The work described in this Thesis is focused on the assembly of oligosaccharide fragments derived from a fungal polysaccharide, galactosaminogalactan (GAG) and fragments of the exopolysaccharide... Show moreThe work described in this Thesis is focused on the assembly of oligosaccharide fragments derived from a fungal polysaccharide, galactosaminogalactan (GAG) and fragments of the exopolysaccharide Pel, generated by Pseudomonas aeruginosa. To assemble the corresponding oligosaccharides, synthetic methodologies, enabling the stereoselective construction of the required cis-glycosidic linkages has been developed. These synthetic fragments will be valuable tools to elucidate the biosynthesis of GAG and Pel, and characterize the enzymes involved therein. Show less
Objectives: In the pre-azole era, central nervous system (CNS) infections with Aspergillus had a dismal outcome. Survival improved with voriconazole but CNS infections caused by azole-resistant... Show moreObjectives: In the pre-azole era, central nervous system (CNS) infections with Aspergillus had a dismal outcome. Survival improved with voriconazole but CNS infections caused by azole-resistant Aspergillus fumigatus preclude its use. Intravenous liposomal-amphotericin B (L-AmB) is the preferred treatment option for azole-resistant CNS infections but has suboptimal brain concentrations.Methods: We describe three patients with biopsy-proven CNS aspergillosis where intraventricular L-AmB was added to systemic therapy. Two patients with azole-resistant aspergillosis and one patient with azole-susceptible CNS aspergillosis were treated with intraventricular L-AmB at a dose of 1 mg weekly.Results: We describe three patients successfully treated with a combination of intravenous and intraventricular L-AmB. All three patients survived but one patient developed serious headaches, most likely not related to this treatment.Conclusions: Intraventricular L-AmB may have a role in the treatment of therapy-refractory CNS aspergillosis when added to systemic therapy. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. Show less
The T-cell mediated immune response to Aspergillus fumigatus was studied in healthy individuals and in several patient groups. In peripheral blood of healthy individuals low frequencies of... Show moreThe T-cell mediated immune response to Aspergillus fumigatus was studied in healthy individuals and in several patient groups. In peripheral blood of healthy individuals low frequencies of Aspergillus-specific CD4+ T-cells with a Thelper 1 profile were present. In patients with invasive aspergillosis after allogeneic stem cell transplantation Aspergillus-specific T-cells with a Thelper 1 phenotype increased in peripheral blood at the moment of improvement of aspergillus lesions. On the other hand, in patients with allergic bronchopulmonary aspergillosis Aspergillus-specific T-cells with a Thelper 2 phenotype were present, these were directed both to the classical described Aspergillus allergens Aspf1, Aspf2, Aspf3 and Aspf4, as well as to other Aspergillus antigens Crf1 and Catalase1. In COPD patients lung-derived Aspergillus-specific T-cells were characterized and showed a Thelper17 phenotype, in contrast to the Thelper1 phenotype that was present in peripheral blood. Finally, the interplay between different immune cells was studied in an in vitro model. CD4+ T-cells improved the phagocytosis capacity of neutrophil granulocytes, but not of monocytes. Show less
