lead to the realisation of all kinds of corporate entrepreneurship outcomes, such as innovation, strategic renewal, and internal or external ..
Inactivating mutations in the BRCA1 and BRCA2 genes predispose to breast and ovarian cancer. A defect in error-free DNA double strand break repair through homologous recombination is thought to contribute largely to this predisposition as genomic instability ensues that facilitates cancer cell transformation. However, this deficiency may open therapeutic options as it has been identified that treatment with double strand break inducing agents kills such BRCA deficient cells. Furthermore, synthetic lethality between BRCA deficiency and Poly(ADP)Ribose polymerase inhibitors offers another treatment option that has been introduced clinically over the last years. To treat these BRCA deficient patients it is necessary to identify and validate bi..
Like options on stocks, options on commodities and options on business activities provide ﬁrms with protection against ﬁnancial risks. Both are routinely used by non-ﬁnancial ﬁrms; however the former is an OTC contract between the buyers and suppliers used to hedge ﬁnancial risks arising from the procurement and production of commodities, while the latter are called real options and are used for certain business activities such as switching by utilizing the inherent ﬂexibility to maximize the value of ﬁrms and minimize the risk they face. The current thesis addresses both in four chapters. Chapters 2 and 3 focus on the OTC option contracts, while Chapters 4 and 5 concern real options. However, in the all four chapters we adhere to our main ..
Curative treatments for CF patients are still an unmet need. In this thesis, we developed new approaches that can assist the identification and development of CFTR-targeting treatments, and to use those treatments in a more personalized fashion. These included an improved fluorescent sensor for CFTR function measurement in heterologous expression systems. We also applied a primary cell model to study drugs that modulate CFTR function. This primary cell model allowed us to perform small scale screening for existing biological and chemical modulators of CFTR, which may upon pharmacological targeting be useful for treatment of CF. Our data provided important insights into individual mechanisms that may impact the efficacy of such drugs in vivo..
The outline of this thesis is provided in chapter 1. In summary, the aims of this thesis were to examine 1) the clinical applicability of a novel, intra-operative high resolution, multi-site epicardial mapping approach of the entire atria as a routine procedure during cardiac surgery, 2) whether there are preferential sites of electropathology during sinus rhythm in patients with various underlying heart diseases, 3) the relevance of conduction abnormalities during sinus rhythm at Bachmann’s Bundle, 4) the role of endo-epicardial asynchrony in persistence of AF, 5) characteristics of post-operative atrial ectopy and AF, 6) the relation between electrical parameters assessed with high resolution mapping, atrial ectopy and post-operative AF...
De positieve resultaten van drie onderzoeksprojecten die ik uitvoerde in de periode 1998-2010, waren voor mij aanleiding voor de vraag waarom de projecten succesvol waren. Wat was het verband met de aanpak waarbij het lerend vermogen van mensen in relatie tot organisatieverandering en sociale netwerken centraal stond. De projecten hadden als inzet vernieuwing van beleid en betroffen veranderingen op zowel strategische als operationeel niveau. Ook ging het om vraagstukken die verband hielden met de samenleving. De rode draad in de drie projecten was de wisselwerking tussen individuele ontwikkeling en sociale systeemverandering. Dit vooronderstelt dat individuen en structuur elkaar beïnvloeden en op elkaar betrokken zijn. Dat resulteerde in s..
This dissertation aimed to investigate how both rational and affective determinants drive new venture team outcomes. An overview of the relevant literature, as presented in the introduction chapter of this dissertation, revealed a number of important theoretical and methodological limitations that required further scholarly attention. I categorized these limitations into three distinct, but interrelated research themes and formulated three research questions as they relate to the three key relationships (see Figure 1.1). The objective of this concluding chapter is to demonstrate how the results of the four studies contribute to a better understanding of how new venture teams influence the performance of their ventures. To achieve this objec..
Since 2015 the Dutch national government emphasizes the shift from a welfare society towards a participatory society. In the long term, this shift could have a huge effect on society and the social inclusiveness of elderly people. Mainly because participatory societies build on peoples own responsibilities for their health and wellbeing and making people help each other, which requires a different mindset on the part of citizens. New legislations in the Netherlands means new ways for municipalities to collaborate, but at the same time it is important to: 1) balance financial costs and benefits, 2) spread risks, 3) ensure service quality, and 4) manage and safeguard the social system...
The main aims of this thesis were to: 1) examine associations between the gut microbiota composition and childhood (over)weight development; 2) examine the impact of childhood exposure to oral antibiotics and (over)weight development; and 3) address the methodological challenge of reducing high dimensional data of the gut microbiota in relation to latent BMI z-scores trajectories. To address these aims, a combination of advanced molecular microbial methods, a well-designed prospective epidemiological study and state-of-the-art biostatistical methods were used. A schematic overview of the main findings in this thesis is presented in Figure 1...
Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection1, remains an increasing cause of morbidity and mortality worldwide2. In this thesis, we have explored the epidemiology, outcome and host response in critically ill patients admitted with sepsis to, or developing sepsis while on, the intensive care unit (ICU). For this, we have used the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) data collection initiative and biobank study as backbone. Two tertiary teaching hospitals in the Netherlands participated in the inclusion of extensive clinical, microbiological, interventional, outcome and follow up data of 8305 consecutively admitted critically ill patients during a study pe..
The prevalence of obesity is reaching epidemic proportions worldwide. Environmental factors like consumption of high-caloric diets and low levels of physical activity are likely to underlie this increasing prevalence. Obesity is one of the most important risk factors contributing to mortality and the overall burden of disease. Type 2 diabetes mellitus (T2DM) may be the most devastating disease condition associated with obesity. T2DM is characterized by a gradual decline in insulin sensitivity, which impairs the effect of insulin and eventually elevates blood glucose values. The International Diabetes Federation (IDF) reported that 366 million people worldwide were suffering from diabetes in 2011. Ninety percent of those people suffered from..
Samenvatting Hoofdstuk 1 * In dit proefschrift worden de resultaten beschreven van een onderzoek naar grondtransacties tussen de overheid en private grondeigenaren. Grondtransacties hebben vaak een belangrijke invloed op de bestemming van grond en zijn daarmee nauw gerelateerd aan ruimtelijke planning. Een perceel grond is niet te verplaatsen en elk stuk grond is uniek vanwege de ruimtelijke locatie. Dit zorgt ervoor dat elke grondeigenaar een monopolypositie heeft. Voor overheden kan het belang van grond(eigendom) groot zijn als geplande ontwikkelingen niet worden gerealiseerd door de betreffende grondeigenaren zelf. Er zijn verschillende studies gedaan naar de relatie tussen grondbeleid, grondverwerving en de grondmarkt. Het onderzoek dat..
Opinionated Family Migration Policies? Public opinion and resistance to EU harmonization of family reunification policies in Europe. Despite the harmonizing efforts of the European Union [EU], family reunification policies remain diverse across its member states in terms of, among many other aspects, income requirements for sponsors and the requirements for the reuniting family member obtaining an autonomous residence permit. This thesis examines whether member states’ resistance to the harmonization of family migration policies can be partly explained by divergent public opinion about gender roles and/or about immigration/immigrants across the EU. Using data from the European Social Survey (2002-2012), the European Value Study (1990-2008) ..
The aim of this thesis was to extend our knowledge on the role of different non-coding RNA species in the development of heart failure (HF). Over the last years it has been acknowledged that multiple cell types are critically involved in HF, including cardiomyocytes, cardiac fibroblasts, and resident or infiltrating immune cells. This thesis comprises research on the involvement of these three cell types in HF with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as regulators of cell function. Only very recently, the cell type-specific effects of miRNAs in HF and their role in paracrine signaling have come to the center of attention1-5. Here we extend this knowledge by identifying miR-139 as regulator of cardiomyocyte funct..