Multiple acyl-CoA dehydrogenase deficiency and population newborn screening:Connecting the dots

Multiple acyl-CoA dehydrogenase deficiency (MADD; also known as glutaric aciduria type II) is an ultra-rare inborn error of metabolism (IEM). The disorder is not included in the Dutch newborn blood spot (NBS) screening program due to a lack of evidence for sufficient health gain upon early detection. Complicating factors concern the limited knowledge on the natural history, disease severity prediction and monitoring of the spectrum of MADD patients, and the absence of systematic evidence of an effective treatment for severely affected patients. MADD is also an exemplary IEM that can escape identification due to nonspecific symptoms and unexpected childhood death. In this thesis, we combined reviews of the literature, with experimental research and studies on clinical outcome in patients. In part I, we present the IEMs that are associated with unexpected death in early childhood, and how their detection through acylcarnitine profile analysis can be improved. We recommend that every child participates in a population NBS program, even after death. In part II, we describe that functional studies in patient fibroblasts can predict the MADD phenotype, we propose a clinical monitoring system, and we describe the efficacy and safety of D,L-3-hydroxybutyrate treatment in severe MADD. The results of this thesis can guide clinicians in their care of MADD patients and their families, and can also support decision-makers in their aims to improve NBS programs and facilitate access to novel treatments for (ultra-)rare diseases

Dendritic cells in asthma: a function beyond sensitization

The aim of this thesis is to characterize the involvement of dendritic cells in the induction and maintenance of the secondary immune response leading to an eosinophilic airway inflammation as seen in asthma. Special attention was attributed to the mechanisms by which these cells accumulate in the airways of challenged mice, to their interaction with primed CD4+ T cells as well as to their functional contribution to primed T cell activation. These questions were addressed in a well-established murine model of eosinophilic airway inflammation Balb/c mice were sensitized to OVA by an intratracheal injection of OVA-pulsed bone marrow-derived DCs. Ten days post-sensitization, mice were challenged with an aerosol of the same antigen resulting in an eosinophilic airway inflammation as shown by histological analysis of lungs revealing peribronchial and perivascular inflammatory infiltrates and goblet cell hyperplasia, increased numbers of eosinophils in bronchoalveolar lavage fluid and Th2 cytokine production by draining lymph nodes of the lung. To determine the role of the dendritic cell in the secondary immune response to inhaled allergen the following research questions were addressed in this thesis using a murine model for asthma: - Does the number of dendritic cells in the airways increase during a secondary immune response? (Chapter 4) - Is an intratracheal injection of antigen pulsed dendritic cells sufficient to induce a secondary immune response in already sensitized mice? (Chapter 5 en 6) - Does depletion of dendritic cells in sensitized mice before and during challenge inhibit the development of an eosinophilic airway inflammation? (Chapter 5) - Does the capacity of dendritic cells to provide CDS0/86 costimulation contribute to the function of dendritic cells in the secondary immune response? (Chapter 6) - Do eosinophils play a role as antigen presenting cells during the secondary immune response? (Chapter 7

Resummed propagators in multi-component cosmic fluids with the eikonal approximation

We introduce the eikonal approximation to study the effect of the large-scale motion of cosmic fluids on their small-scale evolution. This approach consists in collecting the impact of the long-wavelength displacement field into a single or finite number of random variables, whose statistical properties can be computed from the initial conditions. For a single dark matter fluid, we show that we can recover the nonlinear propagators of renormalized perturbation theory. These are obtained with no need to assume that the displacement field follows the linear theory. Then we extend the eikonal approximation to many fluids. In particular, we study the case of two non-relativistic components and we derive their resummed propagators in the presence of isodensity modes. Unlike the adiabatic case, where only the phase of small-scale modes is affected by the large-scale advection field, the isodensity modes change also the amplitude on small scales. We explicitly solve the case of cold dark matter-baryon mixing and find that the isodensity modes induce only very small corrections to the resummed propagators.Comment: 18 pages, 9 figures, matches published version as PR

Iedereen verantwoordelijk

Goede palliatieve zorg gaat iedereen aan: wij worden immers allemaal op enig moment met de dood geconfronteerd, zowel persoonlijk als binnen onze familie- en kennissenkring. En als zorgverleners dragen de meeste van ons zorg voor patiënten die lijden aan ziektes waaraan ze uiteindelijk zullen overlijden. Het is dan ook opmerkelijk, dat zorgverleners zelf, beleidsmakers en onderzoekers nog maar kort specifieke aandacht aan palliatieve zorg geven. Een groot deel van de dagelijkse zorg die wij bieden aan patiënten met een korte levensverwachting, of zelfs patiënten die stervende zijn, is niet gebaseerd op wetenschappelijke kennis van voldoende niveau. Waar praten we over? In Nederland overleden in 2006 136.000 mensen. Vierenvijftig procent van het totaal, te weten 73.000 mensen, overleed ten gevolg van een chronische ziekte. Bij hen werd het overlijden dus voorafgegaan door een ziekteperiode en komt palliatieve zorg nadrukkelijk aan de orde. Kanker is meest voorkomende ziekte die leidt tot een niet-acuut overlijden, maar 45% van de mensen overlijdt t.g.v. andere aandoeningen zoals hart- en vaatziekte, dementie en chronisch longlijden. In Nederland overlijdt ongeveer een derde van de mensen met een chronische ziekte thuis, een ander derde in een verpleeg- of verzorgingshuis, 27% in het ziekenhuis en een klein deel van de patiënten in andere instellingen, waar onder de speciale hospice voorzieningen