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It is taken for granted that the key route for the sensitization of asthma is the respiratory tract, but emerging evidence indicates that airway sensitization may not necessarily occur only via respiratory route. The causing agents for asthma can be classified as high- or low-molecular-weight agents. Skin exposure to low-molecular-weight agents has been recognized as one of the origins for selective airway hyper-responisiveness in some literature, but the paradigm has not been accepted widely. In addition, the association between allergic contact dermatitis and occupational asthma to specific agents has rarely been studied in clinical studies. Understanding the pathway for sensitization in asthma helps to correctly estimate the respiratory health risk in the workplace and facilitate early diagnosis.Metals are important low-molecular-weight causing agents for occupational asthma. Several metal compounds possess capability to induce both sensitization on skin and airway. However, the mechanism of occupational asthma induced by metal compounds is not well understood. Dendritic cells and innate lymphoid cells have been known to play important role in asthma, but their role in metal-induced asthma have never been studied.In this thesis, we have investigated the effect of skin exposure to low-molecular-weight (LMW) agent on asthma. We first reviewed the literature systematically and graded the evidence, focusing whether the skin exposure to LMW agents can induce the airway sensitization. Then we investigated the effect of skin exposure to cobalt chloride on airway hypersensitivity on a mouse model. Finally, we identified patients with occupational asthma in the past 10 years, and analyze whether different type of exposure was related a higher prevalence of contact dermatitis.

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Effective delivery of antibodies across the blood-brain barrier (BBB) is a serious limiting factor in the further development of antibody based therapies for AD but also for other diseases of the central nervous system (CNS). The BBB is composed of a tightly sealed monolayer of brain endothelial cells (BECs), which normally precludes free exchanges of solutes between blood and brain (and vice versa), including biologics, but yet enabling the supply of nutrients (e.g. amino acids, glucose, insulin, etc.). Therefore, the potential treatment of many CNS-related diseases is severely hampered because of the fact that numerous potential drug candidates are not able to cross the BBB.To overcome this problem, much research efforts are currently focused on the development and application of safe and efficient delivery methods to cross the BBB. These efforts include the delivery by means receptor mediated transcytosis (RMT). One of the more successful targeting strategies makes use of monoclonal antibodies (mAbs) or antibody fragments targeting a BBB nutrient transporter. For example, mAbs have been generated against human insulin receptor (InsR) and transferrin receptor (TfR). For both antibodies an increased transport over the BBB was observed. When coupled to an appropriate drug candidate pharmacological effects could, for example, be observed in rats (anti-InsR coupled to glial-derived neurotrophic factor) and non-human primates (bispecific antibody, anti-BACE1/anti-TfR). However the efficiency of BBB transport is still rather low as shown by Pardridge et al. (2009) for their anti-InsR mAb and Yu et al. (2014) for their anti-TfR mAb (respectively 0.55 % and 1-2 % of the injected dose reached the brain in their respective monkey studies).In the current project an innovative method is followed to identify new potential RMT targets to cross the BBB. Simultaneously, because of the intelligent design of the proposal, not only new RMT targets might be discovered but also Nanobodies (heavy-chain only antibody fragments originating from camelids) capable of shuttling the BBB. Next to this unbiased approach, a specific potential RMT target expressed at the BBB is selected to generate Nanobodies against. Initially, based on its expression both on human and mice BECs by Uchida et al. (2011), the heavy chain of the Na+ independent neutral amino acid transporter (CD98hc) is selected as potential RMT target. Recently (December 2015), indeed, CD98hc was confirmed as a robust RMT pathway for antibody delivery to the brain.In vivo proof of concept in mice will be obtained by coupling a BBB-shuttling Nanobody to a BACE1 inhibiting Nanobody, previously discovered by the host lab (patent EP 2281005 B1). If a therapeutically relevant dose of the construct crosses the BBB successfully, a reduction in brain Aβ levels should be observed. The host lab has an ELISA and other assays available which makes an easy read out of therapeutic efficiency possible. This will allow us to provide proof of concept that the brain is targeted in a therapeutic relevant way.Discovery of BBB-shuttling Nanobodies would be a major breakthrough in the treatment of CNS related diseases as they can be used as generic entities which can be coupled to drug candidates with poor BBB permeability.

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Critical illness is a complex interplay of metabolic, endocrine and inflammatory changes within the human body. Overall, critical illness is defined as any acute life threatening medical condition that requires vital organ support, without which death would ensue. A myriad of events can elicit critical illness, ranging from serious trauma to major surgery or severe sepsis. Although the initial cause can be diverse, critical illness generally follows a uniform disease pattern hallmarked by hyperinflammation, endocrine alterations and hypercatabolism. Despite a decreasing mortality in the acute phase due to medical advances, implementation of best clinical practice guidelines and early initiation of supportive care, an increasing number of patients progress into a prolonged phase of critical illness that still requires supportive care in order to survive. During this chronic phase of critical illness, patient are at higher risk of developing ICU-acquired weakness (ICUAW). Generalized muscle weakness, solely attributed to acute illness or the treatment thereof is a frequent occurring pathology among prolonged critically ill patients. Despite current preventive measures, such as aggressive sepsis treatment, withholding parenteral nutrition for a minimum of 7 days, tight glycemic control and early mobilization, effective treatment options are still lacking.Interestingly, the Leuven Laboratory of Intensive Care Medicine showed that premorbid obesity, but not nutrition, prevented loss of muscle mass and function during critical illness in ICU-patients and septic mice. Additionally, these septic mice presented with increased markers of fatty acid mobilization and ketogenesis. Furthermore, parenteral administration of high doses of lipids to lean septic mice attenuated muscle weakness, but not the wasting. Although this nutritional strategy resulted in unfavorable liver steatosis, it clearly upregulated fatty acid oxidation and ketogenesis, similarly as in the obese. Remarkably, the Leuven laboratory next demonstrated that supplementation of mixed parenteral nutrition (PN) with the ketone body 3-hydroxybutyrate (3HB) by itself was also able to protect against loss of muscle strength in lean critically ill mice, although loss of muscle mass was not prevented.Overall, ketone bodies are best known as an alternative fuel source for energy production in glucose-deprived situations like fasting and intensive exercise. During such metabolic challenging conditions, ketone bodies serve as a glucose sparing carbon source that can be readily oxidized in most tissues to provide energy through ATP production, while preserving gluconeogenic reserves and muscle protein stores. In addition to their energetic potential 3HB also can induce a myriad of signaling and regulatory effects and this at physiologically relevant concentrations. As such, ketone bodies have been reported to exert anti-inflammatory and autophagy-stimulating properties and to induce mTOR-mediated protein synthesis and muscle regeneration.The overall goal of this thesis is to gain more insight into the role of ketone bodies as protection against ICU acquired weakness. The first aim, studied in the objective 1 and 2, is to identify the underlying pathways explaining the protection against ICU-acquired weakness with 3HB supplementation. The second aim, studied in objective 3 and 4, is to translate the protective effect of ketone bodies to a usable therapy for the human patient.In our first objective, we investigated whether subcutaneous bolus injections of the ketone body D,L-3HB sodium salt (3HB-Na) rather acts as an energy substrate or as a signaling molecule, when supplemented to septic mice. We documented that the protective effect of 3HB against muscle weakness coincided with enhanced markers of muscle regeneration, and not with markers of substrate handling. With this experiment, we showed that 3HB supplementation rather acts as a signaling molecule rather than to serve as a super fuel during critical illness. The observation that 3HB enhanced markers of muscle regeneration suggests that this intervention could possibly also contribute to the attenuation of muscle weakness on the long term.In a second objective, we assessed whether cholesterol homeostasis plays a role in the development of ICU-acquired weakness and whether the protective effect of 3HB supplementation on weakness is related to its effects on cholesterol homeostasis. Serum cholesterol concentrations were lower in weak than in non-weak critically ill patients, and serum cholesterol was inversely correlated with weakness. In addition, plasma cholesterol correlated positively with muscle force in septic mice, and exogenous 3-hydroxybutyrate supplementation increased plasma cholesterol and altered cholesterol homeostasis, by normalization of plasma mevalonate (cholesterol precursor) and elevation of muscular, but not hepatic, expression of cholesterol synthesis genes. Furthermore, tracer technology revealed that 3-hydroxybutyrate in septic mice was preferentially taken up by muscle and metabolized into cholesterol-precursor mevalonate, rather than TCA metabolites. The 3-hydroxybutyrate protection against weakness was not related to ubiquinone or downstream myofiber mitochondrial function, whereas cholesterol content in myofibers was increased. These findings point to a role for low cholesterol in critical illness-induced muscle weakness and to a protective mechanism-of-action for 3-hydroxybutyrate-supplementation.In a third objective, we assessed efficacy versus toxicity of stepwise escalating doses of 3HB-Na in septic mice. In this experiment, we used a 3HB-Na dose of 40 mmol/kg/day as a reference dose as this dose was previously shown to prevent muscle weakness in septic mice without obvious signs of toxicity. By doubling the reference dose of 40 mmol/kg/day to 80 mmol/kg/day 3HB-Na, illness severity scores doubled and mortality increased from 30.4% to 87.5%. De-escalating this dose to 60 mmol/kg/day still increased mortality and reducing the dose to 48 mmol/kg/day still increased illness severity. Doses of 48 mmol/kg/day and higher caused more pronounced metabolic alkalosis and hypernatremia and increased markers of kidney damage. Doses of 60 mmol/kg/day 3HB-Na and higher caused dehydration of brain and lungs and increased markers of hippocampal neuronal damage and inflammation. Among survivors, 40 mmol/kg/day and 48 mmol/kg/day increased muscle force compared with placebo up to healthy control levels. This study indicated that 40 mmol/kg/day 3HB-Na supplementation prevented sepsis-induced muscle weakness in mice. However, this dose appeared maximally effective though close to the toxic threshold, possibly in part explained by excessive Na+ intake with 3HB-Na. Therefore, we concluded that the clinical use of ketone salts in human critically ill patients is precluded.In a fourth and final objective, we investigated 3-hydroxybutyl-3-hydroxybutanoate (3HHB) esters as a potential alternative for 3HB-Na. These esters are metabolized by the body to form two 3HB molecules, and thus would avoid excessive Na+ supplementation. In septic mice, we assessed efficacy versus toxicity of stepwise escalating doses of 3HHB, potential stereospecific characteristics of 3HHB and compared bolus versus continuous administration of 3HHB to identify the most usable therapy for human patients. In septic mice, as compared with placebo, severity of illness and mortality was increased by bolus injections of L-3HHB at 40 mmol/kg/day and by all other 3HHB formulations at a dose of 80 mmol/kg/day. Compared with placebo, muscle force was increased at 20 mmol/kg/day L-3HHB and at 40 mmol/kg/day D- and D,L-3HHB. Up to a dose of 40 mmol/kg/day 3HHB, signs of organ damage or liver toxicity were absent. However, septic mice showed a higher peak plasma concentration and slower 3HB- clearance than healthy controls. Unlike bolus injections, continuous infusion at doses up to 80 mmol/kg/day D,L-3HHB did not increase severity of illness or mortality as compared with placebo, whereas muscle force was increased at 40 mmol/kg/day. Based on our findings, we concluded that treatment of septic mice with pure and racemic mixtures of the ketone ester 3HHB partly prevented muscle weakness. Doubling the effective ester bolus dose to 80 mmol/kg/day in septic mice was 100% lethal, whereas this toxicity was completely avoided by continuous infusion of the same dose.The studies performed in this doctoral thesis have highlighted the protective potential of 3HB against the loss of muscle force during critical illness. Furthermore, these experiments have shed a light on the underlying mechanisms of the muscle force protective effect of ketone body supplementation during critical illness and provided valuable information on formulation and mode of administration, which is essential for further development of this treatment for future clinical use in the human patient.

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Josquin des Prez and His Musical Legacy is the most up-to-date contribution to the research on one of the most important and internationally famous composers of the Renaissance. This monograph offers factual information on the composer as well as insights into his 16th-century and modern reception, a survey of the sources of his music, and a discussion of the thorny issue of authorship. Willem Elders, one of the most distinguished scholars of Josquin's music, also discusses the influence of Gregorian chant as a source of inspiration and explains the various aspects of Josquin's symbolic language. Each individual work (including some of those in the old Josquin edition now considered inauthentic) receives a short discussion of relevant contextual aspects and interesting musical features. Ranges and lengths are given for each work. The style is adapted to the professional musicologist as well as to the 'music lover' and performer.

78 DES PREZ, JOSQUIN --- Muziek--DES PREZ, JOSQUIN --- Academic collection