System-level metabolic effects of trematode infections in rodent models

Background: Trematode infections impose a great burden on the developing world by impairing life quality, productivity and life span of an individual. The prerequisite for efficient treatment and control of the diseases is the use of a quick and sensitive diagnostic tool which could replace the multi-diagnostic approach that is still used. The metabolic profiling approach implies the use of spectroscopic tools such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) on potentially interesting biofluids and tissues, and is coupled with multivariate mathematical data modelling. It has been applied to many different field of research, such as biochemistry, medical sciences, drug pathway discovery, non-communicable diseases, nutrition and psychological disorders, and has been established as an efficient method for biomarker recovery and pathway deciphering. There is growing interest in metabolic profiling in systems biology. The first attempt to bring together metabolic profiling with the epidemiology of neglected tropical diseases was in mid-2002, when urine samples were obtained from more than 500 individuals in a rural Western part of Côte d’Ivoire. However, it was impossible to extract any meaningful information with regard to specific parasitic infection. The high degree of metabolic variation of the studied population in terms of age, genetic and nutritional background and the fact that the majority of individuals harboured three or more parasites concurrently might explain this observation. My thesis outline was put forward once the metabolic profiles of selected parasitic infections in suitable rodent models, namely Schistosoma mansoni and Trypanosoma brucei brucei in the mouse, and Schistosoma japonicum in the hamster, were established as an alternative to directly exploring human populations in order to ascertain if characteristic biomarkers of infection could be found for single host-parasite scenarios. The success of these experimental investigations encouraged further studies, including the extension of metabolic profiling to other host-parasite models, in order to gain insight into specificity of biomarkers and to reveal the diagnostic potential of this metabolic profiling approach. Goal and objectives: The overarching goal of this Ph.D. project was to deepen our understanding of trematode-induced metabolic changes in selected rodent models, and to critically assess the potential of a metabolic profiling approach applied to biofluids and tissue samples for biomarker recovery that may contain diagnostic and prognostic properties. The specific objectives were (i) to optimise faecal sample preparation for subsequent 1H NMR spectroscopy, and to assess metabolic variation in faecal samples with regard to species (i.e. human, rat and mouse), gender and age, (ii) to assess longitudinally the biochemical changes in urine, plasma and faecal water of E. caproni-infected mice, and to compare the diagnostic capacity of different biofluids collected from infected and uninfected control mice, (iii) to gain information about E. caproni-induced changes in selected tissue samples e.g. (liver, kidney, spleen, ileum, jejunum and colon) of infected mice and correlate identified biomarkers with the previously extracted markers in the biofluids, which might reveal infection-related systems level changes (iv) to evaluate the remote and direct impact of three different trematodes (E. caproni, F. hepatica, S. mansoni) on the rodent host neural metabolic composition. Findings: Comparing the diagnostic templates, all three biofluids showed interesting deviations between uninfected control and E. caproni-infected mice. Urine and plasma were considered as most suitable biofluids due to the large number of potential biomarkers identified and because faecal water showed high fluctuations in the metabolic concentrations over time and a high degree of variation from one animal to another which was significantly higher than in urine and plasma. More detailed metabonomic investigations were performed with E. caproni to assess systems impact on the mouse host. Resulting changes in the metabolic profiles of biofluids and tissue samples were correlated with each other, and revealed new insights into the biological pathomechanisms of this trematode, e.g. impact on gut microbial species and a trematode-induced imbalance of the transporter system in the gut. Whereas E. caproni did not induce any biochemical changes in the neural profile, rats infected with F. hepatica, and mice infected with S. mansoni showed strong deviations from uninfected control animals. F. hepatica-induced changes in the rat brain nucleotide metabolism was correlated to certain cytokine levels, e.g. IFN-γ, IL-5 and IL-13, and was consistent with modulation of the immune mechanisms.This finding provides a rationale for deeper analysis into the interaction of parasitic worms with the central nervous system of the host organism

Discovery of Infection Associated Metabolic Markers in Human African Trypanosomiasis

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Research productivity and main publishing institutions in Côte d'Ivoire, 2000-2016

The research productivity of countries commonly grouped within sub-Saharan Africa is as diverse as their cultural, economic, linguistic, political, and social profiles. While South Africa has been the science hub on the subcontinent for decades, publishing original research articles in the thousands, Mauritania struggles to have a single publication in international indexed journals in any given year. Detailed country-specific accounts on the co-evolution of research productivity and demographic and economic indicators from sub-Saharan Africa are lacking and render an accurate evaluation and cross-country comparison of internal research progress challenging.; We assessed the research productivity of Côte d'Ivoire, a francophone West African country that has gone through considerable socio-political unrest, for the period 2000-2016, and determined the main publishing institutions. We considered original research articles extracted from PubMed and Web of Science Core Collection, emphasizing life sciences and biomedical sciences.; We found the quantity of publications doubling from 4.1 to 8.5 per million population and the 'total product' - a measure for quantity and quality of published articles - rising from 0.8 to 22.1 per million population between 2000 and 2016. Since 2010 there was a marked increase in the proportion of English publications and a concomitant drop in the proportion of articles with Ivorian first and last authors. The percentage of foreign author contribution increased from 38.7% in 2000 to 71.6% in 2016, suggesting an 'internationalization' of the country's research production and output. Mixed authorship compared with 'Ivorian only' showed higher representation in journals with an official impact factor by Web of Science with proportions of 73% versus 28% for 2008 and 91% versus 45% for 2016. Two universities and university hospitals and three autonomous research institutions were consistently among the top 10 institutions publishing peer-reviewed material in three selected years (2000, 2008, and 2016). The main features of the most successful publishing institutions were research staff size, diversification of research portfolio and funding, multiple research bases across the country, and established and productive partnerships with foreign institutions.; Since the turn of the millennium, research productivity in Côte d'Ivoire has steadily grown at an above regional and global rate despite recurring economic pressures and sociopolitical unrest. We have observed benefits of internationalization throughout this current analysis reaching from improved publishing standards to increasing resilience of research institutions in times of crisis

Chemometric analysis of biofluids from mice experimentally infected with Schistosoma mansoni

BACKGROUND: The urinary metabolic fingerprint of a patent Schistosoma mansoni infection in the mouse has been characterized using spectroscopic methods. However, the temporal dynamics of metabolic alterations have not been studied at the systems level. Here, we investigated the systems metabolic changes in the mouse upon S. mansoni infection by modeling the sequence of metabolic events in urine, plasma and faecal water. METHODS: Ten female NMRI mice, aged 5 weeks, were infected with 80 S. mansoni cercariae each. Ten age- and sex-matched mice remained uninfected and served as a control group. Urine, plasma and faecal samples were collected 1 day before, and on eight time points until day 73 post-infection. Biofluid samples were subjected to 1H nuclear magnetic resonance (NMR) spectroscopy and multivariate statistical analyses. RESULTS: Differences between S. mansoni-infected and uninfected control mice were found from day 41 onwards. One of the key metabolic signatures in urine and faecal extracts was an alteration in several gut bacteria-related metabolites, whereas the plasma reflected S. mansoni infection by changes in metabolites related to energy homeostasis, such as relatively higher levels of lipids and decreased levels of glucose. We identified 12 urinary biomarkers of S. mansoni infection, among which hippurate, phenylacetylglycine (PAG) and 2-oxoadipate were particularly robust with regard to disease progression. Thirteen plasma metabolites were found to differentiate infected from control mice, with the lipid components, D-3-hydroxybutyrate and glycerophosphorylcholine showing greatest consistency. Faecal extracts were highly variable in chemical composition and therefore only five metabolites were found discriminatory of infected mice, of which 5-aminovalerate was the most stable and showed a positive correlation with urinary PAG. CONCLUSIONS: The composite metabolic signature of S. mansoni in the mouse derived from perturbations in urina faecal and plasma composition showed a coherent response in altered energy metabolism and in gut microbial activity. Our findings provide new mechanistic insight into host-parasite interactions across different compartments and identified a set of temporally robust biomarkers of S. mansoni infection, which might assist in derivation of diagnostic assays or metrics for monitoring therapeutic respons

Methodological approaches for conducting follow-up research with clinical trial participants: a scoping review and expert interviews

Evidence-based establishment and implementation of best principles, laws and ordinances that regulate clinical research depend on the consultation and involvement of trial participants. Yet, guidance on methodological approaches to obtain trial participants' perspectives is currently missing. This scoping review therefore aimed at identifying, describing and evaluating research approaches to obtain trial participants' feedback on their views and experiences.; We searched the electronic databases Medline and PsycInfo via Ovid and the Web of Science Core Collection. Clinical trials were included that involved adult participants that were conducted in selected high-income countries and that were published in peer-reviewed journals between 1985 and 2018. In addition, 29 expert interviews were conducted between March and May 2019.; Out of 5994 identified records, 23 articles were included in this review. Twelve studies used a qualitative approach, 10 were quantitative and one study used a mixed-method design. More than 75% of all work was conducted in the USA and the UK. The scoping review and the expert interviews highlighted that recruitment of participants was generally done through direct contact by principal investigators and/or study nurses or through searches in de-identified patient databases. Authors used surveys, interviews or focus group discussions. The tools used were either based on existing validated ones or developed and verified de novo with the support of experts and/or patient representatives.; To our knowledge, this is the first methodological literature review of approaches to researching experiences of clinical trial participants where findings were triangulated with expert interviews. Covering a range of indications, trial phases and study settings, it demonstrates that clinical trial participant perspectives and experience is heavily under-researched. This casts doubt on the overall robustness of available insight into trial participants' views and experiences. Our results demonstrate that the methodology for studying participant opinion, perception and experience should be adapted to the measure of interest and conform to the study population. Using valid patient experience data is the basis to evaluate existing legal and regulatory human subject research frameworks for their appropriateness from a patient perspective. Such an evaluation will be critical to empower research participants

Research−implementation organisations and their role for sustainable development

Over the past decade, considerable progress has been made by higher education institutions (HEIs) to align with sustainable development goals. Specifically, aspects of sustainable development have been integrated into the existing mandates of HEIs – education, research and operations. The main objective of the current study was to assess a sub-group of African HEIs that have an explicit mandate for implementation science and pursue development assistance-type services and to describe their added value to advance sustainable development. We conducted a qualitative situational assessment, including 22 institutions from 13 countries. Interviews and surveys were done with 42 participants composed of director-level representatives and staff members engaged both in research and implementation. The data were subjected to qualitative content analysis. The main strengths of the participating organisations vis-à-vis implementation projects and wider sustainable development were the quality of implementation, local relevance of the research and uptake of research evidence into policy and practice. A major weakness was the challenge of operating such a bi-sectoral model, while maintaining high-level performance in both areas. Yet, the examined research implementation institutions draw from and combine the competences of research, education and implementation and have a distinctive role to play in the attainment of sustainable development, especially when operating by an optimised support system and within strong research ecosystems. Based on our study, we provide a definition of research implementation organisations that may serve institutions to enhance their standing, their operations and their significance for sustainable development

Typology, technical efficiency and scale economy of dibiteries in Dakar, Senegal

In recent years, a profound transformation has been observed in the eating habits of the populations of African cities, induced by accelerated socioeconomic and demographic growth. In Senegal, these changes have manifested in the proliferation of collective informal catering enterprises, such as the '; dibiteries; ', where the roasted meat of sheep is prepared and sold. The rise of the average household income has contributed substantially to increasing levels of meat consumption, leading to the expansion of the; dibiteries; . The purpose of the current work was to evaluate the managerial performance of these establishments in Dakar, Senegal.; To achieve this, a cross-sectional study was conducted among 152 ; dibiteries; using a questionnaire. Efficiency scores were determined via the data envelopment analysis method. The pure technical scores thereby obtained were subsequently used as dependent variables in a Tobit model to identify the socioeconomic determinants of; dibiterie; efficiency.; The resulting average score of the; dibiteries; suggests that the majority are operating inefficiently (79.6%). Moreover, it was demonstrated that this inefficiency seems to be related to scale rather than technical issues. However, few of the; dibiteries; assessed (20.4%) were nevertheless in a situation of constant scale economy. Among the socioeconomic variables tested, experience, leadership (family or individual-run), the ownership status of the restaurant building (own or lease) and the type of workforce (family, recruited, mixed or without) had a significant impact on the efficiency of the establishments.; The scale economy and waste reduction in food production can result in economic gains that can in turn be used in the safety of finished products. Indeed, by following best practices,; dibiteries; can make gains which could be used to invest in good hygiene practices on handwashing, cleaning and disinfecting grilling tools, optimizing work space and training staff

Metabonomic Investigation of Single and Multiple Strain Trypanosoma brucei brucei Infections

Although co-infections are common and can have important epidemiologic and evolutionary consequences, studies exploring biochemical effects of multiple-strain infections remain scarce. We studied metabolic responses of NMRI mice to Trypanosoma brucei brucei single (STIB777AE-Green1 or STIB246BA-Red1) and co-infections using a 1H nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling strategy. All T. b. brucei infections caused an alteration in urinary biochemical composition by day 4 postinfection, characterized by increased concentrations of 2-oxoisocaproate, D-3-hydroxybutyrate, lactate, 4-hydroxyphenylacetate, phenylpyruvate, and 4-hydroxyphenylpyruvate, and decreased levels of hippurate. Although there were no marked differences in metabolic signatures observed in the mouse infected with a single or dual strain of T. b. brucei, there was a slower metabolic response in mice infected with T. b. brucei green strain compared with mice infected with either the red strain or both strains concurrently. Pyruvate, phenylpyruvate, and hippurate were correlated with parasitemia, which might be useful in monitoring responses to therapeutic interventions

Pharyngeal Carriage of Beta-Haemolytic Streptococcus Species and Seroprevalence of Anti-Streptococcal Antibodies in Children in Bouaké, Côte d’Ivoire

The pharynx of the child may serve as a reservoir of pathogenic bacteria, including beta-haemolytic group A streptococci (GAS), which can give rise to upper airway infections and post-streptococcal diseases. The objective of this study was to determine the prevalence of beta-haemolytic Streptococcus spp. in pharyngeal samples stemming from children aged 3–14 years in Bouaké, central Côte d’Ivoire. Oropharyngeal throat swabs for microbiological culture and venous blood samples to determine the seroprevalence of antistreptolysin O antibodies (ASO) were obtained from 400 children in March 2017. Identification was carried out using conventional bacteriological methods. Serogrouping was performed with a latex agglutination test, while an immunological agglutination assay was employed for ASO titres. The mean age of participating children was 9 years (standard deviation 2.5 years). In total, we detected 190 bacteria in culture, with 109 beta-haemolytic Streptococcus isolates, resulting in an oropharyngeal carriage rate of 27.2%. Group C streptococci accounted for 82.6% of all isolates, whereas GAS were rarely found (4.6%). The ASO seroprevalence was 17.3%. There was no correlation between serology and prevalence of streptococci (p = 0.722). In conclusion, there is a high pharyngeal carriage rate of non-GAS strains in children from Bouaké, warranting further investigation

Metabolic Profiling of an Echinostoma caproni Infection in the Mouse for Biomarker Discovery

Consumption of raw fish and other freshwater products can lead to unpleasant worm infections. Indeed, such worm infections are of growing public health and veterinary concern, but they are often neglected, partially explained by the difficulty of accurate diagnosis. In the present study we infected 12 mice with an intestinal worm (i.e., Echinostoma caproni) and collected blood, stool, and urine samples 7 times between 1 and 33 days after the infection. At the same time points, blood, stool, and urine were also sampled from 12 uninfected mice. These biofluid samples were examined with a spectrometer and data were analyzed with a multivariate approach. We observed important differences between the infected and the uninfected control animals. For example, we found an increased level of branched chain amino acids in the stool of infected mice and subsequent depletion in blood plasma. Additionally, we observed changes related to a disturbed intestinal bacterial composition, particularly in urine and stool. The combination of results from the three types of biofluids gave the most comprehensive characterization of an E. caproni infection in the mouse. Urine would be the biofluid of choice for diagnosis of an infection because the ease of sample collection and the high number and extent of changed metabolites