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Contains fulltext : mmubn000001_026634295.pdf (Publisher’s version ) (Open Access) Promotor : C. Haanen 79 p.

Contains fulltext : 30950_reguofal.pdf (Publisher’s version ) (Open Access) Contains fulltext : 53670.pdf (Publisher’s version ) (Open Access) RU Radboud Universiteit Nijmegen, 19 december 2007 Promotor : Pauw, B.E. de Co-promotores : Joosten, I., Hilbrands, L.B. 192 p.

Contains fulltext : 51787.pdf (Publisher’s version ) (Open Access) RU Radboud Universiteit Nijmegen, 24 mei 2007 Promotor : Pauw, B.E. de Co-promotores : Joosten, I., Hilbrands, L.B. 159 p.

Contains fulltext : 26945_mucobaina.pdf (Publisher’s version ) (Open Access) The intensive chemotherapy with or without radiation therapy used to prepare for a haematopoietic stem cell transplant (HSCT) is unfortunately complicated by damage to the mucosa of the digestive tract. The resultant, mucosal barrier injury (MBI) causes painful ulcerations, which are readily apparent in mouth and are known as mucositis. This makes eating and drinking difficult at a time when patients need optimal nutrition. Moreover until very recently there were no specific remedies of proven value. Patients had to rely on pain relief and other palliative measures to alleviate the symptoms of mucositis. MBI is a dynamic and complex pathobiological process consisting of 4 phases; an inflammatory-, epithelial-, ulcerative/infective- and a healing phase. Initially, small intestinal epithelial cells secrete pro-inflammatory cytokines after exposure to cytotoxic therapy. This phase is mediated by nuclear factor-kappa B activation. Curcumin is able to inhibit this process, resulting in partial amelioration of villous atrophy providing a potentially new approach preventing MBI. MBI was measured among more than 100 HSCT recipients by scoring oral mucositis, determining gut toxicity (nausea, vomiting, diarrhoea and cramps) and by undertaking a permeability test consisting of four sugars (D-xylose, 3-O-methyl-D-glucose, L-rhamnose and lactulose). These features of MBI were significantly correlated with each other but each tool measured a different aspect of MBI. Gut integrity and absorption were still abnormal 3 to 4 weeks after transplant. Novel use was also made of serum citrulline to determine intestinal MBI since the amino acid is a marker of small bowel enterocyte mass. The results showed citrulline to be a more sensitive and specific marker of gut MBI than the other tools. A prospective, randomised, double-blinded, placebo-controlled study with glutamine-dipeptide supplementation failed to ameliorate MBI in HSCT recipients. However it became clear that a significant increase in the levels of inflammatory response markers (IL-8, LBP and CRP) was seen in patients mirroring the pattern of MBI. These markers were already significantly elevated before the onset of fever or bacteraemia during profound neutropenia suggesting that the degree of MBI rather than bacteraemia determines the intensity of this inflammatory response. Hence, aiming either to down-regulate the inflammatory response or at restoring the barrier by stimulating epithelial cell functioning may be more fruitful in protecting HSCT recipients from infectious complications than antimicrobial therapy. RU Radboud Universiteit Nijmegen, 27 juni 2005 Promotor : Pauw, B.E. de Co-promotores : Donnelly, J.P., Schattenberg, A.V.M.B. 186 p.

Contains fulltext : 19528.pdf (Publisher’s version ) (Open Access) Transplantation of an allogeneic donor organ results in recipient T cell activation. Under normal circumstances there is a balance between aggressive T cells and suppressive regulatory T cells. In case of transplantation especially the aggressive T cells will divide and initiate rejection. Nowadays, immunosuppressive drugs are used to inhibit T cell expansion, thereby preventing graft rejection. These drugs have many side effects and act in a non-antigen specific way, meaning that also desired T cell responses against pathogens are inhibited. Hence, it is crucial to develop donor specific immuno suppressive modalities. This might be established by therapeutic approaches that shift the balance between aggressive and suppressive regulatory T cell towards donor specific regulatory T cells. In our laboratory we focus on donor specific immunotherapy with ex vivo generated donor (alloantigen)-specific regulatory T cells. In this thesis, ex vivo generation and expansion protocols are described that result in donor antigen-specific regulatory T cells. These cells are of great importance for donor specific immunotherapy in transplantation and offer a route to permanent graft survival without the need for life-long non-specific immunosuppression. KUN Katholieke Universiteit Nijmegen, 12 november 2004 Promotor : Pauw, B.E. de Co-promotor : Joosten, I. 200 p.

Item does not contain fulltext KUN, 08 oktober 2003 Promotor : Pauw, B.E. de Co-promotores : Verweij, P.E., Meis, J.F.G.M.

Item does not contain fulltext KUN, 08 oktober 2003 Promotores : Pauw, B.E. de, Hoog, G.S. de Co-promotores : Verweij, P.E., Meis, J.F.G.M.

Item does not contain fulltext KUN, 27 februari 2002 Promotor : Pauw, B.E. de Co-promotores : Donnelly, J.P., Raemaekers, J.M.M.

Contains fulltext : 19230_antisutea.pdf (Publisher’s version ) (Open Access) In this thesis two parameters of in vitro antifungal susceptibility testing of filamentous fungi, the medium and the quantification of fungal growth, were investigated and different drug interaction models were used for analyzing the in vitro combination of various antifungal drugs. A microbroth kinetic system was developed in order to analyze the growth curves of three species of filamentous fungi in five different nutrient media. Two colorimetric methods based on the reduction of the tetrazolium salts, MTT and XTT, was evaluated for the MIC determination of different antifungal drugs against different species of filamentous fungi. High levels of agreement were found between the colorimetric medthods and the NCCLS method for all drugs and species tested. The in vitro combination of terbinafine with three azoles, namely itraconazole, voriconazole and miconazole was tested against clinical S. prolificans isolates using the spectrophotometric method, the colorimetric MTT method and a modified MTT method. In addition, the results were analyzed with parametric and non-parametric approaches of the Loewe additivity and Bliss independence zero interaction theories. Strong synergy was found between terbinafine and the three azoles with miconazole and voriconazole showing the strongest synergy based on Loewe additivity and Bliss independece theory, respectively. Less variable results were obtained with the modified MTT method. Despite its simplicity, results of the FIC index model depended on the choice of MIC endpoints and interpretation endpoints. Furthermore it lacked of good summary. Although the model described by Prichard et al. resulted in a concentration dependent mosaic of interactions, replicates were required for statistical evaluation of the results, good summary was absent and the results were dependent on the concentration range used. The fully parametric model described by Greco et al., although it did not describe precisely the response surface of antifungal combinations, was able to distinguish synergistic and antagonistic interactions and summarized the interaction with a non-unit concentration independent interaction parameter including statistically significance levels without requiring replicates 130 p.