The results described in this thesis expand and deepen the knowledge of the disease burden that several groups of Dutch travelers can face while traveling abroad and after returning home, varying... Show moreThe results described in this thesis expand and deepen the knowledge of the disease burden that several groups of Dutch travelers can face while traveling abroad and after returning home, varying from young medical students to the older traveler. One can think of communicable diseases (e.g. enteric- and respiratory infections), non-communicable diseases (e.g. exacerbation of cardiovascular diseases or mental disorders) and (road-traffic-related) injuries. In addition, travelers can also face non-medical challenges such as culture shock and violence. Travelers can also become colonized with resistant bacteria (e.g. ESBL-E) while staying abroad. Active surveillance and contact isolation precautions may then be recommended when a traveler returns from a destination in Asia, and is admitted to the hospital in the home country. The different studies provide more insights and practical advices regarding pre-travel information, which attributes both to practical tailored travel advice for Dutch travelers and will also be of interest for future research in the evolving world of travel medicine. Show less
Aims: Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and... Show moreAims: Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria -specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on fem-oral implants using clinical -grade image guidance methods. Methods: 99mTc-UBI29-41- Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cul-tured on femoral prostheses using fluorescence imaging and freehand single photon emis-sion CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria. Results: Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be com-plemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were iden-tified using imaging, which included 500 to 2,000 viable bacteria.Conclusion: The hybrid tracer99mTc-UBI29-41-Cy5 allowed effective bacterial staining. Qualitative real -time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Show less
Aims Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and... Show moreAims Arthroplasty surgery of the knee and hip is performed in two to three million patients an-nually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiot-ics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria -specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on fem-oral implants using clinical -grade image guidance methods.Methods 99mTc-UBI29-41- Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cul-tured on femoral prostheses using fluorescence imaging and freehand single photon emis-sion CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria.Results Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be com-plemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were iden-tified using imaging, which included 500 to 2,000 viable bacteria.Conclusion The hybrid tracer99mTc-UBI29-41-Cy5 allowed effective bacterial staining. Qualitative real -time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Show less
Background: Travelers can experience health problems while abroad. This descriptive study aimed to quantify the disease burden leading to hospital-based care, repatriation or death in Dutch... Show moreBackground: Travelers can experience health problems while abroad. This descriptive study aimed to quantify the disease burden leading to hospital-based care, repatriation or death in Dutch travelers during a stay in a foreign country, including Europe. Methods: Retrospective study of demographic and clinical data from three medical assistance centers (MACs) and the Dutch Ministry of Foreign Affairs on Dutch travelers receiving hospital-based care or who died abroad in the years 2010-2014. Diagnoses were coded according to the International Classification of Diseases (ICD) and classified using the Global Burden of Disease tool. Results: Data was available for 77,741 travelers' incidents: 75,385 medical consultations and 2,356 deaths. Four in five travelers received inpatient care, of which 36% concerned older travelers (65+) who had significantly longer hospital stays. Overall the top three diagnoses were: injuries (29%), infectious diseases (17%), and car-diovascular diseases (17%). Mental illness was reported in nearly 1.5% of the travelers. Incidence proportions were highest in South-Eastern Asia, with enteric infections as most common diagnosis. Injuries and communi-cable diseases occurred most often in South-Eastern Asia, while non-communicable diseases were mostly re-ported in South America. One in five travelers who consulted a physician was repatriated back home, mostly on a scheduled flight with or without medical escort. Cardiovascular diseases and injuries were the leading causes of death. Conclusions: Not only communicable diseases, but also injuries and chronic diseases (in particular cardiovascular diseases) frequently affected travelers' health while staying abroad and frequently necessitated hospital-based care. This should be addressed during the pre-travel counseling. Show less
Despite developments in the prevention of invasive aspergillosis, the incidence rates are up to 10% in high risk groups. Within high risk groups, individual patients with an even higher risks can... Show moreDespite developments in the prevention of invasive aspergillosis, the incidence rates are up to 10% in high risk groups. Within high risk groups, individual patients with an even higher risks can be identified, such as those suffering from relapsed AML. Mortality of IA is high within all populations and is mainly found in the first 30 days after diagnosis. Because of the serious nature of the underlying diseases that predispose for IA, it can be challenging to quantify the contribution of IA to mortality; crude mortality rates cannot distinguish death due to IA-unrelated causes from IA-related death, almost certainly leading to inflation of mortality rates. It can be helpful to assess contributability of IA to death to provide a better understanding of the impact of IA in this vulnerable patient population. Additionally, we have explored the new problem that is posed by the increase of triazoleresistant Aspergillus fungi, resulting in challenges in the application of antifungal therapies. Treatment strategies involving the use of LAmB are becoming more prevalent in areas withhigh resistance rates, but should be applied with care due to concerns of renal toxicity and decreased efficacy against triazole-susceptible isolates when compared to voriconazole. Rational application of PCR could help us to initiate the right therapy sooner, by possibly providing information about the susceptibility of the Aspergillus fungus. Show less
Background Bacterial infections are still a major global healthcare problem. To combat the increasing antimicrobial resistance, early diagnosis of bacterial infection-including the identification... Show moreBackground Bacterial infections are still a major global healthcare problem. To combat the increasing antimicrobial resistance, early diagnosis of bacterial infection-including the identification of bacterial specie-is needed to improve antibiotic stewardship and to help reduce the use of broad-spectrum antibiotics. To aid successful targeted antibiotic treatment, specific detection and localisation of infectious organisms is warranted. Nuclear medicine imaging approaches have been successfully used to diagnose bacterial infections and to differentiate between pathogen induced infections and sterile inflammatory processes.Aim In this comprehensive review we present an overview of recent developments in radiolabelled bacterial imaging tracers.Methods The PubMed/MEDLINE and Embase (OvidSP) literature databases were systematically searched for publications on SPECT and PET on specific imaging of bacterial using specific guidelines with MeSH-terms, truncations, and completion using cross-references. Tracers in literature that was extensively reviewed before 2016 were not included in this update. Where possible, the chemical structure of the radiolabelled compounds and clinical images were shown.Results In 219 original articles pre-clinical and clinical imaging of bacterial infection with new tracers were included. In our view, the highest translational potential lies with tracers that are specific to target the pathogens: e.g., Tc-99m- and Ga-68-labelled UBI29-41, Tc-99m-vancomycin, m-[F-18]-fluoro-PABA, [methyl-C-11]-D-methionine, [F-18]-FDS, [F-18]-maltohexaose and [F-18]-maltotriose. An encouraging note is that some of these tracers have already been successfully evaluated in clinical settings.Conclusion This review summarises updates in tracer development for specific (pre-clinical and clinical) imaging of bacterial infections. We propsed some promising tracers that are likely to become innovative standards in the clinical setting in the near feature. Show less
Antibiotic resistance is an increasing problem in the battle against (bacterial) infectious diseases. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) threatens to render... Show moreAntibiotic resistance is an increasing problem in the battle against (bacterial) infectious diseases. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) threatens to render tuberculosis (TB) untreatable. Efforts to develop novel antibiotics have so far been unsuccessful, calling for additional approaches for treatment of bacterial infections. Intracellular pathogens like Mtb and Salmonella can survive in the host by manipulating host cell signaling. This provides opportunities for novel therapeutic strategies by targeting the host, rather than the bacterium (host-directed therapy). In this thesis we report the development and application of novel (in vitro and in vivo) methods for identifying host genes and proteins involved in host control of intracellular bacteria, as well as chemical compounds that target host molecules as a basis for drug development for host-directed therapies. As a result, we report the identification of RTK inhibitors, the novel kinase inhibitor 97i, the human kinase family PCTAIRE and the host protein DRAM1 as promising leads for further drug development for host-directed therapeutic strategies for intracellular bacterial infections. Show less
Wijnakker, R.; Visser, L.E.; Schippers, E.F.; Visser, L.G.; Burgel, N.D. van; Nieuwkoop, C. van 2019
Infection of burn wounds remains the leading cause of death in burn patients. Topical treatment of such infections with conventional antibiotics is often unsuccessful due to the presence of... Show moreInfection of burn wounds remains the leading cause of death in burn patients. Topical treatment of such infections with conventional antibiotics is often unsuccessful due to the presence of drug-resistant bacteria and/or to the formation of bacterial biofilms. Taken together there is a clear need for novel antimicrobial agents with modes of action different that of current antibiotics. Identification of new synthetic peptide antibiotics for topical use holds a promising approach. In vitro skin models pose many similar properties as normal human skin, and are often used in laboratory settings. In this thesis in vitro models were used to study the effect of colonization and infection of healthy skin, (thermally) wounded skin (chapter 2), mucosal membranes (chapter 3) and skin with characteristics of atopic dermatitis (chapter 6). In addition, the difference in bacterial biofilm formation on biotic (in vitro skin models) versus a-biotic surfaces (polystyrene) was investigated (chapter 7). Finally, skin models were used to identify potent synthetic antimicrobial peptides against drug-resistant bacteria such as Staphylococcus aureus (chapter 3,4). These peptides proved to be effective when applied topically in saline, but also in a hydrogel (chapter 5). Show less
Groot, B. de; Stolwijk, F.; Warmerdam, M.; Lucke, J.A.; Singh, G.K.; Abbas, M.; ... ; Rijpsma, D. 2017
Currently, only one tuberculosis (TB) vaccine is available: Mycobacterium bovis Bacille Calmette-Gu_rin (BCG). This vaccine induces highly variable protection against pulmonary TB, the most common... Show moreCurrently, only one tuberculosis (TB) vaccine is available: Mycobacterium bovis Bacille Calmette-Gu_rin (BCG). This vaccine induces highly variable protection against pulmonary TB, the most common and contagious form of TB. There is an urgent need for an effective TB vaccine which is safe also in the immunocompromised host. The main focus of this thesis was to identify Mycobacterium tuberculosis (Mtb) infection phase related antigens and to evaluate these as potential antigens for TB vaccines. The studies presented in this thesis describe: (i) the immunogenic potential of two previously described sets of antigens; resuscitation promoting factor (Rpf) and dormancy regulon encoded (DosR) antigens, (ii) the identification and immunogenicity of a third set of antigens known as in vivo expressed Mtb (IVE-TB) antigens, (iii) the protective value of IVE-TB antigen Rv2034 and (iv) the analysis of Rv2034-specific T cell r esponses at the clonal level. Together, these data illustrate the vaccine potential of infection phase related antigens. Show less
Lalwani, P.; Raftery, M.J.; Kobak, L.; Rang, A.; Giese, T.; Matthaei, M.; ... ; Schonrich, G. 2013
Analysis of the transcriptome, the total of all expressed RNA transcripts in a cell or an organism, contributes to our understanding of gene regulation during development and disease processes and... Show moreAnalysis of the transcriptome, the total of all expressed RNA transcripts in a cell or an organism, contributes to our understanding of gene regulation during development and disease processes and is therefore of great importance in the field of genomic research. This thesis focuses on the analysis of transcriptome complexity during infectious disease and cancer. The zebrafish was applied as an immunological model organism, due to the remarkable similarities of its immune system to that of human. The studies took advantage of novel opportunities for transcriptome profiling provided by recent developments in microarray and next generation sequencing technology that have made an enormous impact on biology. In addition to studying expression of protein coding genes, the work addressed regulatory functions of microRNAs, small non-coding RNAs playing important roles in the function of the immune system and other processes. The transcriptome data provide a valuable reference set of infection-responsive genes and microRNAs in zebrafish models and have identified microRNAs conserved between human and zebrafish liver cancer. These genomic data sets provide a strong basis for future applications of zebrafish as an infection and cancer model and contribute to the understanding of pathogenesis and the development of novel strategies for disease treatment. Show less
