Hyperglycemia: causes and consequences

Dekker, J.M. [Promotor]Nijpels, M.G.A.A.M. [Promotor]Alssema, M.J. [Copromotor

Flux switching in magnetic circuits

Flux switching in magnetic circuit

Feasibility study for reliable magnetic connection switch, phase I Final report

Feasibility of magnetic circuits for high reliability computer switche

Axion-de Sitter wormholes

We construct wormholes supported by axion flux in the presence of a positive cosmological constant. The solutions describe compact, one-handle bodies colloquially known as kettlebell geometries. The wormholes are perturbatively stable, but regularity of the Euclidean geometry implies an upper bound on the axion flux. Viewed as no-boundary saddle points, wormholes are suppressed relative to the round sphere. The symmetric kettlebell with maximal axion density has vanishing Euclidean action. Continuing into the Lorentzian across the equator, the solutions describe two expanding branches of de Sitter space filled with an axion field that rapidly dilutes and connected by a quantum bounce across which the arrow of time reverses.Comment: 18 pages, 6 figures. Version to be appear in JHE

Surface coating and particle size are main factors explaining the transcriptome-wide responses of the earthworm Lumbricus rubellus to silver nanoparticles

Due to the unique properties of differently sized and coated silver nanoparticles (AgNPs), they are used in important industrial and biomedical applications. However, their environmental fate in soil ecosystems and potential mechanisms of toxicity remain elusive, especially at the level of transcriptional regulation. We investigated the transcriptome-wide responses of the earthworm Lumbricus rubellus exposed to nine AgNPs differing in surface coating/charge (bovine serum albumin/negative AgNP_BSA, chitosan/positive AgNP_Chit, and polyvinylpyrrolidone/neutral AgNP_PVP) and sizes (20, 35 and 50 nm) at concentrations close to the EC50 value related to reproduction. AgNO3 was used in two concentrations to benchmark the AgNP effects against those of the Ag salt. A correlation was observed between the number of differentially expressed genes (DEGs) and Ag internal body concentration. Only metallothionein was regulated by all treatments. Medium sized AgNPs caused the most pronounced transcriptional responses, while AgNO3 affected the transcriptome less. Medium sized AgNP_BSA exposure caused the most extensive transcriptional responses with 684 DEGs. Gene ontology enrichment analysis of medium sized AgNP_BSA affected DEGs revealed that mitochondrial electron transport, autophagy and phagocytosis, mesoderm and heart development and microtubule organisation were affected. This was also confirmed by gene set enrichment for KEGG pathway analysis, indicating that phagocytosis, autophagy and signalling pathways related to mesoderm formation were significantly up regulated. All AgNP_BSA and AgNP_PVP exposures caused severe down regulation of ribosomal translation, suggesting that the high energy-demanding protein synthesis process is inhibited. Our data confirm the mechanisms previously identified among other animal models and human cell lines. To conclude, coating formulation and particle size severely impact transcriptional responses at a particular nanoparticle size, suggesting diverse mechanistic responses depending on the coating type

Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13(-/-) mice display a strong protection in LPS- and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13(-/-) mice compared to MMP13(+/+) mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13(-/-) mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential

European Paediatric Formulation Initiative workshop report: Improving the administration of oral liquid medicines in paediatrics using dosing syringes and enteral accessories

Accurate dosing of the right medicine to the right patient is a key element of safe and efficacious pharmacotherapy, yet prone to technical challenges and human error when dosing involves the administration of small volumes of liquid medicines. For this reason, the topic has gained increased attention over the last decade from multiple stakeholder parties e.g. academia, hospital pharmacy, the medical device and pharmaceutical industry, and regulatory agencies. It is now well acknowledged that spoons and cups are not suitable for the measurement of small volumes of oral liquid medicines and that syringes are a better alternative, but syringes for parenteral use should not be used for oral dosing in order to avoid accidental parenteral delivery of oral products. However, dosing accuracy of very small volumes of liquid medicines to young children, and especially pre-term neonates, is still not sufficiently ensured. A workshop was organised in 2018 by the European Paediatric Formulation Initiative to reflect on current status and challenges (first part) and possible strategies to improve the present situation (second part). A voting system (n = 24) was used to consider the most favourable solutions. The harmonisation and/or standardisation of the technical design of oral syringes (including e.g. female/male connection) was considered a key priority

Development of cross-protective influenza a vaccines based on cellular responses

Seasonal influenza vaccines provide protection against matching influenza A virus (IAV) strains mainly through the induction of neutralizing serum IgG antibodies. However, these antibodies fail to confer a protective effect against mismatched IAV. This lack of efficacy against heterologous influenza strains has spurred the vaccine development community to look for other influenza vaccine concepts, which have the ability to elicit cross-protective immune responses. One of the concepts that is currently been worked on is that of influenza vaccines inducing influenza-specific T cell responses. T cells are able to lyse infected host cells, thereby clearing the virus. More interestingly, these T cells can recognize highly conserved epitopes of internal influenza proteins, making cellular responses less vulnerable to antigenic variability. T cells are therefore cross-reactive against many influenza strains, and thus are a promising concept for future influenza vaccines. Despite their potential, there are currently no T cell-based IAV vaccines on the market. Selection of the proper antigen, appropriate vaccine formulation and evaluation of the efficacy of T cell vaccines remains challenging, both in preclinical and clinical settings. In this review, we will discuss the current developments in influenza T cell vaccines, focusing on existing protein-based and novel peptide-based vaccine formulations. Furthermore, we will discuss the feasibility of influenza T cell vaccines and their possible use in the future.Drug Delivery Technolog

Impact of dizziness on everyday life in older primary care patients: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Dizziness is a common and often disabling symptom, but diagnosis often remains unclear; especially in older persons where dizziness tends to be multicausal. Research on dizziness-related impairment might provide options for a functional oriented approach, with less focus on finding diagnoses. We therefore studied dizziness-related impairment in older primary care patients and aimed to identify indicators related to this impairment.</p> <p>Methods</p> <p>In a cross-sectional study we included 417 consecutive patients of 65 years and older presenting with dizziness to 45 general practitioners in the Netherlands from July 2006 to January 2008. We performed tests, including patient history, and physical and additional examination, previously selected by an international expert panel and based on an earlier systematic review. Our primary outcome was impact of dizziness on everyday life measured with the Dutch validated version of the Dizziness Handicap Inventory (DHI). After a bootstrap procedure (1500x) we investigated predictability of DHI-scores with stepwise backward multiple linear and logistic regressions.</p> <p>Results</p> <p>DHI-scores varied from 0 to 88 (maximum score: 100) and 60% of patients experienced moderate or severe impact on everyday life due to dizziness. Indicators for dizziness-related impairment were: onset of dizziness 6 months ago or more (OR 2.8, 95% CI 1.7-4.7), frequency of dizziness at least daily (OR 3.3, 95% CI 2.0-5.4), duration of dizziness episode one minute or less (OR 2.4, 95% CI 1.5-3.9), presence of anxiety and/or depressive disorder (OR 4.4, 95% CI 2.2-8.8), use of sedative drugs (OR 2.3, 95% CI 1.3-3.8) , and impaired functional mobility (OR 2.6, 95% CI 1.7-4.2). For this model with only 6 indicators the AUC was .80 (95% CI .76-.84).</p> <p>Conclusions</p> <p>Dizziness-related impairment in older primary care patients is considerable (60%). With six simple indicators it is possible to identify which patients suffer the most from their dizziness without exactly knowing the cause(s) of their dizziness. Influencing these indicators, if possible, may lead to functional improvement and this might be effective in patients with moderate or severe impact of dizziness on their daily lives.</p