Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium

Prediction of second neurological attack in patients with clinically isolated syndrome using support vector machines

The aim of this study is to predict the conversion from clinically isolated syndrome to clinically definite multiple sclerosis using support vector machines. The two groups of converters and non-converters are classified using features that were calculated from baseline data of 73 patients. The data consists of standard magnetic resonance images, binary lesion masks, and clinical and demographic information. 15 features were calculated and all combinations of them were iteratively tested for their predictive capacity using polynomial kernels and radial basis functions with leave-one-out cross-validation. The accuracy of this prediction is up to 86.4% with a sensitivity and specificity in the same range indicating that this is a feasible approach for the prediction of a second clinical attack in patients with clinically isolated syndromes, and that the chosen features are appropriate. The two features gender and location of onset lesions have been used in all feature combinations leading to a high accuracy suggesting that they are highly predictive. However, it is necessary to add supporting features to maximise the accuracy. © 2013 IEEE

Diagnostics and pathophysiology of acute myocardial infarction and stress-induced myocarditis

Niessen, J.W.M. [Promotor]Krijnen, P.A.J. [Copromotor]Kubat, B. [Copromotor

De-internationalization of Small and Medium Sized Enterprises : How do the drivers and determinants affect the form and the path of de-internationalization for SME’s?

More and more SME’s, which create entrepreneurial spirit and innovation, which are primarily responsible for wealth and economic growth, are internationalizing. This increases their probability of business closure due to the increased risk they face from operating in foreign markets. Much of the world blames the U.S. financial excesses for these business closures, but at the same time there are also SME’s withdrawing activities from foreign markets in economic stable times. This indicates that there are more and other reasons for de-internationalization and raises the problem of how do SME’s close their businesses in foreign markets. The purpose of this study is to explore how the drivers and determinants of deinternationalization affect the form and the paths of de-internationalization for SME’s. The aim is to provide and contribute to a better understanding of deinternationalization. This was studied through developing four case studies with Dutch SME’s with a qualitative research approach. For empirical data collection interviews were conducted with the persons closely involved with the de-internationalization of the SME’s. This in combination with the developed theoretical framework, based on a theory discussion and synthesis, provided more insight into the de-internationalization topic. The findings of this study show that a unique combination of drivers and determinants of de-internationalization is present in each case study and the relative influence of them differs. Most of the de-internationalization took place in a voluntary way, due to the nature and predictability of the occurring drivers. Moreover, it was found that the drivers of de-internationalization combined with the determinants influence the form in which de-internationalization can take place. It was also found that the form of deinternationalization, which SME’s have chosen, determines the two paths of deinternationalization, which are partial divestment and full market exit. This study contributes to the better understanding of de-internationalization, by identifying the forms and paths which SME’s can choose when withdrawing activities in foreign markets. Moreover, the main drivers and determinants have been identified and it was analysed how they affect the different forms and paths of de-internationalization and this was conceptualized in a model. The recommendations are, that deinternationalization should be seen as a strategic option SME’s have and should be considered in corporate strategies. Therefore, the associations with this phenomenon could be seen (more) positive

The parietal epithelial cell: a key player in the pathogenesis of focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.

Contains fulltext : 57133.pdf (publisher's version ) (Open Access)Focal segmental glomerulosclerosis (FSGS) is a hallmark of progressive renal disease. Podocyte injury and loss have been proposed as the critical events that lead to FSGS. In the present study, the authors have examined the development of FSGS in Thy-1.1 transgenic (tg) mice, with emphasis on the podocyte and parietal epithelial cell (PEC). Thy-1.1 tg mice express the Thy-1.1 antigen on podocytes. Injection of anti-Thy-1.1 mAb induces an acute albuminuria and development of FSGS lesions that resemble human collapsing FSGS. The authors studied FSGS lesions at days 1, 3, 6, 7, 10, 14, and 21, in relation to changes in the expression of specific markers for normal podocytes (WT-1, synaptopodin, ASD33, and the Thy-1.1 antigen), for mouse PEC (CD10), for activated podocytes (desmin), for macrophages (CD68), and for proliferation (Ki-67). The composition of the extracellular matrix (ECM) that forms tuft adhesions or scars was studied using mAb against collagen IV alpha2 and alpha4 chains and antibodies directed against different heparan sulfate species. The first change observed was severe PEC injury at day 1, which increased in time, and resulted in denuded segments of Bowman's capsule at days 6 and 7. Podocytes showed foot process effacement and microvillous transformation. There was no evidence of podocyte loss or denudation of the GBM. Podocytes became hypertrophic at day 3, with decreased expression of ASD33 and synaptopodin and normal expression of WT-1 and Thy-1.1. Podocyte bridges were formed by attachment of hypertrophic podocytes to PEC and podocyte apposition against denuded segments of Bowman's capsule. At day 6, there was a marked proliferation of epithelial cells in Bowman's space. These proliferating cells were negative for desmin and all podocyte markers, but stained for CD10, and thus appeared to be PEC. The staining properties of the early adhesions were identical to that of Bowman's capsule, suggesting that the ECM in the adhesions was produced by PEC. In conclusion, the authors propose the following sequence of events leading to FSGS lesions in the Thy1.1 tg mice: (1) PEC damage and denudation of Bowman's capsule segments; (2) podocyte hypertrophy and bridging; and (3) PEC proliferation with ECM production

Classification of condom lubricants in cyanoacrylate treated fingerprints by desorption electrospray ionization mass spectrometry

Traces of condom lubricants in fingerprints can be valuable information in cases of sexual assault. Ideally, not only confirmation of the presence of the condom but also determination of the type of condom brand used can be retrieved. Previous studies have shown to be able to retrieve information about the condom brand and type from fingerprints containing lubricants using various analytical techniques. However, in practice fingerprints often appear latent and need to be detected first, which is often achieved by cyanoacrylate fuming. In this study, we developed a desorption electrospray ionization mass spectrometry (DESI-MS) method which, combined with principal component analysis and linear discriminant analysis (PCA-LDA), allows for high accuracy classification of condom brands and types from fingerprints containing condom lubricant traces. The developed method is compatible with cyanoacrylate (CA) fuming. We collected and analyzed a representative dataset for the Netherlands comprising 32 different condoms. Distinctive lubricant components such as polyethylene glycol (PEG), polydimethylsiloxane (PDMS), octoxynol-9 and nonoxynol-9 were readily detected using the DESI-MS method. Based on the analysis of lubricant spots, a 99.0% classification accuracy was achieved. When analyzing lubricant containing fingerprints, an overall accuracy of 90.9% was obtained. Full chemical images could be generated from fingerprints, showing the distribution of lubricant components such as PEG and PDMS throughout the fingerprint, while still allowing for classification. The developed method shows potential for the development of DESI-MS based analyses of CA treated exogenous compounds from fingerprints for use in forensic science.OLD ChemE/Organic Materials and Interface