References of "Dissertations and theses"
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See detailLes dystonies focales de l'enfant
DEPIERREUX, Frédérique ULiege

Master of advanced studies dissertation (2020)

Children focal dystonias: their etiologies, differential diagnosis, investigations and treatment. Case report serie (DYT1, DYT28, DYT11, etc.).

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See detailBioanalytical applications of surface-enhanced Raman scattering: The protein corona challenge
Dumont, Elodie ULiege

Doctoral thesis (2020)

Concurrently with the recent expansion and diversification of bioanalytical applications, a wealth of analytical tools has developed to meet the expectations of bioanalysis. Among these tools, surface ... [more ▼]

Concurrently with the recent expansion and diversification of bioanalytical applications, a wealth of analytical tools has developed to meet the expectations of bioanalysis. Among these tools, surface-enhanced Raman scattering (SERS) stands out as an attractive alternative to separative techniques. SERS is indeed non-destructive, fast and can be used for identification and quantification purposes. In addition, SERS benefits from an increased sensitivity compared to conventional Raman spectroscopy, making it more suited to the detection of low concentrations of analytes that are often encountered in bioanalysis. However, some roadblocks on the way towards the use of SERS in routine bioanalyses have been identified. Complex biological matrices often call for either sample preparation or smart SERS substrate surface functionalisation. The former denatures the sample and requires additional steps of sample handling with frequent use of organic solvents, which are harmful for the environment. The latter can be laborious to carry out, needs experienced staff and is limited to some specific analytes. Moreover, in view of routine analyses, repeatability and reproducibility of the SERS substrate preparation must be achieved since they are prerequisites to successfully validate the analysis method. This unfortunately remains an exception in the field. Consequently, this thesis was dedicated to the investigation of easily implementable strategies to conduct SERS analyses in biological matrices. To guarantee simple method transposal, these strategies essentially made use of suspensions of chemically reduced nanoparticles, which represent the most straightforward and economical SERS substrates. Dopamine was selected as analyte, given its great SERS activity and its involvement in several widespread diseases (e.g. Parkinson’s disease, schizophrenia, addictions). The resulting matrix was the complete culture medium of a model cell line used to study dopamine secretion, namely rat phaeochromocytoma PC-12 cells. A major issue was experienced all thesis long, the protein corona. This corona consists of a layer of proteins that coats the surface of the SERS substrates, preventing nanoparticles aggregation, thus hot-spot formation, and that competes with analytes for the surface of the SERS substrate. As a result, this work focussed on solving protein coronarelated problems. First and foremost, after having identified gold nanoparticles (AuNPs) as the most suitable SERS substrate for dopamine detection, the transfer of their synthesis protocol was assessed between two laboratories. Despite the use of different laboratory hardware, an exhaustive characterisation of the synthesised AuNPs demonstrated that the synthesis protocol could be successfully transferred, providing that critical parameters are under control. Then, a first strategy was established for the quantification of dopamine in cell culture media through colloidal AuNPs. It was based on the pre-aggregation of the colloid before adding the matrix, in order to circumvent the stabilisation issue brought about by the protein corona. The optimal proportions of reagents, determined by experimental design, enabled dopamine quantification from 0.5 to 50 ppm (2.64 – 264 µM) in the culture medium of PC-12 cells. The specificity of the method towards dopamine was also demonstrated and the exocytosis process of dopamine in PC-12 cells could be studied with the developed methodology. A preliminary study was afterwards carried out to investigate whether it was possible to increase the sensitivity and the specificity of dopamine detection with smartly functionalised AuNPs. A dual-mode SERS and fluorescence aptasensor was ergo imagined to benefit from both techniques advantages and its synthesis and sample preparation were optimised. The binding of dopamine to its specific aptamer was confirmed by surface plasmon resonance spectroscopy. Nonetheless, the determination of dopamine in a phosphate buffer by fluorescence lacked sensitivity, with an approximate limit of detection of 12.5 ppm (65.9 µM). Dopamine determination by SERS was also tricky because of the complex and noisy spectra obtained. Another solution to the protein corona stabilisation problem lay in the use of solid SERS substrates, since hot-spots naturally occur in this kind of substrates. The performances of three classes of solid SERS substrates were compared, in terms of dopamine detection in culture medium, of immersion resistance and of biocompatibility. Unlike substrates prepared by advanced physical technologies, polymeric substrates entrapping NPs were able to quantify dopamine in complex matrices. However, cells could not be cultured on these substrates due to a lack of cellular adhesion. The last kind of substrate investigated, glass coated with poly-L-lysine and AuNPs, was biocompatible. Still, dopamine determination in biological matrices was hampered due to protein surface fouling. This is why an original device capable of removing proteins from the analysed medium was developed. It derived from the use of ultracentrifugation membranes as effective protein retaining element between 2 compartments: the upper one containing the biological sample and the bottom one holding the SERS substrate and a clean collection medium like phosphate buffer. After the investigation of the acquisition and configuration parameters, the device was successfully applied to real-time monitoring. Gradually adding sample complexity, the diffusion process of a SERS label, 2-mercaptopyridine, followed by that of a neurotransmitter, serotonin, were first tracked. The distinction between highly and weakly metastatic pancreatic ductal adenocarcinoma cells was afterwards examined with the device. Based on differential metabolic metabolites production rates, discrimination between both cell types could be established. Finally, some clues were given about surface functionalisation important features. It was indeed noticed during this work that parameters such as the label nature and concentration, the solvent, the pH or the preservation conditions of the label solutions could impact the intensity and band position in SERS spectra. In conclusion, the results expounded in this thesis clearly confirm the potential of SERS for bioanalyses. Even so, remaining challenges will need to be taken up to see clinical applications of SERS methods flourishing. Achieving reproducible and efficient SERS substrates preparation and specifically attracting the analytes onto their surface are examples of such challenges to be risen. [less ▲]

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See detailEtat de santé des détenus en milieu carcéral: cas de la Prison Centrale de Mbujimayi
Kalonji, Muasa Patoka ULiege

Doctoral thesis (2020)

Cette thèse tend à identifier les problèmes de santé de la population pénitentiaire de la prison centrale de Mbujimayi. Elle tente de démontrer que les milieux pénitenciers restent moins salubres et ... [more ▼]

Cette thèse tend à identifier les problèmes de santé de la population pénitentiaire de la prison centrale de Mbujimayi. Elle tente de démontrer que les milieux pénitenciers restent moins salubres et favorisent la contamination des maladies. Les conditions d’hygiène restent précaires et exposent les détenus aux potentielles maladies infectieuses. Les décès qui ont été enregistrés à la prison avaient pour origine le manque d’une alimentation adéquate, le manque d’une pratique de dépistage et les conditions de détention précaires dans un espace très exigu. A ce tableau vient s’ajouter une surpopulation carcérale, trois fois supérieure à la construction du départ. Les cellules dortoirs qui étaient pour dix personnes sont devenues de plus de cinquante personnes. L’accessibilité aux soins de santé reste un problème tant que le patient n’a pas en retour ce qu’il attend des soignants. Le personnel de santé est présent sans moyens pour administrer convenablement les soins de santé aux patients détenus. Le détenu qui se trouve dans un état d’indulgence est incapable de survenir à ses besoins les plus élémentaires, ajouter à celui de se faire soigner et faire face aux frais qu’exigent la procédure de la justice, tout cela ne fait qu’aggraver son état de santé. La perception négative de leur vécu carcéral est révélatrice d’un mauvais traitement qui contraint les détenus à vivre dans l’indignité. Cette dissertation plaide pour que les responsables sanitaires au plus haut niveau prennent en charge la santé des prisonniers et garantissent un traitement humain. Une bonne législation sanitaire devrait garantir une détention digne. [less ▲]

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See detailÉvaluation sur le retentissement psycho-affectif du patient de l'utilisation de l'imagerie médicale combinant les images du scanner et la dosimétrie en tant qu'outil d'éducation thérapeutique en radiothérapie médicale : une étude de faisabilité
Kirkove, Delphine ULiege

Master's dissertation (2020)

Problem studied: Lung cancer is major public health problem because of its high frequency and high mortality. Its usual treatment consists in taking advantage of radiotherapy, combined or not with ... [more ▼]

Problem studied: Lung cancer is major public health problem because of its high frequency and high mortality. Its usual treatment consists in taking advantage of radiotherapy, combined or not with chemotherapy, with significant medical side-effects and psycho-affective impact, which harms the quality of life. Even though information is already given to patients, the use of the personal medical images as a tool for therapeutic education has not been studied yet. Population: Adult patients with lung cancer or with lung metastasis, benefiting from external radiotherapy treatment in the radiotherapy department of the CHU of Liège. Method: Experimental study of type “randomized controlled trial”, where the patients were followed over four periods of time and distributed by randomization into an experimental group and a control group. The sample size consisted of a total of 42 patients. As the considered intervention, the patients from the experimental group have viewed their personal CT-Scanner combined with the dosimetry associated with their personal treatment plan, thanks to the “Stone of Orthanc” software, together with explanations from the radiotherapist. The aim of the study was to measure the impact of the intervention according to Kirkpatrick's levels: satisfaction, feeling of involvement, perception of knowledge, feeling of to be prepared, therapeutic adherence and psycho-social impact (anxiety, depression and emotional distress). Two secondary objectives were aimed at the evaluation of the computer program and the indirect impact of the intervention on the nursing staff. Key elements of the critical analysis: The data collection had to be prematurely stopped because of the COVID-19 crisis. Nonetheless, this study highlights several positive, although non-significant results on the side of the experimental group, in particular an improvement of knowledge and a reduction of the psychosocial impacts. As a consequence, the use of medical imaging could bring added value through the individualization of the content and its ability to create and internalize cognitive links, thus developing the skills of the patient. [less ▲]

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See detailPatient-Specific Metabolic Variability and Precision Glycaemic Control in Critical Care
Uyttendaele, Vincent ULiege

Doctoral thesis (2020)

Critically ill patients often experience stress-induced hyperglycaemia. Elevated blood glucose levels are associated with increased morbidity and mortality. Glycaemic control demonstrated improved ... [more ▼]

Critically ill patients often experience stress-induced hyperglycaemia. Elevated blood glucose levels are associated with increased morbidity and mortality. Glycaemic control demonstrated improved outcomes for these patients. However, other studies failed to replicate the results, primarily blaming the increased risk of hypoglycaemia and glycaemic variability, both associated with worse outcomes. These confounding outcomes have resulted in acceptance of hyperglycaemia and reduced outcomes, causing ongoing debate on glycaemic control. The goal of the thesis is to define what makes glycaemic control hard to achieve safely, prove safe, effective control impacts patient outcome, and demonstrate it is possible to achieve safe, effective control for all patients, despite targeting lower glycaemic ranges. Metabolic variability is the main factor making glycaemic control hard to achieve safely. More specifically, sudden changes in patient-specific response to insulin (intra-patient variability) can lead to severe hyper- and hypo- glycaemia. Novel analysis of model-based insulin sensitivity and its variability clearly showed while inter-patient variability can be significantly different across patients, intra-patient variability is equivalent. Therefore, no patient is harder nor easier to control, and thus all patients should be able to benefit from similar quality of control. In turn, conclusions on glycaemic control from studies failing to do so may be biased due to poor protocol design, rather than physiological factors related to severity and outcome. Intra-patient variability is still very large, and it is not possible to discriminate more and less variable patients, reducing the quality of control deliverable in practical clinical scenarios. This research developed a novel 3D stochastic model to optimally segregate more and less variable patients based on prior behaviours. This approach enabled significantly improved, and tighter prediction of risks associated with a given insulin and/or nutrition intervention. Clinical trial results in NZ have shown improved control and safety using this new 3D stochastic model. To demonstrate these outcomes, a clinical trial using STAR, a model-based, patient-specific glycaemic control framework, was designed and implemented at the University Hospital of Liège. Results showed STAR succeeded in providing safe, effective control to virtually all patients, despite targeting lower target bands associated with better outcomes. However, increased workload compared to the standard protocol was identified as a limitation. Finally, this thesis develops a means to dramatically increase the STAR measurement interval from 1-3 hourly to 1-6 hourly without significantly degrading performance or safety. Virtual trials clearly defined the risk and reward trade-off between control performance, patient safety, workload, and nutrition. This result allows clinical staff to choose from a far wider range of options and approaches to provide safe, effective control, with clearly defined risk trade-offs. Overall, a series of analyses and clinical trials have shown safe, effective control is necessary to improve outcomes, and can be achieved for all patients. These outcomes are possible using patient-specific, model-based glycaemic control protocols developed in this thesis, which directly account for both intra- and inter- patient variability and reduce workload. [less ▲]

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See detailNon-invasive Brain Stimulation in Post Comatose States
Martens, Géraldine ULiege

Doctoral thesis (2020)

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See detailInvestigation de l'accès à des plantes médicinales et des médicaments antipaludiques de qualité en territoires périurbains de Kinshasa
Mavungu Landu, Don Jethro ULiege

Doctoral thesis (2020)

This study was conducted with the aim of providing a better understanding of the access to and quality of herbal and antimalarial medicines, as well as the pharmacodynamic interactions that could result ... [more ▼]

This study was conducted with the aim of providing a better understanding of the access to and quality of herbal and antimalarial medicines, as well as the pharmacodynamic interactions that could result from their concomitant use in the peri-urban areas of Kinshasa. The first part of the study aimed to describe the characteristics of the peri-urban areas of Kinshasa that can influence the access to antimalarials through pharmacy and health and administrative entities surveys within four health areas (Mont Ngafula 1, Kikimi, Kisenso and N'sele). Of the 196 pharmacies, about 1% have an operating license from the Ministry of Health, and 37% have the one from the municipality authority. All four health areas are affected by insecurity and erosion at various degrees and 68.9% of shops operate along the roads. In 252 pharmacies, sellers are either Medical Doctors (1.6% of cases), or Pharmacists (2.4% of cases), or Nurses (54.8% of cases). However, in 41.2% of cases, sellers have no medical training or no education level at all. National Malaria Control Program standards and policies were met by 12.7% of clients without any medical prescription and 57.9% of client with medical prescription, 29.8% of vendors' advices met National Malaria Control Program guidelines. The second part of this study aimed at evaluating the existing pharmaceutical system in peri-urban areas of Kinshasa. The most widely used antimalarials have been identified using/through household and pharmacy surveys. They were analyzed with generic separation methods using high-performance liquid chromatography technique coupled to a diode-array detector. Registration status has been evaluated for 126 antimalarial brand-names. A characterization was carried out in 196 pharmaceutical establishments on the basis of standards set out by the Ministry of Health. Of the 75 samples tested, 14 (18.7%) were non-compliant. Of 126 brand-names, 58 (46%) were unlicensed and 14.5% had an expired license. Of the 196 pharmaceutical establishments, none met all the Ministry of Health minimum standards, 48 pharmaceutical establishments (24.5%) met the World Health Organisation Guidelines for the Storage of Essential Medicines. The purpose of the third part was to validate the traditional antimalarial care practices in Kinshasa using plant vendor and household surveys on the one hand, and analyses of anti-plasmodial activity and the interaction between herbal medicines with antimalarial medicines, on the other hand. In Kinshasa, 11 antimalarials are the most used. Thirteen extracts collected from 7 different plants display anti-plasmodial activity (IC50 <50 μg / ml). Four species show moderate activity (15 μg / ml <IC50 <50 μg / ml), one species shows promising anti-plasmodial activity (5 μg / ml <IC50 <15 μg / ml) and two species are very active (IC50 < 5 μg / ml) and are the only ones for which the three extracts have an activity. This study is the first to report the antiplasmodial activity of the three plants. The interaction analyses of the three herbal medicine combinations with quinine reveal two synergistic combinations that are Morinda morindoides + Quinine and Quassia africana + Quinine, and a combination with Cymbopogon citratus + Quinine additivity. [less ▲]

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See detailModulation of innate immune cells with obesity and glucose intolerance
Colonval, Megan ULiege

Doctoral thesis (2020)

Obesity is a worldwide epidemic now recognized as a low-grade inflammatory disease, favouring the development of metabolic diseases and cancers. It is characterised by an expansion of the adipose tissue ... [more ▼]

Obesity is a worldwide epidemic now recognized as a low-grade inflammatory disease, favouring the development of metabolic diseases and cancers. It is characterised by an expansion of the adipose tissue, accompanied by a release of fatty acids from dead adipocytes. Immunity is modified in this enlarged tissue, with macrophage enrichment (up to 50% increased) and a general shift towards pro-inflammatory immune cells. These changes get systemic with time, as we can see higher rates of circulating free fatty acids as well as circulating immune cells favouring the general low-grade inflammatory state. In this work, we tried to better understand the role of free fatty acids-induced changes in macrophages. We also attempted to bring a finer characterization of innate immune changes befitting obesity and glucose intolerance. Stearate, a saturated fatty acid, is able to reshape the transcriptome of human monocyte derived macrophages (MDM), in opposition to oleate, its unsaturated counterpart. Gene set enrichment analysis of the stearate-induced transcriptome highlights metabolic pathways such as glycolysis and fatty acid metabolism. Increase of glycolysis is confirmed by lactate assay, and seems to be mediated by mTORC1 pathway. Phospholipidomic profiling of stearate-treated MDM shows an increase of saturated phospholipids, which is characteristic of de novo lipogenesis. Seeing these changes in vitro, we asked ourselves if they were also observed with obesity and glucose intolerance. Phospholipidomic profiling of peripheral blood mononuclear cells underlines an increase of saturated and monounsaturated phospholipids with obesity, but more specifically with glucose intolerance. Flow cytometry experiments indicate higher amount of circulating inflammatory monocyte subtypes with obese glucose intolerant patients. Monocytes also uptake higher amounts of glucose with obesity, which might mirror a glycolytic change. Metabolic variation of immune cells is usually linked to activity alteration. No differences of monocyte phagocytosis are observed, whereas CCL2 and IL8 secretion vary for obese patients. In this work, we also studied variations for circulating NK cells. CD56bright NK cells levels increase with obesity and glucose tolerance where CD56dim NK cells decrease. CD56bright NK cells phenotype differs with obesity and glucose tolerance and these cells show variations of their activating receptors expression. NK cells from obese patients are less cytotoxic against cancer cells, which is not observed with glucose intolerant patients. These cells ability to secrete cytokines also decreases with obesity, showing a global restraining of NK cells with this disease. Altogether, our results indicate that saturated fatty acids induce a metabolic switch in human MDM, with increased glycolysis and fatty acid metabolism. Signs of metabolic changes are also observed in circulating immune cells, which show phenotype and activity variations with obesity and / or glucose intolerance. [less ▲]

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See detailMultiparameter MRI quantification of microstructural brain alteration in multiple sclerosis
LOMMERS, Emilie ULiege

Doctoral thesis (2020)

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS), which stands as the most common cause of neurological disability in young ... [more ▼]

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS), which stands as the most common cause of neurological disability in young adults. Traditionally, MS is primarily characterized by the accumulation of focal demyelinated plaques within the white matter (WM). With the advent of highly developed histopathological techniques in the second half of the 20th century, it became clear that focal lesions are also present in grey matter (GM), and that neurodegeneration diffusely affects macroscopically normal-appearing brain tissues (NABT). These observations are particularly evident in the progressive forms of the disease. Nevertheless, in vivo evaluation of MS patients remains unsatisfactory, because conventional MRI is insensitive to many pathological mechanisms underpinning MS. In the present work, we precisely aimed at improving the impact of 3 Tesla MRI on the detection and characterization of these processes, using quantitative MRI (qMRI) parameters sensitive to iron and myelin contents: magnetization transfer (MT) saturation, effective transverse relaxation rate R2* (1/T2*) and longitudinal relaxation rate R1 (1/T1). We designed a prospective cross-sectional study, contrasting 36 MS patients to 36 age-matched healthy controls. Processing and statistical analyses of MRI data were conducted on the basis of two distinct approaches: general analysis looked for differences in qMRI parameters summarized over three different NABT classes (normal appearing cortical and deep grey matters, normal appearing white matter), whereas voxel-based analyses assessed the spatial distribution of qMRI changes within normal appearing cortical and deep grey matters. Consistent with histopathological findings, results suggest a widespread reduction in myelin and/or iron contents within NABT of MS patients, both at the global and loco-regional levels, and beyond the ability of atrophy measurements. Interestingly, these microstructural alterations tend to be more pronounced and diffuse in progressive MS population. Moreover, correlation analyses indicate that they might play a significant role in determining brain volume loss as well as irreversible disability in MS. Our cross-sectional study proves that simultaneous quantification of multiple MRI parameters can sensitively assess NABT microstructure in MS. However, future large-scale studies should evaluate the reproducibility and predictive values of these results. [less ▲]

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See detailAssessment of pain perception in patients with disorders of consciousness: a behavioral and neurophysiological bedside approach
Lejeune, Nicolas ULiege

Doctoral thesis (2020)

Because patients with disorders of consciousness (DoC) are unable to communicate verbally, the assessment of their pain perception is highly problematic and probably, often inadequate. The aim of this ... [more ▼]

Because patients with disorders of consciousness (DoC) are unable to communicate verbally, the assessment of their pain perception is highly problematic and probably, often inadequate. The aim of this thesis was to develop non-invasive means to assess the ability of these patients to perceive pain that are usable at bedside, independently of the patients’ communication skills. The approach is twofold: the behavioral approach helps refining the use of the Nociception Coma Scale – Revised in a clinical context and the understanding of its neural correlates; the neurophysiological approach demonstrates the need of a specific approach dedicated to patients with DoC and assesses several methods of somatosensory stimulus presentation to create an experimental setup which is easily transportable and usable at bedside. Understanding how pain experience emerges from the brain is essential for ethical and clinical implications of these discoveries on the care of these highly vulnerable patients. [less ▲]

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See detailExploration of near-death experience accounts
Cassol, Helena ULiege

Doctoral thesis (2019)

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See detailMachine Learning applications for characterizing brain-damaged patients' level of consciousness
Antonopoulos, Georgios ULiege

Doctoral thesis (2019)

Consciousness is the result of an extremely complicated brain function. The exact functionality of the brain resulting in consciousness remains unsolved. Combined forces from many different scientific ... [more ▼]

Consciousness is the result of an extremely complicated brain function. The exact functionality of the brain resulting in consciousness remains unsolved. Combined forces from many different scientific fields are working on this to get a better understanding on consciousness and its disorders. Medicine, neuropsychology, mathematics and biology are only a few of those fields. Specifically, the medical model can provide us with unique insights as to the functions of typical states of consciousness. This thesis is focusing on patients with disorders of consciousness. This kind of patients are brainlesioned individuals which in numerous cases are incapable of responding to requests, despite the fact that they might still have preserved conscious functions. Often, the remaining functionality of a brain is sufficient for perceiving and decoding the surrounding environment or the position of patients in it. Nowadays, we know that lack of responses do not necessarily indicate lack of consciousness. Behavioural-assessment scales for the evaluation of consciousness often provide a vague diagnosis. Mis-diagnosis of consciousness raises clinical as well as ethical issues. Functional neuroimaging can be used to address this problem by providing an inner overview of the brain functionality of patients with disorders of consciousness. Functional Magnetic Resonance Imaging and Positron Emission Tomography are two commonly used modalities of functional neuroimaging, which are used in the projects of this thesis. They provide a quantification of different brain properties in combination with an accurate spatial representation, which makes them a unique source of information. Machine Learning, being part of the wider Artificial Intelligence field, incorporates algorithms that can efficiently handle high-dimensional data. Such algorithms can unveil patterns of data and undercover interactions of brain regions, using data-driven approaches. Additionally, they provide tools that can ensure success in predicting unseen data. Therefore, they can constitute a necessary and complementary tool to classical statistics for the analysis of Functional Neuroimaging data in Disorders of Consciousness. The combination of behavioural assessments and functional neuroimaging form an extremely important and unique source of information, for both clinical use and the scientific study of consciousness. The former is showing the thin line between consciousness and un-consciousness and the latter provides the means to explore it. This thesis aims at providing tools to assist the behavioral diagnosis of consciousness using Machine Learning in functional neuroimaging data from patients with disorders of consciousness. The studies composing it focused mainly on the two groups that are considered to lie on the border line of responsiveness: i) Minimally Conscious State, and ii) Unresponsive Wakefulness State. Two different modalities, which capture different properties of brain function, have been used. At first we used functional Magnetic Resonance Imaging, from which we extracted brain connectivity features. To those features we applied machine learning techniques to identify the contribution of brain networks to the classification of patients. In the second project, we used the metabolic activity of the brain extracted from Positron Emission Tomography, to classify patients with brain lesions and extract regional information. We applied certain practices, in order to overcome problems such us noisy images, redundant features and limited samples. Both projects are highlighting these brain regions with the maximum contribution to the classification process, assuming that they are significant to higher order cognitive functions, therefore shedding light on the mechanistic counterpart of the phenomenon of consciousness. [less ▲]

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See detailContribution à une meilleure gestion de la nociception peropératoire
DEFRESNE, Aline ULiege

Doctoral thesis (2019)

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See detailProduction de TGF β1-2-3 à partir de cellules d'expectoration de patients asthmatiques et BPCO : relation avec l'obstruction des voies respiratoires
Bricmont, Noémie ULiege

Master's dissertation (2019)

L’asthme est une maladie chronique courante caractérisée par une respiration sifflante, un essoufflement et une oppression thoracique. Il est associé à une obstruction variable, une hyperréactivité ... [more ▼]

L’asthme est une maladie chronique courante caractérisée par une respiration sifflante, un essoufflement et une oppression thoracique. Il est associé à une obstruction variable, une hyperréactivité, une inflammation persistante et un remodelage des voies respiratoires. Ce dernier est l'un des processus caractéristiques les plus importants. La BPCO est une maladie obstructive des voies respiratoires commune, principalement liée à la fumée de cigarette et sa physiopathologie inclut la fibrose bronchique. Le TGF-β est connu pour être un médiateur important dans la fibrose des voies respiratoires, mais il a été peu étudié dans le contexte de l'asthme avec obstruction fixe des voies respiratoires. Ce projet visait à évaluer le TGF-β total et actif ainsi que ses 3 isoformes présents dans le surnageant des expectorations de patients asthmatiques par rapport à la BPCO et aux témoins grâce à un essai basé sur un gène rapporteur spécifique du TGF-β (TMLC). Les résultats préliminaires ont montré que le TGF-β était augmenté chez les patients asthmatiques et atteints de BPCO par rapport aux témoins. Dans l’asthme, cette augmentation n’était pas liée aux habitudes tabagiques mais à la maladie elle- même et le taux de TGF-β était plus élevé chez les asthmatiques avec obstruction irréversible par rapport aux obstructions réversibles. Cependant, aucune différence significative n’a pu être observé en ce qui concerne le phénotype inflammatoire des voies respiratoires. En ce qui concerne les isoformes de TGF-β, les résultats ont montré que le TGF-β1 total était plus élevé chez les asthmatiques que chez les patients atteints de BPCO et les témoins. Aucune différence n’a pu être observée pour le TGF-β2 mais le TGF-β3 total et actif (connu pour présenter des propriétés antifibrosantes) est apparu plus élevé chez les témoins que chez les patients asthmatiques et atteints de BPCO. Lors de l’analyse des données en fonction du profil inflammatoire des voies respiratoires ou de la présence ou non d’une obstruction irréversible des voies respiratoires, aucune différence n’a été mise en évidence. Une analyse ELISA évaluant les 3 isoformes a été réalisée, mais les isoformes étaient indétectables dans la majorité des échantillons. [less ▲]

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See detailÉtude des potentialités antiplasmodiales de plantes endémiques des Mascareignes: Poupartia borbonica Gmel., une nouvelle source de composés antimalariques prometteurs ?
Ledoux, Allison ULiege

Doctoral thesis (2019)

Ce travail de thèse a été mené dans l’optique de participer à la recherche de nouveaux antipaludiques provenant de plantes endémiques des Mascareignes. La première partie de ce travail est consacrée au ... [more ▼]

Ce travail de thèse a été mené dans l’optique de participer à la recherche de nouveaux antipaludiques provenant de plantes endémiques des Mascareignes. La première partie de ce travail est consacrée au criblage antiplasmodial in vitro réalisé sur 64 plantes provenant de l’île de la Réunion. Ces plantes ont été sélectionnées selon plusieurs critères : leurs endémismes, leurs usages traditionnels, ainsi que leurs inscriptions à la Pharmacopée. L’objectif principal de cette partie du travail consistait à mettre en évidence les plantes présentant une activité antiplasmodiale prometteuse (IC50 < 15µg/mL). Parallèlement, le second objectif était de valoriser la flore locale. Plusieurs plantes se sont avérées être intéressantes : le Casearia coriaceae, le Poupartia borbonica et le Vernonia fimbrillifera dont les IC50 sont inférieures à 10 µg/mL. Le Poupartia borbonica a été sélectionné en vue de réaliser des tests phytochimiques et pharmacologiques approfondis. La deuxième partie du travail est consacrée à l’exploration phytochimique et pharmacologique de cette plante endémique. Un fractionnement bioguidé a été entrepris et a conduit à la mise en évidence de trois nouveaux composés, des dérivés d’alkylcyclohexenones, les poupartones A, B, et C. Ces trois molécules présentent une activité antiplasmodiale prometteuse (IC50<2 µM). La poupartone majoritaire, la poupartone A, a été testée in vivo sur un modèle murin. Son potentiel antipaludique a été confirmé, puisqu’une dose de 15 mg/kg a permis une réduction de la parasitémie de presque 70%, 7 jours après l’infection. Cependant, une certaine toxicité a été observée. La troisième partie de cette thèse a consisté à mettre en évidence des pistes quant aux mécanismes de toxicité liés aux poupartones. Des tests sur larves de Zebrafish exprimant une fluorescence vasculaire ou une fluorescence musculaire ont permis de mettre en évidence qu’une toxicité cardiaque semblait être une conséquence d’un mauvais état général. L’atteinte la plus rapide et la plus marquée, sur toutes larves confondues, était liée à une toxicité de contact importante. Des tests de toxicité cellulaire réalisés avec des techniques d’imagerie en temps réel sur deux lignées cellulaires ont mis en évidence une hétérogénéité d’action. Cependant, la poupartone B induit des modifications importantes de l’adhésion cellulaire, ainsi que des mécanismes de type apoptotique. La dernière partie de ce travail a eu pour principal objectif de neutraliser cette toxicité périphérique en ciblant spécifiquement les globules rouges parasités par P. falciparum. Des liposomes contenant la poupartone B ont été réalisés, ceux-ci ont été entourés d’héparine, connue pour lier spécifiquement certaines protéines exprimées par les globules rouges infectés. Des tests réalisés sur larves de Zebrafish ont démontré une diminution de la toxicité, et les tests réalisés sur P. falciparum ont établi que l’activité était améliorée, même sur les Plasmodium partiellement résistants à l’artémisinine.   [less ▲]

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See detailLe norovirus humain : contribution à la détection, à la caractérisation et l'épidémiologie clinique et moléculaire.
HUYNEN, Pascale ULiege

Doctoral thesis (2019)

Noroviruses are non-enveloped single stranded RNA viruses. The norovirus genus contains seven genogroups (G) including genogroups I, II and IV which infect humans. Human noroviruses (NoV) are recognized ... [more ▼]

Noroviruses are non-enveloped single stranded RNA viruses. The norovirus genus contains seven genogroups (G) including genogroups I, II and IV which infect humans. Human noroviruses (NoV) are recognized as worldwide leading pathogens causing viral gastro-enteritis, and as the main pathogenic agent responsible for foodborne gastro-enteritis. Ten years ago, NoV were not well known by microbiologists and clinicians in Belgium. The commercial detection methods now available did not yet exist and NoV were not routinely detected in patients. In particular, the University Hospital of Liège did not have a method for NoV detection in patients. As a prerequisite to further NoV study, development and implementation of a NoV detection method was necessary. This work describes the development of a quantitative real time PCR, allowing the detection of pathogenic human NoV genogroups I, II and IV in a single reaction. When dealing with a gastro-enteritis outbreak of suspected viral etiology, a rapid NoV identification is the key to effective control of viral transmission. To enable this, a given diagnostic laboratory needs a simple and rapid method that does not require expensive or complicated equipment. Despite molecular diagnosis methods remaining the gold standard for NoV detection, a rapid immunologic test for viral antigen detection was also evaluated and implemented in this study. In the context of a gastro-enteritis outbreak, these easy-to use tests are a rapid and efficient diagnosis method which can leading to quick implementation of prevention strategies. NoV outbreaks are difficult to control, mainly since NoV are highly contagious and resistant in the environment, complicating complete disinfection and leading to recurrent outbreaks. In hospitals in particular, NoV outbreaks can have a real public health impact and can lead to high costs. The rapid implementation efficient hygiene measures is essential to limit the size of such outbreaks. In developing countries, gastro-enteritis remains an important cause of morbidity and mortality. In Africa in particular, NoV detection is not or not often performed due to the prohibitive cost; the impact of NoV infections is thus probably under-estimated. In this continent very few studies have been realized. Via a collaboration with the Bobo Dioulasso health care center in Burkina Faso, the second study performed in the context of this thesis addressed this lack of information and allowed the investigation of molecular epidemiology of NoV strains circulating in 418 children from this region. While NoV GII.4 is typically identified as the predominant genotype in most studies performed in Africa, a large circulating strain diversity was observed in the study realized in Burkina Faso, with a surprisingly high NoV GI proportion. The number of NoV carriers observed in asymptomatic young children was high. These children could therefore play a reservoir role for NoV infections. The frequent contacts with NoV and exposure to numerous different strains, probably due to limited access to drinking water and a low hygiene level, could explain the host protection and the high carrier level in these countries. After a short incubation period of 24 to 72 hours, the usual clinical presentation of a NoV infection in a healthy patient is a gastro-enteritis, benign in most cases and spontaneously resolved in two to three days. In immunocompromised patients, clinical evolution of a NoV infection in not the same. In these patients, NoV are responsible for persistent and chronic diarrhea, and often remain under-diagnosed. Such persistent infections have long been described in hematopoietic stem cell transplant patients and, more recently, in solid organ transplant patients. Chronic diarrhea has also been reported in patients with high immunosuppression due to HIV infection. In a university hospital where more than 2000 patients have been transplanted up to the time of writing, a NoV study in this patient category was indicated. Via an effective collaboration with the Service of Nephrology and financial support obtained from the University Hospital of Liège, a prospective study was realized during more than four years in 117 kidney transplanted patients, presenting or not gastro-intestinal symptoms. In this study, prolonged viral excretion was observed in symptomatic kidney transplanted patients but also in asymptomatic patients, with maximal excretion duration of more than to eight and six months respectively. During these prolonged excretions, viral loads remained high in some patients, which could represent a potential source of viral transmission. NoV detection with molecular biology methods should be a part of the exploration of persistent digestive troubles in immunocompromised patients to allow differentiation with other origins of digestive and improvement of clinical care of these patients. Indeed, solving NoV chronic infections in immunocompromised, transplant patients is linked with the immune system recovery. This study has shown a positive impact of immunosuppressive treatment reduction on symptomatology. The study of NoV has undoubtily contributed to develop specific skills in this field, and had improved knowledge concerning this enteropathogen that is still underinvestigated in patients. [less ▲]

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See detailContribution à l'évaluation de la fonction musculaire rachidienne du sportif
Grosdent, Stéphanie ULiege

Doctoral thesis (2019)

Aims: to clarify the muscular function of the trunk and to study the relationships between low back pain (LBP) and the spinal muscles in athletes. The literature review presented in the first section ... [more ▼]

Aims: to clarify the muscular function of the trunk and to study the relationships between low back pain (LBP) and the spinal muscles in athletes. The literature review presented in the first section discusses athlete spinal pathology, lumbar spinal musculature characteristics and highlights the prevalence and risk factors associated with the occurrence of LBP in athletes. The second part of our work specifies the trunk muscle profile in relation to sport and LBP. After a review of the literature on muscle and joint evaluation (step 1), our studies compare on the one hand the muscular and articular lumbopelvic performances of asymptomatic competing athletes practicing different sports disciplines (tennis, football, swimming, rowing) and a controlled population (step 2), and on the other hand, competitive athletes (football and tennis players) with and without LBP (step 3). While there are some specificities in the trunk muscles profile related to the sport discipline, our studies do not report a link between the presence of LBP and the maximum voluntary force, the asymmetries of strength of the trunk muscles or the lumbopelvic flexibility in tennis and elite football players. In young elite crawl swimmers, a complementary study (step 4) highlights two sprint performance indicators: the maximum isometric strength of the extensor muscles and the fatigue resistance of the trunk flexor muscles. In the third part, our work focuses on the quality of sensorimotor control and stability of the trunk and lumbopelvic region of athletes with LBP or with a history of disabling LBP. A review of the literature (step 1) confirms the current lack of standardized criteria for the evaluation of functional lumbar instability (FLI) and lumbopelvic movement control (LMC). The study of an athletic population with LBP (step 2) highlights that athletes with signs suggestive of FLI are an important subgroup and highlights the relevance of some elements of the history and clinical examination for the diagnosis of FLI in athletes with LBP. The assessment of the LMC of young elite football and tennis players (step 3), using a battery of five field tests, discriminates players with and without a history of LBP and confirms that the disappearance of symptoms and the sports recovery is not enough to restore an optimal LMC. Finally, the implementation of a specific and progressive training of LMC among young elite tennis and football players with a deficit of LMC (step 4) improves the LMC and tends to reduce the prevalence of LBP in these athletes in the short and medium term. In conclusion, athlete's low back pain appears to be correlated with the quality of muscular contraction and lumbopelvic movement, rather than the amount of activation or muscle strength produced. The LMC impairment appears to be a result of lower back pain and advocates for the management of athletes with a history of pain and / or lumbar lesions (secondary prevention). [less ▲]

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See detailPrise en charge d’une méningite à Cryptococcus neoformans chez un patient VIH positif
Benchimol, Lionel ULiege

Master's dissertation (2019)

Alors que les progrès concernant le dépistage et la prise en charge des patients atteints du virus de l’immunodéficience humaine (VIH) ont été considérables, il constitue toujours à ce jour un ... [more ▼]

Alors que les progrès concernant le dépistage et la prise en charge des patients atteints du virus de l’immunodéficience humaine (VIH) ont été considérables, il constitue toujours à ce jour un problème majeur de santé public. En effet, il est estimé qu’en 2017 près d’1,8 millions de personnes ont été infectées1. Pour les patients inconscients de leur séropositivité s’installe une course contre la montre avant de développer le syndrome d’immunodéficience acquise (SIDA). Ce syndrome se définit par le développement d’une ou plusieurs infections opportunistes ou de cancers tel que le sarcome de Kaposi, apparaissant plusieurs mois ou années après l’infection par le VIH, ou un compte de lymphocyte T CD4+<200/mm3,2. Il apparait alors un défi médical d’introduire au bon moment la thérapie anti-rétrovirale (ART) sans risquer l’ «immune reconstitution inflammatory syndrome» (IRIS), source d’une mortalité importante chez les patients présentant une ou plusieurs infections opportunistes3. Il sera présenté la prise en charge d’un patient nouvellement diagnostiqué au stade SIDA (groupe C dans la classification HIV/SIDA du Center for Disease Control and Prevention) ayant développé une méningite à Cryptoccocus neoformans. Quelle est alors la stratégie thérapeutique prenant en compte à la fois l’infection opportuniste du patient et les risques de l’introduction de l’ART? C’est cette même question qui a fait débat au sein de l’équipe médicale tout au long de la prise en charge et à laquelle nous tenterons de répondre au cours de ce travail. [less ▲]

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See detailEffects of the implantation of intrabdominal protheses in a mouse model of ovarian peritoneal carcinosis
Dias Da Silva, Isabelle ULiege

Master's dissertation (2019)

This study was carried out in order to categorize visual signs of peritoneal cacirnomatosis after mesh implantation following resection and/or cytoreduction. Using the murine model of ovarian-type ... [more ▼]

This study was carried out in order to categorize visual signs of peritoneal cacirnomatosis after mesh implantation following resection and/or cytoreduction. Using the murine model of ovarian-type peritoneal cancer (PC) which is induced by intraperitoneal injection of ID8 – Luc ovarian cancer cells in immunocompetent C57BL/6 mice in the presence or the absence of intraabdominal prostheses (Surgimend or Ventralex) shows that these prostheses promote pro-tumor development assessed by bioluminescence. The biosynthetic mesh (Ventralex) decreases the survival of the animals whatever the experimental time of prosthesis implantation. Moreover, Ventralex is completely invaded by tumor nodules. In contrast, a vascular network was well visible naked eye on the biological mesh (Surgimend). However, it seems to be devoid of tumor nodules. Using scanning electron microscopy (SEM) allowed us to deny this macroscopic observation. In addition, these SEM observations revealed a probable epithelial-mesenchymal (TEM) transition. In other hand, the in vitro ID8-Luc cell interaction with both protheses assessed by SEM showed similar modified cell phenotype. Using such murine PC model, the safety of this pre-clinical prosthesis implantation strategy shows us that our incompetence to reduce tumor growth and to obtain better tumor control after resection or cytoreduction. The results obtained with prostheses encourage us not to recommend their use in case of intraabdominal pathology (hernia, evisceration, carcinosis). This should prompt providers to change the structure and composition of intra-abdominal prostheses to improve survival and prevent tumor development. [less ▲]

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See detailStealth and pH-sensitive lipid nanocapsules : targeting the tumor microenvionement of melanoma
Pautu, Vincent ULiege

Doctoral thesis (2018)

Tumor acidity has been shown to play a major role in resistance to chemotherapy. The use of nanomedicines, as lipid nanocapsules (LNC), allows to protect drugs from this acidic environment. They can also ... [more ▼]

Tumor acidity has been shown to play a major role in resistance to chemotherapy. The use of nanomedicines, as lipid nanocapsules (LNC), allows to protect drugs from this acidic environment. They can also improve the biodistribution of therapeutics and to target the tumor environment. The aim of this thesis concerns the evaluation and characterization of stealth and pH-sensitive LNC in the context of melanoma. Firstly, these works consisted in characterizing the vascularization of human and mice melanoma. These studies allowed to compare different tumors (density, size and structure), and determine if the used of nanocarrier is suitable in the context of melanoma. The second part of this thesis described the development and the characterization of new copolymers, combining stealth and pH-sensitive properties. These copolymers, composed of N-vinylpyrrolidone (NVP) and vinylimidazole, were synthesized by RAFT polymerization and were post-inserted onto LNC surface. These modifications allowed to obtain charge reversal nanocarriers, leading to increase their melanoma cell uptake under acid pH. Finally, biodistribution of these modified nanoparticles was studied in vivo and highlighted the interest of NVP in the development of stealth nanocarriers. To conclude, the developed copolymers able to extend nanocarrier circulation time and to provide pH-responsive properties which should increase the tumor internalization of LNC in vivo and potentiate the effect of anticancer drugs. [less ▲]

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See detailRégulation du facteur tissulaire par la vimentine lors des processus de transition épithélio-mésenchymateuse : impact pour la progression métastatique
Francart, Marie-Emilie ULiege

Doctoral thesis (2018)

Au cours de la propagation métastatique, des cellules tumorales circulantes (CTC) sont libérées dans la circulation sanguine, dont seule une faible proportion seront capables de former des métastases ... [more ▼]

Au cours de la propagation métastatique, des cellules tumorales circulantes (CTC) sont libérées dans la circulation sanguine, dont seule une faible proportion seront capables de former des métastases détectables. La contribution des processus de transition épithélio-mésenchymateuse (TEM) à la biologie des CTCs représente aujourd'hui une hypothèse plausible étayée par une littérature abondante, associant la TEM à des propriétés de survie plus élevées mais aussi plus invasives et plus métastatiques. Le sang représente un aspect important de la biologie des CTCs puisqu’elles y rencontrent un nouvel environnement particulièrement hostile. De plus, les données de la littérature et du laboratoire suggèrent une contribution du système de coagulation dans les premières étapes de la propagation métastatique (survie, persistance, arrêt et extravasation). Au cours de cette thèse de doctorat, nous avons démontré que les voies de la TEM induisent l’expression du facteur tissulaire (FT) (un activateur majeur de la cascade de la coagulation) dans les cellules tumorales. Nous avons montré que cet axe de régulation TEM / FT conférait aux CTCs TEM+ des propriétés procoagulantes et une capacité accrue à survivre dans la circulation sanguine et à nicher dans les organes colonisés une fois injectées par voie intraveineuse à des souris. Nous avons identifié la vimentine en tant que régulateur potentiel du FT et nous avons donc examiné son implication dans cet axe TEM / FT / coagulation. Nous avons ainsi montré que l’inhibition de la vimentine diminuait l'expression de la protéine du FT. Nous avons également démontré que la transfection de siARN dirigés contre la vimentine diminuait les propriétés coagulantes in vitro et les métastases précoces lors d’injection par voie intraveineuse à des souris. Pour décrypter les mécanismes moléculaires impliqués dans la régulation du FT par la vimentine, des expériences au cours du temps ont révélé une inhibition de l'ARNm du FT dès 4h après transfection d’un siARN dirigé contre la vimentine. Nous avons également montré que la vimentine pouvait interagir avec l'ARNm du FT et le stabiliser. Jusqu'ici, nos données soutiennent un mécanisme par lequel la vimentine pourrait interagir avec la région 3'UTR de l’ARNm du FT, empêchant ainsi un mécanisme de régulation impliquant la famille miR-520. Pris dans leur ensemble, nos résultats renforcent une implication fonctionnelle de la vimentine dans l’axe de régulation TEM / FT et qui pourrait réguler et stabiliser l'ARNm du FT en se liant à son 3’UTR interférant avec une régulation négative de miARNs favorisant ainsi les métastases précoces dépendantes de la coagulation. [less ▲]

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See detailDeterminants and consequences of abnormal visual cortex responsiveness in migraine without aura
Lisicki Martinez, Marco ULiege

Doctoral thesis (2018)

La migraine est une maladie multifactorielle complexe, qui résulte de l'interaction entre une prédisposition génétique et un environnement facilitant. La majeure partie de l' information venant de notre ... [more ▼]

La migraine est une maladie multifactorielle complexe, qui résulte de l'interaction entre une prédisposition génétique et un environnement facilitant. La majeure partie de l' information venant de notre entourage nous atteint via le système visuel, ce qui fait de la vision la modalité sensorielle la plus développée chez l'Homme et celle qui met en jeu les aires cérébrales les plus tendues. Un faisceau de données cliniques et expérimentales a montré que les patients migraineux sont hyper-réactifs à la stimulation visuelle, mais les déterminants de ce phénomène restent méconnus. De plus, bien qu'étroitement associée à la migraine, l‟hyper-réactivité visuelle n'est ni suffisante, ni nécessaire pour développer la, maladie ce qui suggère l'existence de mécanismes physiopathologiques additionnels. Dans cette thèse nous avons analysé des facteurs environnementaux, métaboliques, anatomo-fonctionnels, et neurochimiques liés à la réactivité visuelle chez les migraineux, et la possible implication de leur interaction dans la pathogénie de la maladie. Pour ce faire, nous avons réalisé une série d‟études neurophysiologiques et de neuroimagerie qui explorent des aspects distincts de la physiologie du cerveau. Les résultats montrent que (1) une part de la variabilité interindividuelle de la réactivité visuelle peut être expliquée par des influences environnementales; (2) l‟hyper-réactivité visuelle dans la migraine est le résultat d'un déséquilibre complexe entre les mécanismes qui favorisent une perception renforcée, et ceux qui protègent contre une surcharge sensorielle; (3) la réserve métabolique au niveau cortical est insuffisante face à la demande énergétique accrue due à l'hyper-réactivité visuelle. Ces résultats illustrent la complexité des mécanismes responsables de l'hyperréactivité visuelle dans la migraine, améliorent notre compréhension de la physiopathologie de cette maladie, et ouvrent la voie à des axes de recherche innovants. [less ▲]

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See detailImprovement of the Indoor Air Quality in Housings of Ho Chi Minh City (Vietnam) by Adapting the Ventilation System to Minimize the Pollutants Concentrations
Tran Thi Thu, Thuy ULiege

Doctoral thesis (2018)

We spend about 90% of our time inside buildings, where we could control the quality of the environment for health, thermal comfort, security and productivity. The quality of the indoor environment is ... [more ▼]

We spend about 90% of our time inside buildings, where we could control the quality of the environment for health, thermal comfort, security and productivity. The quality of the indoor environment is affected by many factors including design of the building, ventilation, thermal insulation, energy provision and use. It is evident from preliminary studies that Indoor Air Quality (IAQ) in Vietnam housing is under-researched and there is a clear lack of awareness among housing occupants of the harmful effects of chemicals that exist inside housings. Houses in warm-humid regions depend on large openings and through ventilation for thermal comfort. Openings allow air pollution and noise to penetrate these houses easily, thereby affecting the health, comfort and well-being of residents. Closing all openings and changing from natural ventilation to air conditioning is not however a practical solution for low cost housing. As a result, the study was set out to review the previous related research studies in the field of IAQ, identify the current status of IAQ in HCMC, and find solutions to implement IAQ best practice in three sample houses as a pilot for achieving good IAQ. Through this study, we found evidences that residents of rental houses were exposed to slightly high levels of CO2 during the night-time or at anytime when the occupants closed the door for sleeping or for personal activities. The indoor CO concentrations were over 20 ppm in rush hours in some houses which located nearby streets and opened the entrance doors for sale. We found that housing residents might be disproportionately exposed to high levels of PM2.5 and TVOC due to the presence of many indoor sources. Poor thermal comfort was also found to be a prevalent issue in most of sample houses, but there was not enough data on comparable indoor and outdoor to make a definitive statement about relative prevalence. Indoor air quality is influenced by location of the house, opening design, and opening behavior. Air quality in residential buildings, especially in the living-rooms, was generally poorer with the houses having no outlets to outside and no exhaust fans and this was true for both houses near or far from a road. Lastly, the study indicated that there were feasible and practical solutions to the reduction of indoor air pollution in such housings by changing opening design, changing opening habits and applying local ventilation. The renovations were found high efficiency to reduce indoor CO and TVOC in hot and humid condition. Based on low cost development, this application can be applied with natural ventilation system in housings in big cities of Vietnam. [less ▲]

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See detailInnovative Orthodontic Treatment using Piezosurgery
CHARAVET, Carole ULiege

Doctoral thesis (2018)

An increasing number of adult patients are seeking orthodontic treatment for functional or aesthetic reasons, but treatment time is often a limitation. Several surgical techniques such as corticotomies ... [more ▼]

An increasing number of adult patients are seeking orthodontic treatment for functional or aesthetic reasons, but treatment time is often a limitation. Several surgical techniques such as corticotomies have been developed to accelerate orthodontic treatment; however, these procedures are rather invasive. Recently, some authors have proposed minimally invasive techniques such as piezocision, possibly combined with tissue augmentation. Piezocision is a localized alveolar decortication approach that combines buccal micro-incisions and minimally invasive corticotomies (3mm in depth – 5 mm in length) performed with a piezotome. However, the level of clinical evidence backing this approach is scarce, and the underlying biological response regarding piezocision surgery is not fully understood. The aim of this PhD project was to investigate and understand the effects of piezocision on orthodontic treatment based on several clinical trials and multi-level biological analyses in a preclinical setting. Based on two randomized controlled trials, the present work demonstrates the first clinical evidence of tooth movement facilitation with piezocision. A reduction in treatment time of respectively 40% and 36% was observed in cases of minor to moderate overcrowding. Moreover, patient-reported outcome measures (PROMs) regarding the piezocision procedure were investigated and revealed limited pain scores as well as high levels of acceptance and patient satisfaction. Furthermore, the potential benefit of combining piezocision with alveolar bone augmentation in the anterior mandibular region using biomaterial was explored in a prospective study. Most of the cases demonstrated a significant increase of the alveolar bone envelope and therefore expand the orthodontic scope in cases presenting bone deficiencies or thin buccal bone plate prior to orthodontic treatment. Beyond the clinical validation, this PhD thesis was also dedicated to understanding the biological phenomenoma associated with the piezocison concept. Within the limit of a preclinical study, the efficacy of piezocision in accelerating orthodontic tooth movement was demonstrated, and the underlying biological responses at the tissue, cellular and molecular levels were highlighted. Increased three-dimensional bone demineralization and osteoclast recruitment were observed in the piezocision group compared to a conventional orthodontic approach. Moreover, an increase in bone remodeling, highlighted at the molecular level by the coupled RANKL-OPG expression, was demonstrated for the first time using piezocision-assisted alveolar decortication. These biological phenomena were shown to be transient and completely reversible. The clinical and preclinical data collected in this thesis contributed to the validation of piezocision-assisted orthodontic treatment. According to the present results, this treatment approach can be considered to be a new therapeutic tool in adult orthodontics. [less ▲]

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See detailContribution à la définition sémiologique et diagnostique de différents syndromes en pédopsychiatrie
SCHOLL, Jean-Marc ULiege

Doctoral thesis (2018)

Constat de départ Souvent les enfants avec émergence de difficultés pédopsychiatriques ne reçoivent un diagnostic pertinent qu'après plusieurs années d'évolution. Dans l'intervalle, les parents reçoivent ... [more ▼]

Constat de départ Souvent les enfants avec émergence de difficultés pédopsychiatriques ne reçoivent un diagnostic pertinent qu'après plusieurs années d'évolution. Dans l'intervalle, les parents reçoivent successivement différentes lectures des difficultés de leur enfant : ce manque de cohérence va générer chez eux de la confusion et/ou de l'anxiété. En effet, les professionnels du réseau de l'enfance ont des difficultés à poser adéquatement un diagnostic, d’autant plus que les comorbidités sont quasi la règle chez l'enfant et rendent les tableaux complexes. Les professionnels interviennent sur les enjeux relationnels et la souffrance familiale, mais ils sont bien en peine de trouver des références cliniques et théoriques pertinentes les formant à poser des diagnostics pédopsychiatriques chez l'enfant. Conséquences Les retards de diagnostics sont fréquents et les prises en charge spécifiques ne sont pas entreprises assez précocement : le pronostic du devenir de l'enfant est en question, particulièrement pour des psychopathologies susceptibles de s'aggraver. Recherches sémiologiques L'objectif des études menées dans ces travaux est de donner, dans différents troubles et syndromes, des repères de sémiologie dimensionnelle intégrés à une approche catégorielle. Cette sémiologie est aussi développementale car l'enfant est en évolution constante et l'expression des signes et symptômes cliniques est variable, selon le développement de l'enfant et selon l'évolution de ses pathologies, parfois de type neuro-développementale. Pour cela, le repérage des signes cliniques tient également compte d'une sémiologie développementale. Enfin, cette sémiologie est également appréhendée dans un continuum du normal au pathologique, par exemple pour des tempéraments mis en évidence. Dans un enjeu de Santé Publique, l'objectif final est de donner des repères sémiologiques spécifiques à l'enfant, afin d'accroître l’art des professionnels dans leur pratique. Retour à une observation première Pour éviter de n'appréhender la clinique qu'à partir des présupposés attendus liés aux critères d'un diagnostic catégoriel, le clinicien-chercheur adopte une attitude d'observation première qui cherche "à découvrir toujours à nouveau" la réalité clinique composée de multiples aspects ; chaque signe sémiologique est considéré sous l'angle dimensionnel. Les études précisent une sémiologie spécifique à l'enfance pour : ➢ les Troubles de la Régulation du Traitement des Stimuli Sensoriels ➢ les Troubles Déficitaires de l'Attention avec ou sans Hyperactivité ➢ un Tempérament hyper-énergétique, les Troubles de l'humeur et la Bipolarité ➢ les Symptômes Négatifs dans le spectre des troubles psychotiques [less ▲]

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See detailEvaluation de la propension à payer des patients pour le vaccin antipaludique RTS,S/AS01 (MOSQUIRIX) au Cameroun
Defo Tamgno, Eric ULiege

Master's dissertation (2018)

Introduction: In Cameroon, Malaria is the leading cause of death and morbidity in children under 5years of age and in pregnant women. It also represents 40% of household health expenditure in this country ... [more ▼]

Introduction: In Cameroon, Malaria is the leading cause of death and morbidity in children under 5years of age and in pregnant women. It also represents 40% of household health expenditure in this country. To prevent malaria, the World Health Organisation (WHO) recommends, among other measures, the use of insecticide-treated mosquito nets, indoor insecticide sprays and chemoprevention. However, the effectiveness of these preventive measures remains limited. It is for this reason that, for several years now, research on possible malaria vaccine is being carried out by academics and pharmaceutical companies. An example is the renowned company glaxosmithkline (GSK) who came up with the RTS,S/ASO1 vaccine ("Mosquirix"). To date, the mosquirix vaccine is the only vaccine against malaria to have been validated by the European Medicines Agency. The WHO has authorized the implementation of a pilot study underway in 3 countries of sub-Saharan Africa (Ghana, Kenya and Malawi). Aim: to determine the average maximum price that patients living in Cameroon would be willing to pay for this new vaccine and at the same time determine the factors influencing the prices offered. Materials and methods: We conducted a cross-sectional study, through a semi-open questionnaire in 5 hospitals in Cameroon (Dschang district hospital, protestant hospital of Mbouo in Bandjoun, Efoulan district hospital, CMA of Odza and Yaoundé military hospital). The study included all individuals aged 18 and over, who presented themselves for malaria-related counseling at one of the 5 above mentioned hospitals Results: we were able to obtain data from 1187 respondents aged between18 and 80 years. From these data, we noted that patients are willing to spend on average 1,34% of their income to benefit from this vaccine. This percentage corresponds to a maximum price of 1,850 Fcfa (2,84 euro). This price was significantly associated with respondents' income, having been consulted at least once for malaria within the 12 months preceding the survey and whether the respondent has at least 1 child under 5 years of age or not. Respondents had good knowledge of malaria but very limited knowledge of the vaccine. Conclusion: the maximum price that cameroonian patients would be willing to pay for this RTS,S/ASO1 vaccine ("mosquirix") is 1850 Fcfa. [less ▲]

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See detailDatamining in endocrinology
PETROSSIANS, Patrick ULiege

Doctoral thesis (2018)

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See detailMolécules ciblant les interactions entre cellules myélomateuses et ostéoclastes
Muller, Joséphine ULiege

Doctoral thesis (2018)

BACKGROUND Multiple myeloma (MM) is an hematological malignancy characterized by the accumulation of malignant plasma cells within the bone marrow. Osteolytic bone disease (OBD) is a major feature of ... [more ▼]

BACKGROUND Multiple myeloma (MM) is an hematological malignancy characterized by the accumulation of malignant plasma cells within the bone marrow. Osteolytic bone disease (OBD) is a major feature of myeloma, which leads to pathological fractures and hypercalcemia and affects dramatically the morbidity and mortality of patients. Bisphosphonates are the mainstay therapy of MM bone disease; though they are partially effective and related to adverse effects. Research for new therapeutic approaches are of great interest. OBJECTIVES Inhibition of the kinases SRC and MELK were evaluated as treatment of OBD. In addition, the role of galectin-1 (gal-1) in osteoclast (OCL) biology was investigated. RESULTS SRC inhibition by saracatinib inhibited in vitro OCL formation and function and affected osteoblast (OBL) activity. Saracatinib induced in vivo a high reduction of bone loss through the inhibition of bone resorption. Of note, MM cell proliferation and tumor burden remained unaltered following saracatinib treatment. // MELK inhibition by OTSSP167 inhibited OCL activity by decreasing progenitor viability as well as via a direct anti-resorptive effect on mature OCLs. In addition, OTSSP167 stimulated OBL function. This combined anti-resorptive and OBL-stimulating effect of OTSSP167 resulted in the complete prevention of lytic lesions and bone loss in vivo. // MM-bearing gal-1-/- mice showed higher tumor infiltration and reduced survival compared to wild-type mice. Microarray data analysis revealed a decrease of gal-1 expression during OCL formation, which was confirmed by in vitro OCL cultures. Gal-1-/- OCL cultured ex vivo caused higher bone resorption. Lastly, MM cells-OCLs co-cultures induced a stronger decrease of gal-1 expression in mature OCLs. CONCLUSIONS This thesis indicated SRC and MELK inhibition as promising therapeutic strategies for the treatment of myeloma OBD. Highlighting the implication of gal-1 in OCL biology and MM development warrants further investigation. [less ▲]

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See detailExpérience maternelle en période postnatale : Exploration des besoins et tentatives de réponses à l’ère du numérique
Slomian, Justine ULiege

Doctoral thesis (2018)

Pregnancy and childbirth are two critical stages in a woman’s life. The postnatal period is often a stressful time in the life of a woman with sudden and intense changes in her roles and responsibilities ... [more ▼]

Pregnancy and childbirth are two critical stages in a woman’s life. The postnatal period is often a stressful time in the life of a woman with sudden and intense changes in her roles and responsibilities. Given all the disturbances encountered by mothers, the first objective of this PhD thesis was to explore their needs in the year following childbirth. We therefore proceeded to 22 individual qualitative interviews followed by one focus group with mothers. Needs of mothers after childbirth have been indexed in four categories: need of information, need of psychological support, need to share experience, and need of practical and material support. Women do not feel sufficiently informed about this difficult period of life. They do not feel sufficiently supported, not only from a psychological point of view but also from a more practical point of view. They are often tired and have a lot of questions. They need to share their experience of life, to be reassured and to feel understood. In an effort to meet their needs, mothers are increasingly turning to the digital devices, including the Internet, already during pregnancy. The second objective of this PhD thesis was therefore to assess whether women kept using these digital devices to answer to their questions during the postpartum period; which has been confirmed by a large online survey. This survey also showed that women were not always satisfied with the quality of the information they could find on the Internet. Given that existing tools do not seem to satisfy the main users, the idea of developing new digital tools to try to meet maternal needs started to make sense. The next step was then to determine some coherent digital tools in regard with maternal expectations. Two co-creative workshops: one with parents, health professionals and early childhood professionals and one with technology experts. The aim of the first workshop was to create a list of all the criteria that would have to be developed in future tools to meet the needs of mothers after childbirth. The aim of the second workshop was to conceive those digital tools in response to maternal needs and to the criteria selected during the first workshop. Many digital solutions were therefore investigated during these workshop such as a system of videoconferencing, an online newsletter pre-programmed, virtual reality apps (e.g. serious gaming), a geolocation system, a centralized website dedicated to babysitting systems, a “sponsorship” system, a forum dedicated to the postpartum period that would be supervised by professionals, an online exchange group, etc. After these investigations, two digital tools have been selected to be entirely developed (content and design) with the help of parents (both mothers and fathers) and professionals, health professionals and early childhood professionals: - On one side, a centralised website dedicated to mothers from the end of pregnancy to 1 year after childbirth (Happy-Mums.be) was developed. A Delphi survey – with both parents and professionals – highlighted the key priorities in the process of the website’s content development. The website’s content was then produced in collaboration with professionals who were experts in the various themes covered by the website. The graphic design was subcontracted and all the functionalities were tested throughout two new co-creative workshops. Happy-Mums.be was then submitted to all the parents and professionals who participated in the first 2 rounds of the Delphi survey to check if it met their expectations. Their impression were quite positive and they attributed a mean score of 8.00 ± 1.00 out of 10 regarding their impression about the quality of the information found on Happy-Mums.be. In addition, comments of the participants, led to some improvements of the website. Happy-Mums.be was also tested in a large population of mothers throughout a randomized controlled trial: one group of mothers having access to Happy-Mums.be and the other group not. A similar evolution of the maternal needs was highlighted in both groups but no potential effect of HappyMums.be on these needs could be identified. Nevertheless, the quality of the information found on HappyMums.be was, once again, judged to be significantly much better than the information found on any other websites (mean score regarding the quality: 7.22 ± 1.37/10 vs.5.29 ± 1.48/10 on the other websites; p<0.0001). - On the other side, a digital “gift voucher” system was also developed essentially to meet the need of practical support (Happy Gift). This system invites family or friends of the parents to offer them some practical help (e.g. household chores, activities with the other children, etc.) instead of material gifts. The objective of the digitalisation of this system was to accompany mothers as well as offerors in the realization of the offer by reminding both parties to remember to take advantage of (or to realize) the service offered. The gift’s names were conceived with the help of both potential parents and offerors. The graphic design was subcontracted. A first test using mothers as users of the Happy Gift tool (and so as seekers of help) did no work. Given the important need of practical and material support expressed by mothers and their initial enthusiasm regarding the “gift voucher” system, these results were not really expected. Several hypotheses regarding this failure have been formulated and suggest that this project could work if some modifications are made. That is why the Happy Gift tool has been reoriented for a second test, using, this time, potential offerors as the main users of the tool. In conclusion, although the human and psychological components remain very important and should not be neglected in the postpartum period, several interesting digital tools could be used as a complementary and useful solution to address mothers’ needs; particularly in the current context of shortened maternity stay. The tools developed in this Ph.D. thesis are potential solutions which need to be promoted and re- evaluated on a large scale in order to evaluate their effects on mothers’ satisfaction and needs. [less ▲]

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See detailContribution of capillary electrophoresis at the early stage of drug discovery
Farcas, Elena ULiege

Doctoral thesis (2018)

With the emergence of novel pharmaceutical targets, there is an imperative need for fast, reliable and cost-effective analytical techniques able to shorten the long and expensive process of drug ... [more ▼]

With the emergence of novel pharmaceutical targets, there is an imperative need for fast, reliable and cost-effective analytical techniques able to shorten the long and expensive process of drug development. In this context, we demonstrated that capillary electrophoresis (CE) could be a robust and efficient analytical tool, notably for the quantification of weak ligand-target interactions, for the investigation of ligands impact on targeted enzyme activity and for drug metabolism monitoring. To perform our proof of concept studies, the pathology targeted was thrombosis, since it remains one of the most important causes of morbidity and mortality worldwide. Two affinity CE approaches were designed to quantitate the interaction between thrombin (Thr) and low-affinity ligands in near physiological conditions. The direct binding approach consisted of monitoring the ligand electrophoretic mobility (µep) modification upon binding, while the indirect binding approach was based on the competition of the ligand with a known Thr inhibitor (PL). The modifications of PL µep as a consequence of the competition was in this case monitored. The developed affinity CE approaches allowed not only the accurate determination of complex dissociation constants (Kd)/half maximal inhibitory concentration (IC50) values, but they additionally allowed the conduction of highly discriminant and robust screening campaigns. It should be mentioned that the direct binding approach was suitable for the affinity determination only for cationic molecules that absorb in UV-VIS, while the indirect binding assay was extended to all kind of molecules, no matter their UV-VIS absorbance, or charging state. The information obtained during the affinity CE analyses was completed with the results generated by fast activity CE assays (analysis time less than 3 min). In this case, the capillary was employed as a multifunction nanoreactor on which the reagents were injected, mixed, incubated and the reaction product (the reporter molecule) was electrophoresed and detected. Two different mixing procedures, namely electrophoretically mediated microanalysis (EMMA) and transverse diffusion of laminar flow profiles (TDLFP) were investigated and the reaction parameters were optimized. In the context of molecules screening TDLFP approach proved to be the mixing procedure of choice, especially when the assayed molecules were charged species. The screening of our small library was performed in the optimized conditions and the results obtained were in good concordance with the affinity screening results. Additionally, a monolithic-functionalized GFP capillary column was investigated for method sensitivity enhancement. The usefulness of CE for metabolism studies realization was also demonstrated. A fully automated in-capillary system was developed to monitor the activity of CYP1A1 in physiological conditions. Ethoxycoumarin, the selected substrate, underwent an in-line bioreaction in the presence of CYP1A1 giving rise to hydroxycoumarin. The optimization of the experimental conditions was supported by the application of a design of experiment, providing a better understanding of electrophoretic mixing parameters that influence the metabolic reactions. The developed approaches demonstrate that CE is a powerful and robust tool to be considered in the early stages of drug discovery, due to its minimal sample requirements, ease of automation, its ability to detect and quantify weak interactions and to study drug metabolism in a fully-automated fashion and in near-physiological conditions. [less ▲]

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See detailThe Research to Practice Gap in Child Safety: Tools to promote the implementation of Evidence-Based Practice in Europe
Scholtes, Béatrice ULiege

Doctoral thesis (2018)

Introduction Although average injury rates are decreasing, large inequalities continue to exist between countries within the European Union. Mortality rates from injury for children aged 0-19 in Lithuania ... [more ▼]

Introduction Although average injury rates are decreasing, large inequalities continue to exist between countries within the European Union. Mortality rates from injury for children aged 0-19 in Lithuania in 2014 were 19/100,000 whereas in Spain the rate was 4/100,000. Within countries the picture is mixed and children’s injury risk is related to factors such as their socio-economic status or the education level and employment status of their parents. The impact of these factors means that important inequalities exist within countries in localised pockets of poverty and deprivation but also in wealthy areas. Better prevention of child injury is thus needed; however, it is a multi-sectoral undertaking. Risk factors are multi-faceted: social, environmental, and economic. Responsibility for controlling these risk factors transcends traditional policy sectors. Child injury prevention also occurs at multiple levels of governance; from local action to initiatives at international (European or global) level. Furthermore, injury prevention requires participation from the public and private sector and from civil society. This thesis explores the space between research and practice in the field of child safety in Europe. The research focuses upon the challenges for decision makers to analyse their local situation, choose interventions and put them into practice. Method The thesis focuses on four domains of child injury: road; water and home safety; and intentional injury prevention. Data collection for Chapters Three, Four and Six occurred between 2011 and 2014 within the framework of the EU-funded project; ‘Tools to Address Childhood Trauma and Children’s Safety’ (TACTICS). Participants were also involved in the TACTICS project and came from 27 countries of the WHO European Region. Chapters Two and Five are based on literature reviews conducted outside the framework of the TACTICS project. The theoretical underpinning of the thesis is based first: upon the Public Health Approach to injury prevention from Sleet et al., that underlines the importance of both an evidence-based approach and evidence-based practice within injury prevention. Second: the governance for health framework by Kickbusch and Gleicher which proposes the whole-of-government and whole-of-society approach to effective health governance. Third: the six stages of implementation proposed by Fixsen et al., theoretically guides the process of implementation. A combination of research methods was used throughout. Literature reviews guided the direction of the thesis and informed the content of the models and tools proposed. Quantitative and qualitative data was generated to identify the different sectors implicated in child injury prevention. A public health ethical framework was applied to an existing child safety intervention to explore ethical considerations. Finally, qualitative data was analysed using thematic content analysis to explore the process of implementation. Results A practical tool for use at the local level to address the cross-cutting nature of child injury prevention was developed. The tool is based on Haddon’s matrix and takes a life-course approach to injury prevention. It was developed for use by multi-sector stakeholders at the local level to better understand the complexity of child injury and develop multi-sectoral solutions. Twenty-seven different policy sectors were found to be implicated in child safety. Of these 27 sectors nine sectors were identified as ‘core’ sectors: Education; Health; Home Affairs; Justice; Media; Recreation; Research; Social/Welfare Services; Consumers Core sectors were considered applicable across the whole of child safety. Child safety reference frameworks (CSRF) were developed for use at the sub-national level. CSRF, can be used to inform policy makers about possible evidence-based child safety interventions, to assess the state of affairs in the region and to compare the situation regionally, nationally, internationally or over time. An ethical assessment of an intervention for child safety in the home highlights the relevance of public health ethics to child safety interventions. A thematic content analysis of facilitators and barriers for the adoption, implementation and monitoring of child safety interventions resulted in the identification of eight themes found to be applicable, to a varying degree, throughout the three phases of the process: Management and collaboration; Resources; Leadership; Nature of the intervention; Political, social and cultural environment; Visibility; Nature of the injury problem; Analysis and interpretation. Conclusion The findings demonstrate the multi-sectoral nature of child injury prevention and the challenges of implementation within an issue of such complexity. With a greater uptake of interventions it is hoped that the inequalities between and within countries could be reduced. The findings and tools presented in this thesis may help stakeholders at the local and regional levels to take action to protect children from injury. [less ▲]

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See detailIntroduction à l’evidence-based practice dans la formation initiale en logopédie et en médecine : évaluation de dispositifs mis en place à l’Université de Liège
Durieux, Nancy ULiege

Doctoral thesis (2018)

Le présent travail de thèse a pour objectif principal d’évaluer – afin de proposer des pistes d’amélioration – les dispositifs de formation à l’approche evidence-based practice (EBP) développés pour les ... [more ▼]

Le présent travail de thèse a pour objectif principal d’évaluer – afin de proposer des pistes d’amélioration – les dispositifs de formation à l’approche evidence-based practice (EBP) développés pour les étudiants en logopédie et en médecine à l’Université de Liège et de contribuer ainsi à l’évolution de l’enseignement de l’EBP dans ces disciplines. [less ▲]

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See detailDevelopment of new derivatives of a natural alkaloid, Crispine E, as SK channel blockers
Vitello, Romain ULiege

Master's dissertation (2018)

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See detailDébit de filtration glomérulaire : Détermination de formules d’estimation adaptées à l’adulte noir ouest-Africain
Yayo, Sagou Eric-Didier ULiege

Doctoral thesis (2018)

La maladie rénale chronique (MRC) est reconnue comme un problème de santé publique. L’estimation du débit de filtration glomérulaire (DFG) est une donnée fondamentale à son dépistage et à sa prévention ... [more ▼]

La maladie rénale chronique (MRC) est reconnue comme un problème de santé publique. L’estimation du débit de filtration glomérulaire (DFG) est une donnée fondamentale à son dépistage et à sa prévention particulièrement dans les pays Africains au sud du Sahara où les moyens de prise en charge de la maladie sont limités. Or dans les principales formules (MDRD et CKD-Epi) recommandées pour la détermination du DFG chez les Africains, un facteur ethnique est actuellement appliqué. Cependant, ces facteurs ont été déterminés à partir de l’étude de sujets afro-américains (AA) et leur validité chez le sujet africain (non américain) reste une question. Le présent travail a visé à déterminer la valeur de référence du DFG par une méthode de référence en population générale noire, ouest-africaine et à évaluer la pertinence des équations d’estimation actuellement en vigueur. L’étude a porté sur 254 Ivoiriens adultes présumés sains (120 femmes et 134 hommes). Chez chaque participant, le DFG a été mesuré par la clairance plasmatique de l’iohexol et estimé par les formules de CG, MDRD et CKD-Epi (à base de créatinine et/ou cystatine C). Les performances des équations d’estimation ont été évaluées à partir du biais, de la précision et de l’exactitude. A l’issue de nos travaux, les valeurs de référence de DFG ont été établies en population noire Africaine à partir d’une méthode de référence. Elles sont de l’ordre de 104 ml/min/1,73m2. Concernant les formules d’estimation, l’usage du facteur actuel donne une surestimation systématique des résultats du DFG estimé et devrait être abandonné. Il ressort également que la formule CKD-Epi sans facteur AA présente les meilleures performances pour l’estimation du DFG chez l’adulte noir Africain. Enfin, l’introduction de la cystatine C dans les différentes équations d’estimation n’a pas apporté de valeur ajoutée significative par rapport à la créatinine dans notre cohorte. [less ▲]

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See detailInfluence d'une prise en charge posturale sur la position assise, les capacités cognitives, le comportement et le bien-être de l'enfant en classe
Fettweis, Tatiana ULiege

Doctoral thesis (2017)

Cette thèse analyse l’impact d’une prise en charge posturale associée à l’utilisation d’un coussin triangulaire dynamique sur la position assise, les capacités cognitives, la concentration et le bien-être ... [more ▼]

Cette thèse analyse l’impact d’une prise en charge posturale associée à l’utilisation d’un coussin triangulaire dynamique sur la position assise, les capacités cognitives, la concentration et le bien-être de l’enfant en début d'école primaire. Elle comporte 4 sections principales. La revue de la littérature présentée dans la première section souligne le rôle de l’école et plus spécifiquement l’impact du mobilier scolaire sur la santé et les apprentissages des élèves. La deuxième section consiste à mettre en place et à étudier les qualités métrologiques d’une batterie de tests permettant d’évaluer la qualité de la position assise, les capacités posturales, le comportement en classe et les capacités cognitives d’enfants du premier cycle du primaire. La troisième section comprend trois études de terrain évaluant l’influence de la prise en charge en milieu scolaire. La partie principale consiste en un suivi longitudinal réalisé au cours des deux premières années primaires. Dans ce cadre, le cousin dynamique a amélioré la qualité de la position assise, les plaintes musculo-squelettiques, les capacités cognitives et le comportement des enfants en classe. Une première étude complémentaire a mis en évidence le caractère instantané de l’effet de la prise en charge et une seconde a confirmé l’impact positif du coussin dans une population présentant des troubles de l’attention. Enfin, la quatrième section comporte deux études réalisées au sein du Laboratoire d’Analyse du Mouvement Humain : une analyse biomécanique de la position assise a précisé l’effet positif et immédiat du coussin dynamique et une évaluation du contrôle moteur lombaire a démontré une meilleure proprioception lombaire chez les enfants habitués à utiliser le coussin. En conclusion, bien que cette recherche ne porte que sur une partie des facteurs entrant en ligne de compte pour le bien-être des élèves en classe ainsi que pour leur réussite scolaire, les différentes analyses et perspectives développées tout au long de cette thèse suggèrent la pertinence d’un coussin dynamique dans la mise en place de campagnes posturales préventives. [less ▲]

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See detailImpact of Murid Herpesvirus 4 Imprinting against Heterologous Respiratory Immunopathologies
Dourcy, Mickael ULiege

Doctoral thesis (2017)

Gammaherpesvirus (ɣ-HVs) infections are highly prevalent in both human and animals. They persist in their host by establishing and maintaining latent infections. Murid herpesvirus 4 (MuHV-4) is a wild ... [more ▼]

Gammaherpesvirus (ɣ-HVs) infections are highly prevalent in both human and animals. They persist in their host by establishing and maintaining latent infections. Murid herpesvirus 4 (MuHV-4) is a wild rodent pathogen that can be used as a model of ɣ-HV infection in the laboratory mouse. Like other ɣ-HVs, MuHV-4 profoundly imprints the host immune system to allow completion of its biological cycle. In particular, MuHV-4-induced modulations have been shown to confer bystander protection against heterologous secondary infections. Type 2 respiratory immunopathologies are of major interest in public health, specifically in developped countries. Notably, allergic asthma affects more than 300 million people worldwide and hSRV (human respiratory syncytial virus) inactivated vaccine-induced Th2 immunopathology substantially delays the development of vaccines against this virus which is yet the main infectious agent of bronchopneumopathies in children and olders. According to the hygiene hypothesis, epidemiological studies suggest that late primoinfections to human ɣ-HVs are correlated to an increased risk of allergic sensitization later in life. Using the MuHV-4 model, the in vivo impact of a ɣ-HV infection was tested against the development of on one hand, allergic airway inflammation induced by house dust mites (HDM) allergens (study 1) and on the other hand, anti-pneumovirus Th2 immunopathology, using Pneumonia virus of mice (PVM) to faithfully mimic the original hRSV disease in homologous host-virus model (study 2). Our results have shown that MuHV-4-infected mice are protected from the development of both allergic and vaccine-induced type 2 immune disorders. Moreover, MuHV-4-infected mice were also clinically protected from the subsequent heterologous infection with PVM. Finally, the protective mechanism against HDM allergic asthma was deciphered; pulmonary MuHV-4 lytic infection causes the severe depletion of the alveolar niche which is repopulated by bone marrow-derived monocytes. These latter cells then differentiate into alveolar macrophages (AMs) that are both phenotypically and functionally distinct from resident AMs. Indeed, in previously MuHV-4 infected mice, these monocyte-derived AMs express regulatory functions to block the activation of dendritic cells involved in allergic sensitization, therefore, conferring protection against allergic airway inflammation. In conclusion, the present thesis has unambiguously unraveled that ɣ-HV infection can protect the host against the development of main public health-related respiratory type 2 immune disorders. Replacement of embryonic AMs by regulatory monocytes is thus a major feature underlying the long-term training of the lung immunity after infections, and could provide a possible mechanistic explanation for the hygiene hypothesis. Altogether, this work opens interesting perspectives for the prevention of respiratory type 2 immunopathologies. [less ▲]

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See detailContribution to the Study of Percutaneous Left Atrial Appendage Occlusion
LEMPEREUR, Mathieu ULiege

Doctoral thesis (2017)

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See detailTowards a system of concepts for Family Medicine. Multilingual indexing in General Practice/ Family Medicine in the era of Semantic Web
Jamoulle, Marc ULiege

Doctoral thesis (2017)

UNIVERSITY OF LIÈGE, BELGIUM Executive Summary Faculty of Medicine Département Universitaire de Médecine Générale. Unité de recherche Soins Primaires et Santé Doctor in biomedical sciences Towards a ... [more ▼]

UNIVERSITY OF LIÈGE, BELGIUM Executive Summary Faculty of Medicine Département Universitaire de Médecine Générale. Unité de recherche Soins Primaires et Santé Doctor in biomedical sciences Towards a system of concepts for Family Medicine. Multilingual indexing in General Practice/ Family Medicine in the era of SemanticWeb by Dr. Marc JAMOULLE Introduction This thesis is about giving visibility to the often overlooked work of family physicians and consequently, is about grey literature in General Practice and Family Medicine (GP/FM). It often seems that conference organizers do not think of GP/FM as a knowledge-producing discipline that deserves active dissemination. A conference is organized, but not much is done with the knowledge shared at these meetings. In turn, the knowledge cannot be reused or reapplied. This these is also about indexing. To find knowledge back, indexing is mandatory. We must prepare tools that will automatically index the thousands of abstracts that family doctors produce each year in various languages. And finally this work is about semantics1. It is an introduction to health terminologies, ontologies, semantic data, and linked open data. All are expressions of the next step: Semantic Web for health care data. Concepts, units of thought expressed by terms, will be our target and must have the ability to be expressed in multiple languages. In turn, three areas of knowledge are at stake in this study: (i) Family Medicine as a pillar of primary health care, (ii) computational linguistics, and (iii) health information systems. Aim • To identify knowledge produced by General practitioners (GPs) by improving annotation of grey literature in Primary Health Care • To propose an experimental indexing system, acting as draft for a standardized table of content of GP/GM • To improve the searchability of repositories for grey literature in GP/GM. 1For specific terms, see the Glossary page 257 x Methods The first step aimed to design the taxonomy by identifying relevant concepts in a compiled corpus of GP/FM texts. We have studied the concepts identified in nearly two thousand communications of GPs during conferences. The relevant concepts belong to the fields that are focusing on GP/FM activities (e.g. teaching, ethics, management or environmental hazard issues). The second step was the development of an on-line, multilingual, terminological resource for each category of the resulting taxonomy, named Q-Codes. We have designed this terminology in the form of a lightweight ontology, accessible on-line for readers and ready for use by computers of the semantic web. It is also fit for the Linked Open Data universe. Results We propose 182 Q-Codes in an on-line multilingual database (10 languages) (www.hetop.eu/Q) acting each as a filter for Medline. Q-Codes are also available under the form of Unique Resource Identifiers (URIs) and are exportable in Web Ontology Language (OWL). The International Classification of Primary Care (ICPC) is linked to Q-Codes in order to form the Core Content Classification in General Practice/Family Medicine (3CGP). So far, 3CGP is in use by humans in pedagogy, in bibliographic studies, in indexing congresses, master theses and other forms of grey literature in GP/FM. Use by computers is experimented in automatic classifiers, annotators and natural language processing. Discussion To the best of our knowledge, this is the first attempt to expand the ICPC coding system with an extension for family physician contextual issues, thus covering non-clinical content of practice. It remains to be proven that our proposed terminology will help in dealing with more complex systems, such as MeSH, to support information storage and retrieval activities. However, this exercise is proposed as a first step in the creation of an ontology of GP/FM and as an opening to the complex world of Semantic Web technologies. Conclusion We expect that the creation of this terminological resource for indexing abstracts and for facilitating Medline searches for general practitioners, researchers and students in medicine will reduce loss of knowledge in the domain of GP/FM. In addition, through better indexing of the grey literature (congress abstracts, master’s and doctoral theses), we hope to enhance the accessibility of research results and give visibility to the invisible work of family physicians. [less ▲]

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See detailContribution à l'étude de l'influence de la circulation extracorporelle sur la fonction rénale en période postopératoire.
LAGNY, Marc-Gilbert ULiege

Doctoral thesis (2017)

L’insuffisance rénale aiguë postopératoire est une complication fréquente et grave après chirurgie cardiaque. Elle alourdit considérablement la morbi-mortalité et le devenir des patients. Notre thèse ... [more ▼]

L’insuffisance rénale aiguë postopératoire est une complication fréquente et grave après chirurgie cardiaque. Elle alourdit considérablement la morbi-mortalité et le devenir des patients. Notre thèse étudie l’influence de la circulation extracorporelle sur la fonction rénale dans le décours postopératoire. Notre travail de recherche se compose de quatre parties : Incidence de l’insuffisance rénale aiguë dans le décours d’une chirurgie cardiaque au Centre Hospitalier Universitaire de Liège. L’insuffisance rénale aiguë est diagnostiquée à l’aide d’une classification utilisant des critères sériques et urinaires. Cinquante pourcents des patients pris en charge pour une chirurgie cardiaque développent cette complication rénale durant les sept premiers jours postopératoires. Cette étude rétrospective est établie sur une période d’une année complète. L’incidence de cette complication rénale varie considérablement selon les critères observés (sériques seuls ou sériques et urinaires). L’insuffisance rénale chronique préalable à la chirurgie cardiaque constitue un facteur de risque très important. Celui-ci est d’autant plus péjoratif qu’il réduit significativement la probabilité de survie à un an. Les chirurgies valvulaires et combinées constituent des interventions à très haut risque de développer une atteinte rénale postopératoire. Evaluation d'un nouveau type de filtre disposé sur le circuit de circulation extracorporelle : impact clinique sur la fonction rénale. Cette étude prospective randomisée étudie l’impact d’un filtre à déleucocyter et réduire les particules lipidiques. Il est incorporé dans un réservoir de cardiotomie qui comprend un filtre multicouche permettant de filtrer une première fois le sang épanché aspiré par simple passage. Le réservoir est muni d’un siphon dont le but est de piéger le surnageant après un processus de filtration puis de décantation. Ce dispositif est interposé sur les lignes d’aspiration de récupération du sang épanché aspiré du circuit de circulation extra-corporelle. Un réservoir de cardiotomie de volume identique et muni d’un filtre conventionnel de 40-µm sert pour le groupe contrôle. L’utilisation du filtre spécifique n’a pas d’effet protecteur rénal. En effet, le nombre de patients, ayant présenté une insuffisance rénale aiguë, dans les quarante-huit premières heures, est identique quel que soit le groupe concerné. Des biomarqueurs spécifiques (la Neutrophil Gelatinase Associated Lipocalin urinaire et la Cystatine C sérique) témoignent d’une souffrance rénale précoce quel que soit le filtre utilisé. Evaluation de la capacité de réduction des particules lipidiques et de la leucodéplétion d'un nouveau type de réservoir de cardiotomie pourvu d’un filtre spécifique. Cette seconde étude prospective randomisée montre une réduction significative des leucocytes (26 %) par le filtre spécifique contrairement au filtre conventionnel. Cependant, les deux types de filtre étudiés réduisent de manière similaire les particules lipidiques présentes dans le sang aspiré. Aucun des deux filtres ne réduit la concentration des médiateurs inflammatoires libérés par les leucocytes activés. Hydroxyéthylamidon 130/0,04 (HEA) et risque d’insuffisance rénale aiguë après circulation extracorporelle. Cette étude rétrospective compare l’incidence d’insuffisance rénale aiguë avec deux types de solution d’amorçage de circuit de circulation extracorporelle et de perfusion intra-veineuse. La première solution est un colloïde (Hydroxyéthylamidon), la seconde est un cristalloïde balancé (Plasma-Lyte A®). Le diagnostic d’insuffisance rénale aiguë est déterminé sur base de l’évolution de la créatinine sérique observée durant les quarante-huit premières heures postopératoires. L’incidence d’insuffisance rénale est deux fois plus importante chez les patients perfusés avec de l’hydroxyéthylamidon. Cette complication apparaît indépendamment de la transfusion de produits sanguins et de la ré-exploration chirurgicale. L’insuffisance rénale aiguë après circulation extracorporelle est multifactorielle. La technique spécifique de filtration du sang aspiré testée n’apporte pas de bénéfice pour la fonction rénale. Le type de liquide de perfusion intraveineuse et d’amorçage du circuit de circulation extracorporelle joue un rôle dans la survenue de cette complication en période postopératoire immédiate. [less ▲]

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See detailCiliary Videomicroscopy: Standardisation and Use in Ciliary Functional Analysis
KEMPENEERS, Céline ULiege

Doctoral thesis (2017)

Cilia are hair-like organelles, distributed widely throughout the human body, and may be either motile or sensory. Primary ciliary dyskinesia is an inherited motile ciliopathy, in which respiratory cilia ... [more ▼]

Cilia are hair-like organelles, distributed widely throughout the human body, and may be either motile or sensory. Primary ciliary dyskinesia is an inherited motile ciliopathy, in which respiratory cilia are stationary, or beat in a slow or dyskinetic manner. This leads to impaired mucociliary clearance and significant sinopulmonary disease. The diagnosis of primary ciliary dyskinesia is challenging, and a panel of different tests are required. Digital high speed videomicroscopy is one technique which allows real time analysis of complete ciliary function, including ciliary beat frequency and beat pattern, and allows beating cilia to be visualized in three different planes. Despite it being highly sensitive and specific test for diagnosing primary ciliary dyskinesia, digital high speed videomicroscopy lacks standardization. A review of the current state of the art concerning digital high speed videomicroscopy ciliary functional assessment was conducted, and the methodology between different laboratories compared. The data was used to generate recommendations concerning digital high speed videomicrosopy methodology, evaluation, and interpretation. The variability of ciliary beat pattern within healthy respiratory ciliated epithelium, and reproducibility in manual beat pattern analysis, was evaluated using digital high speed videomicroscopy. The results highlighted issues with single and limited manual beat pattern analysis. Compared to the sideways profile, in healthy subjects, cilia beating toward the observer and from above profile were found to be less sensitive in detecting ciliary dyskinesia. However, these beating profiles may be used to calculate ciliary beat frequency. In addition, the evaluation of five beat cycles to measure ciliary beat frequency is as accurate as ten beat cycles. Summary Standardized protocols for ciliary functional analysis using digital high speed videomicroscopy need to be established and applied in different laboratories with appropriate reference ranges. Ciliary beat pattern is not uniform within healthy respiratory ciliated epithelium, emphasizing the risk of limited beat pattern analysis. Further work is needed to evaluate the use of the different beat profiles for evaluation of ciliary function in patients with primary ciliary dyskinesia. [less ▲]

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See detailA TMS–EEG contribution to the multimodal assessment of brain connectivity and consciousness
BODART, Olivier ULiege

Doctoral thesis (2017)

Patients with chronic disorders of consciousness make a challenging population. On the clinical side, establishing an accurate diagnosis is arduous, as the signs of consciousness can be subtle, or even ... [more ▼]

Patients with chronic disorders of consciousness make a challenging population. On the clinical side, establishing an accurate diagnosis is arduous, as the signs of consciousness can be subtle, or even undetectable behaviourally. Both the families and the caregivers need truthful information to make tough decisions about the patient’s management. Transcranial magnetic stimulation, coupled with high-density electroencephalography, is a promising technique to improve our diagnostic ability. The perturbational complexity index derived from this technique is able to distinguish between unconscious and conscious conditions. Its specificity remains to be determined. On the scientific side, the long-standing quest to discover the neural correlates of consciousness is still ongoing. Patients with disorders of consciousness have structural brain damage, and several areas may lose their ability to causally interact in complex patterns with long distance structure. The relation between this ability and structural integrity remains undetermined, despite a vast amount of neuroimaging studies on several networks and connectivities in this population. Our objectives are i) to cross-validate the perturbational complexity index with other neuroimaging techniques, and to determine its specificity, and ii) to determine the relation between global structural integrity and the brain global ability to sustain complex long-range interactions. To do so, we first combined transcranial magnetic stimulation with fluoro-deoxyglucose positron emission tomography, a validated technique studying the brain metabolism, in a population of patients behaviourally characterized by repeated assessments with the gold standard scale, the coma recovery scale – revised. To meet our second objective, we computed and compared the perturbational complexity index and the global fractional anisotropy, a magnetic resonance imaging marker of structural integrity, in patients and in healthy subjects. We found an excellent congruence between electrophysiological and metabolic results in our first study, even in behaviourally unconscious patients showing indirect signs of consciousness. In our second study, we demonstrated that structural integrity largely correlated with the perturbational complexity index, and did not depend on the time since onset or the aetiology. This confirms the diagnostic value of transcranial magnetic stimulation and the perturbational complexity index. It is not only sensitive at the single subject level, but also highly specific. It can detect covert signs of consciousness, as confirmed by other neuroimaging techniques. As such, it could be integrated in diagnostic algorithms and improve their accuracy, leading to better management of these patients. Moreover, the brain’s ability to sustain complex long-range interactions is highly dependant on the global structural integrity. By looking further in detail at the local correlation between these two parameters, our understanding of the emergence of consciousness from fixed structure with variable connectivity would improve. This would be one step forward in the quest for the neural correlates of consciousness. [less ▲]

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See detailValidation préclinique de marqueurs biologiques de l'arthrose
Legrand, Catherine ULiege

Doctoral thesis (2017)

Introduction Osteoarthritis is the most common form of joint disease. It affects more than one million people in Belgium. Considered as a major public health problem among seniors, it is responsible for ... [more ▼]

Introduction Osteoarthritis is the most common form of joint disease. It affects more than one million people in Belgium. Considered as a major public health problem among seniors, it is responsible for many direct and indirect costs generated, in particular, by the increasing number of hip and knee implants. To date, there is no way to detect early, predict or monitor the course of the disease. The association of glycated, oxidized and nitrated amino acids released from the joint with development and progression of knee osteoarthritis (OA) is unknown. We studied this in an OA animal model, patients with OA and interleukin-1β-activated human chondrocytes in vitro. Material and methods Sixty 3-week-old male Dunkin-Hartley guinea pigs were studied. At 4-week-old and 8 week intervals until week 36, twelve animals were sacrificed and histological severity of knee OA evaluated and cartilage rheological properties assessed. Human patients with early and advanced OA, and healthy controls were recruited. Human chondrocytes cultured in multilayers were treated for 10 days with interleukin-1β. Serum, plasma and culture medium were analyzed for glycated, oxidized and nitrated amino acids. Results Severity of OA increased progressively in guinea pigs with age. Glycated, oxidized and nitrated amino acids were increased markedly at week 36, with glucosepane and dityrosine increasing progressively from weeks 20 and 28, respectively. Glucosepane correlated positively with OA histological severity (r = 0.58, p<0.0001) and Young’s Modulus (condyle: r = 0.52, plateau: r=0.56; p<0.0001), oxidation free adducts correlated positively with OA severity (p<0.0009). In clinical translation, plasma glucosepane was increased by 38% in early-stage OA (p<0.05) and 6-fold in patients with advanced OA (p<0.001), compared to healthy controls. Interleukin-1β increased the release of glycated and nitrated amino acids from chondrocytes in vitro. Conclusions In conclusion, we observed in our in vivo study an increase in rigidity as well as a decrease in the thickness of the cartilage during the aging of the animal. In addition, a decrease in average walking speed and swing speed in 36-week-old guinea pigs was observed with CatWalk analysis. Serum concentrations of glycation, oxidation and nitration products increased with the development of osteoarthritis. In vitro, IL-1β increased the concentration of AGE and 3-NT in human chondrocytes cultured in multilayers. Glucosepane, strongly correlated with the histological parameters as well as the mechanical properties of the cartilage is a potential biomarker for the detection and progression of osteoarthritis. [less ▲]

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See detailDacapo regulates axonal transport through the modulation of microtubule acetylation
Le Bail, Romain ULiege

Master's dissertation (2017)

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See detailRôle des lymphocytes T TCR γδ dans la progression des lésions associées à l'infection par les papillomavirus humains
Van Hede, Dorien ULiege

Doctoral thesis (2017)

Cervical cancer was the fourth most frequent cancer in women in 2012, with the majority of cases occurring in less developed countries. Although this cancer is induced by Human Papillomavirus (HPV ... [more ▼]

Cervical cancer was the fourth most frequent cancer in women in 2012, with the majority of cases occurring in less developed countries. Although this cancer is induced by Human Papillomavirus (HPV) infections that have a high prevalence, only a very few percentage of infected women will developed this disease. Host immune defenses are essential to clear infection and to kill virus-infected transformed cells. Indeed, majority of infected women clear the virus within two years while immunocompromised patients are more likely to develop cervical preneoplastic lesions and cancers. γδ T cells have been shown to protect against the formation of squamous cell carcinoma (SCC) in several models. Nowadays, the contribution of γδ T cells in HPV associated uterine cervical SCC is unknown. Here we investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16-oncoproteins. Surprisingly, γδ T cells promoted the development of HPV16-oncoprotein-induced lesions. These oncoproteins induced a decrease in epidermal Skint-1 expression and modification of the associated anti-tumor Vγ5+ γδ T cells (or DETC), which were joined by other γδ T cell subsets actively producing IL-17. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical, IL-17+ γδ T cells could be only observed at the cancer stage (SCC) (but not in less advanced cervical lesions), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16-oncoproteins induce a reorganization of the local epithelial-associated γδ T cell Subpopulations thereby promoting angiogenesis and cancer development. [less ▲]

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See detailField border flowering strips as a source of valuable compounds
Paul, Aman ULiege

Doctoral thesis (2017)

Intensification of agricultural practices has caused irreversible damage to environment during the last few years. Several consumers are now deviating towards healthier diets produced from eco-friendly ... [more ▼]

Intensification of agricultural practices has caused irreversible damage to environment during the last few years. Several consumers are now deviating towards healthier diets produced from eco-friendly and sustainable agricultural systems. In this regard, the possibilities of utilizing edible biomass originating from sustainable agricultural practices have gained recent attention. The underutilized edible plants, especially their seeds could be one of the interesting alternates, as some of these seeds are not only nutritious, but could also be produced using sustainable practices. Similarly, edible insects represent another category of biomass which are rich in nutrients and could be produced sustainably. The seeds from underutilized edible plants and the edible insects could be simultaneously harvested using a sustainable agricultural system involving field border flowering strips. Field border flowering strip is a part of agricultural landscape that is reserved for herbaceous vegetation. These strips are popularly grown throughout the world to enhance biodiversity. The main objective of this thesis is to utilize seeds from some of the plants grown as field border flowering strips and insects that find refuge in these plants for the provision of food and health promoting substances. From the literature reviewed in chapter two, it was observed that: (1). Most plants that are grown in field border flowering strips are edible, and their aerial parts have been extensively analyzed for chemical composition. However, there is a scarcity of literature evaluating chemical composition/food utilization of the seeds from plants that are grown as field border flowering strips. So, the primary objective of this thesis is to investigate the nutritional and health promoting potential of the seeds from some plants that are grown in these strips. (2). A number of grasshopper species find refuge in field border flowering strips. Several grasshopper species are considered edible throughout the world and they are interesting source of nutrients. So the secondary objective of this thesis is to screen some edible grasshopper species that are present in field border flowering strips, analyze their nutritional value, and investigate possibilities to establish their commercial rearing for ensuring year-long availability of edible biomass. The research strategy adopted to achieve the objectives of this thesis is mentioned in chapter three. This chapter includes details about the selection of raw materials (both plant seeds and insects), and subsequent analysis. Chapter four contains the detail about the materials and methods used for analysis during this study. Chapter five includes details about the investigations on edible insects. Chorthippus parallelus Zetterstedt species grasshoppers were shortlisted for detailed investigation due to their high densities in field border flowering strips. This insect species was analyzed for proximate composition, amino acid profile, fatty acid profile and mineral profile. Moreover the toxicity of these insects was also evaluated using two different models. Results indicated that these insects could be consumed as an alternate source of proteins (69%) and omega-3 fatty acid rich lipids (10%). Rearing trials done during this study indicates that commercial rearing could be developed to produce sufficient and safe biomass for human consumption. The selection of seeds from three plant species (Achillea millefolium L., Anthriscus sylvestris (L). Hoffm. and Prunella vulgaris L.), for detailed analysis on the basis of lipid content and fatty acid profile has been mentioned in chapter six. Chapter seven, eight and nine include the details about the composition and anti-oxidant activity of A. millefolium, A. sylvestris and P. vulgaris seeds, respectively. Proximate composition, lipid profile, amino acid profile, mineral profile, lignocellulosic profile, phenolic profile and phytate content of the three plant seeds were investigated during this study. Two new phenolic acids were discovered originating from P. vulgaris seeds. These compounds were named amolsamic acid A and amolsamic acid B. Discovery of these compounds was the true highlight of this thesis. All the three plant seeds were found to contain substantial level of total phenolics (0.8-2.6%) and interesting phenolic profiles (dominated by chlorogenic acid, rosmarinic acids and related compounds). Keeping this in mind, the detailed anti-oxidant activity (including anti-radical scavenging, horseradish peroxidase response modulation, cellular anti-oxidant, myeloperoxidase response modulation and anti-lipid peroxidation activity) of their respective seed extracts was also analyzed. Results obtained during this study indicate that A. millefolium, A. sylvestris and P. vulgaris seeds not only contain interesting level of nutrients, but their extracts also exhibit significant anti-radical scavenging, horseradish peroxidase response modulation, cellular anti-oxidant (IC50 values order: P. vulgaris>A. sylvestris>A. millefolium) and myeloperoxidase response modulation activity (IC50 values order: A. sylvestris>A. millefolium>P. vulgaris for both direct and SIEFED assay). The main conclusions (chapter ten) of this PhD dissertation are: (1). C. parallelus insects could be viewed as an alternative source of nutrients to diversify human diets. The preliminary rearing studies done during this study indicate that commercial rearing could be developed for generation of substantial (and safe) biomass to support human consumption. (2). A. millefolium, A. sylvestris and P. vulgaris seeds could be included in food formulations (or consumed as whole) as a source of proteins, lipids, minerals and phenolics. P. vulgaris seeds could also be used for the extraction of two new phenolic constituents (amolsamic acid A and amolsamic acid B). The first investigations involving A. millefolium, A. sylvestris and P. vulgaris seeds realized during this study, indicate that seed extract (or whole seeds) from all three plants could possibly be consumed for the prevention of neutrophil and myeloperoxidase mediated damage in human body. [less ▲]

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See detailNouvelles combinaisons thérapeutiques pour améliorer l'efficacité anti-tumorale de l'inhibition d'HDAC5
Hendrick, Elodie ULiege

Doctoral thesis (2017)

En oncologie, les 18 membres de la famille des déacétylases d’histone (HDAC) représentent des cibles thérapeutiques d’intérêt croissant. En effet, de nombreuses molécules pharmacologiques ciblant ... [more ▼]

En oncologie, les 18 membres de la famille des déacétylases d’histone (HDAC) représentent des cibles thérapeutiques d’intérêt croissant. En effet, de nombreuses molécules pharmacologiques ciblant l’activité enzymatique de ces protéines (HDACi) montrent des effets anti-tumoraux intéressants in vitro et in vivo ainsi que dans de nombreux essais cliniques sur des patients souffrant de pathologies cancéreuses solides et hématologiques. A ce jour, 4 de ces molécules (Vorinostat®, l’Istodax®, Beleodaq® et le Farydak®) sont d’ailleurs approuvées par la FDA et l’EMA pour le traitement de patients souffrant, notamment, de différents types de lymphomes et de myélomes. Aujourd’hui, les oncologues s’intéressent au développement d’inhibiteurs d’HDAC plus sélectifs avec comme objectifs de maintenir et d’améliorer l’effet anti-tumoral tout en diminuant la toxicité et en réduisant les potentiels effets non désirés. Dans cette optique, il convient de déterminer plus finement les relations qu’il existe entre l’inhibition spécifique d’une HDAC et les effets anti- tumoraux observés et ce, afin d’identifier la (les) HDAC d’intérêt à cibler en thérapie anti-cancéreuse. Dans ce travail, nous nous sommes focalisés sur le rôle et les mécanismes d’action de l’histone déacétylase 5 (HDAC5) dans les cellules cancéreuses. Nos résultats démontrent que l’inhibition sélective d’HDAC5 module l’expression de protéines du complexe I de la chaîne respiratoire mitochondriale, de protéines pro- et anti- oxydantes et des protéines impliquées dans le métabolisme de métaux tel que le métabolisme de stockage du fer labile. Par conséquent, la déplétion d’HDAC5 induit une production accrue d’espèces réactives de l’oxygène (ROS) mitochondriaux accentués par la présence accrue de fer labile intracellulaire disponible pour la réaction de Fenton. Cette accumulation accrue de ROS induit une mort cellulaire par apoptose et un processus d’autophagie de type mitophagie (dégradation sélective des mitochondries endommagées et productrice de ROS). La déplétion d’HDAC5 dans des cellules cancéreuses modifie également le métabolisme énergétique dépendant du glucose et de la glutamine. Nous avons effectivement observé d’une part, une augmentation de l’import du glucose dirigé vers la voie des pentoses phosphates assurant une production de NADPH, force réductrice du glutathion permettant ainsi de contrecarrer le stress oxydant et d’autre part, une glutamino-dépendance nécessaire au maintien des besoins énergétiques de la cellule. Par conséquent, des cellules déplétées en HDAC5 dont l’apport en glucose ou en glutamine est contrecarré par des inhibiteurs métaboliques utilisés en clinique, meurent de manière significative par apoptose in vitro et diminuent la croissance de tumeurs in vivo, suggérant que des stratégies combinatoires couplant l’inhibition sélective d’HDAC5 à des inhibiteurs du métabolisme énergétique actuellement testés en essai clinique pourraient être proposées comme nouvelle stratégie combinatoire en thérapie anti-cancéreuse. [less ▲]

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See detailLes Hormones Glycoprotéiques: de la Clinique à la Recherche.
VALDES SOCIN, Hernan Gonzalo ULiege

Doctoral thesis (2017)

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See detailL’INHIBITION DE LA MÉTHYLTRANSFÉRASE EZH2 DU COMPLEXE RÉPRESSEUR POLYCOMB FAVORISE LA RÉPONSE ANTI-TUMORALE DES MACROPHAGES M2 DIRIGÉE CONTRE LES CELLULES DU MÉSOTHÉLIOME PLEURAL MALIN
Hamaïdia, Malik ULiege

Doctoral thesis (2017)

Context: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm affecting mesothelial cells from the pleura, pericardium and peritoneum. The disease is closely associated to asbestos exposure ... [more ▼]

Context: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm affecting mesothelial cells from the pleura, pericardium and peritoneum. The disease is closely associated to asbestos exposure. Despite of rules to reduce workplace exposure to asbestos, incidence of mesothelioma is predicted to increase until 2020. Since MPM is resistant to conventional cancer therapies such as surgery, irradiation and chemotherapy, development of new options is urgently needed. In my project, I investigate the ability of immunotherapy to improve patients' outcome. My hypothesis postulates that tumor cells are tightly controlled by the immune system. In fact, clinical evidence indicates that tumor infiltration by tumor associated macrophages (TAMs) correlates with poor prognosis in malignant mesothelioma (MM). By attenuating the immune response, TAMs indeed promote survival of MM cells. TAMs share properties with alternative macrophages (M2) and are activated by anti-inflammatory (e.g. IL-10) or Th2-associated (i.e. IL-4, IL-13) cytokines. In contrast, classical (M1) macrophages are stimulated by interferon (IFN)-γ and microbial components (e.g. LPS). Aim: We hypothesized that macrophage activation is mediated by a transcriptional program tightly regulated by epigenetic modifications. We focused on the Polycomb Repressive Complex 2 (PRC2) EZH2 lysine methyltransferase responsible for trimethylation of histone H3 at lysine 27 (H3K27me3). Results: Our data show that inhibition of EZH2 reduces phagocytic activity by M2-polarised macrophages. Moreover, the cytotoxicity of supernatants conditioned by M2-macrophages is increased in presence of the EZH2 inhibitor. Finally, inhibition of EZH2 enhances the tumoricidal potential of M2 macrophages towards MM cells. We further demonstrate that macrophage killing activity requires superoxide radicals (O2.-) and peroxynitrites (ONOO-) derivatives produced by the NADPH oxidase system. Conclusion: EzH2 inhibition implements the tumoricidal potential of macrophages and may therefore improve the efficacy of immunotherapy of MM patients. [less ▲]

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See detailInactivation of DNA damage repair provides additional efficacy to the treatment of thyroid cancer
Neelature Sriramareddy, Sathyanarayana ULiege

Doctoral thesis (2017)

Incidence of thyroid cancer has increased steadily over the last several decades. This type of neoplasm accounts for the majority of deaths due to endocrine cancers. The most frequent form, well ... [more ▼]

Incidence of thyroid cancer has increased steadily over the last several decades. This type of neoplasm accounts for the majority of deaths due to endocrine cancers. The most frequent form, well-differentiated thyroid cancer, is characterized by disease persistence, recurrence and a lack of response to radioiodine-131. With survival rates of 9 weeks to 5 months, anaplastic thyroid cancer has very poor prognosis. To provide additional efficacy to the treatment of thyroid cancer, we investigated the mechanisms of DNA damage and repair. We found that thyroid cancer cells undergo mitosis in presence of unrepaired DNA damage. To proliferate and survive, these cells repair DNA lesions very efficiently using homologous recombination (HR) and non-homologous end joining (NHEJ). Pharmacological inhibition of these pathways significantly increases apoptosis of thyroid cancer cells. This thesis thus demonstrates that targeting DNA damage repair pathways might have therapeutic value in relapsing and advanced thyroid cancers. [less ▲]

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See detailLa faisabilité et l'efficacité du traitement assisté par diacétylmorphine en Belgique
Demaret, Isabelle ULiege

Doctoral thesis (2016)

Objective The aim of our research was to assess the feasibility and efficacy of a treatment assisted by diacetylmorphine in Liège. This treatment is offered to persons dependent on heroin who pursue ... [more ▼]

Objective The aim of our research was to assess the feasibility and efficacy of a treatment assisted by diacetylmorphine in Liège. This treatment is offered to persons dependent on heroin who pursue street heroin use despite existing treatments. Methods Data were collected in a pilot project of Treatment Assisted by Diacetylmorphine (TADAM), which took place in Liège from 2007 to 2013. The heart of this project is a randomised controlled trial comparing a diacetylmorphine treatment – limited to 12 months – with existing methadone treatments. A participant was responder if he/she showed improvement on the level of street heroin use, health or criminal involvement. Other researches (mainly based on interviews) were added in order to understand interactions between the trial and its actors: heroin users (included or not-included), neighbours of the DAM centre, the staff of the DAM centre and staff of other institutions who worked with our target group in Liège. Results With the help of the centres, partners of the trial, 74 participants (of the 200 planned) were included and randomised: 36 in the experimental group and 38 in the control group. These participants were dependent on heroin for 20 years on average and had already tried 9 treatments for their addiction(s). At the end of the trial, the number of responders in the experimental group was greater but not significantly than in the control group (p=0.35). However, participants in the experimental group showed greater improvement than in the control group, on the level of street heroin use (p=0.0011) and physical (p=0.043) or mental (p=0.035) health. During the follow-up study, three months after the end of the 12 months of treatment, street heroin use in the experimental group had significantly increased (p=0.0052) and the difference with the control group was no longer significant (p=0.55). Discussion Participants included in the trial were, as expected, persons severely dependent on street heroin, who could not find a solution to their addiction with the existing treatments. Participants in the experimental group decreased significantly their street heroin use. However, in our follow-up study, street heroin use increased significantly in the experimental group 3 months after the end of the diacetylmorphine treatment. In the foreign studies, diacetylmorphine treatment showed greater efficacy compared to methadone treatment for this target group and the improvement was sustained after the trial even when the treatment was stopped, but not when the end of treatment was forced against the will of the patient. Nevertheless, our research showed the feasibility of a diacetylmorphine treatment in Liège and its acceptance by the actors involved in the trial. Conclusion Diacetylmorphine treatment is feasible in Belgium. In foreign studies, it showed more efficacy than methadone treatment and benefits gained with this approach were maintained during years. But these benefits disappear when the end of treatment is forced, against the will of the patient. [less ▲]

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See detailLes enregistrements infirmiers : un outil d'efficience. Du RIM aux DI-RHM dans les hôpitaux belges.
Thonon, Olivier ULiege

Doctoral thesis (2016)

Le Résumé Infirmier Minimum existe depuis 1988 et un certain nombre des objectifs initiaux ont été atteints. A la fin des années 90, la question de l’actualisation du RIM s’est posée avec acuité étant ... [more ▼]

Le Résumé Infirmier Minimum existe depuis 1988 et un certain nombre des objectifs initiaux ont été atteints. A la fin des années 90, la question de l’actualisation du RIM s’est posée avec acuité étant donné l’évolution des soins de santé en général et de l’art infirmier en particulier. Dorénavant intégré dans une base de données unique, le Résumé Hospitalier Minimal, ce Résumé Infirmier Minimum actualisé, implanté officiellement depuis janvier 2008, a sans aucun doute métamorphosé l’environnement des soins infirmiers. Le chapitre 1 décrit ce processus d’actualisation du RIM. Le cadre conceptuel du RIM « actualisé » définit un tremplin international, en référence à la Nursing Interventions Classification (NIC) utilisée pour sa conception. La visualisation de la variabilité des soins infirmiers se fera dorénavant à travers un langage plus riche et plus précis en passant de 23 à 78 items. La première composante de l’efficience, est abordée dans le chapitre III. Il concerne l’évaluation du niveau de preuve des interventions répertoriées dans les DI-RHM. L’approche justificative de l’outil est abordée dans le chapitre IV de ce travail. Le chapitre V examine dans quelle mesure il serait possible d’allouer les moyens infirmiers de façon plus rigoureuse aux hôpitaux. Le chapitre VI se consacre à l’élaboration de profils de soins infirmiers sur base des DI-RHM et à la mise en évidence de leur potentiel d’utilisation. Nous concluons par une discussion générale reprenant les divers éléments abordés dans ces différentes approches à la lumière du contexte actuel de l’outil. [less ▲]

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See detailIntégration de soins: du patient à une population
Belche, Jean Luc ULiege

Doctoral thesis (2016)

Through our experience of general practice we noticed a lack of coordination between the general practitioner and the hospital that could lead to poor quality patient care. We decided, therefore, to focus ... [more ▼]

Through our experience of general practice we noticed a lack of coordination between the general practitioner and the hospital that could lead to poor quality patient care. We decided, therefore, to focus upon the integration between levels of care as our main research topic. Problem setting Clarifying concepts such as ‘levels of care’ (Chapter 1) and integration of care’ (Chapter 2) was the first step of our work. The concept of ‘levels of care’ is entwined with ‘integration of care’. The historic differentiation between concept of ‘levels of care’ is not only a consequence of the medical specialization process, but also a result of the drive for greater efficiency in the delivery of patient care. In general the differentiation process is a response to complex situation and consecutive integration is necessary to maintain coherent and global action. An in-depth analysis of these two concepts gave us a theoretical framework for our analysis. We explained the distinction between ‘primary health care’ and ‘primary care’ to avoid confusion that might occur when these terms are used. We chose a definition of levels of care based on the work of Barbara Starfield: the first level of care, or ‘primary care’, represents the first access to health care, and is responsible for coordination, comprehensiveness and continuity of care; the second level of care, or ‘secondary care’, performs a support function, of the scientific, technological and logistical aspects. Throughout this work we considered integration of care as a continuous process of variable intensity depending upon the complexity of the care situation. We therefore established a series of supporting tools to integration of care according to this continuum. Additionally, in order to address the different ways to approach integrated care, we chose the Rainbow Model of Integrated Care (RMIC) as a conceptual framework. The RMIC proposes a logical hierarchy of the key dimensions of integrated care, suitable for our research and analysis. Within these theoretical frameworks, we formulated several research questions that address the integration between levels of care: How are the professional and organizational dimensions of integrated care practically developed in the Belgian health care system, at the national and local level? What are the conditions for implementation of a model of integrated care of the two levels of care in a local context? What is the impact of such a model in terms of integration of care? Professional dimension of integration between the levels of care The analysis of the professional dimension of integration of care consisted of two complementary activities. First, we identified the main tools and mechanisms that support integration of care between the general practitioner and medical specialist within the hospital (Chapter 3). We completed our analysis with the findings of several studies on the integration process between those professionals in different care situations, such as treatment management between hospitalisation and discharge of chronic care for HIV patients, cancer patients or obese patients after bariatric surgery (Chapter 4). From this analysis, we confirmed the state of fragmentation between levels of care within the healthcare system. On the professional side, we faced weaknesses on the normative and functional dimension of integration of care. There is a tendency of the secondary care to appropriate the primary care functions, without real consultation and with the risk of gaps in the patient’s care (e.g. preventive care and psycho-social care). Task clarification between professionals of both levels of care occurs too often in the restricted scope of one disease. In this context of unclear role assignment, each professional only relies on his own informal professional network built on interpersonal relationships. Some recent evolutions that may improve integration between professionals have been noticed, such as computerized medical information transfer that may facilitate communication between levels of care. However, the poor structure of primary care, still characterized by solo practice and weak structural links with care coordination function, could represent a barrier to improved professional integration. These findings allow us to acknowledge the added value of Barbara Starfield’s functional conception of levels of care to develop the professional relationships between the general practitioners and medical specialists in the hospital. It also became obvious that we had to complete our analysis at the organizational level, as the professionals frequently mentioned the organizational framework as a barrier. Organizational dimension of integration between levels of care The same analysis process was developed for the organizational dimension of integration between levels of care : identification of existing structures (Chapter 5) and empirical evaluation with a participatory action research (PAR) (Chapter 6). Primary care is fragmented and poorly organized while the hospital is a highly structured and multidisciplinary organization. For general practice in particular, in Belgium, local GP’s organizations, GP’s circles, are asked to play a key role in local health policies but have limited resources, considering governance and leadership. Moreover, existing networks of health organizations covering large areas fail to take local specificities of the health system into account. In this context the participatory action research SYLOS has started in some urban settings in Belgium (Chapter 6). The aim was to organize integration between levels of care at the local level, using a recognised model built on a functional conception of levels of care. The Local Health System model, used in this PAR, is a decentralized and functional unit of the health care system at the local level. It integrates activities of health care services in order to provide primary health care to a determined population. This unit is galvanised and coordinated by a steering group. We followed Grodos & Mercenier’s methodology of participative action research that is recognized on the field of health system research. Our hypothesis was as follows: organizational representatives, initially from hospital and one GPs’ circle, and researchers as moderators, could be the steering group implementing and coordinating local integrated activities. We considered various urban settings, including one with several hospitals. The dynamic of integration initiated by some researchers and hospital and GP’s representatives extended rapidly: other local primary care organizations and hospitals were included This process recreated the complexity of local health system in an urban setting with a multidisciplinary primary care and a multi-hospital secondary care. We still identified reluctance of the actors to include other organizations during the process. This may be explained by the isolation of the medical profession among other caregivers and the market-based organization of secondary care in Belgium. This research allowed us to draw two different models of care territories involved in professional and organizational integration of care. The moderator’s function, detached from both primary and secondary care, was essential during the process. It has been defined during the research action: it requires specific competencies of coordination, group dynamics and technical support to integration of levels of care. This function also compensated structural weakness of primary care in our context. Temporal sequence of activities, observed during this action research, demonstrated the dynamic of the various dimensions of integration of care. It also increased our knowledge of the RMIC. Two of the explored local context in the PAR did not succeed into implementing a steering group. However, it brought useful information concerning motivation and necessary leadership. We also showed that the dynamics of this action research is the result of top-down policies (promoting collaboration of the hospital with other partners and structuring primary care) and bottom-up local initiatives, such as participative action research, acting synergistically. Conclusion The knowledge of professional and organizational integration of levels of care, obtained through this analysis, can directly influence professional practice, professionals’ training and health system organization. If differentiation is an answer to complexity of care, integration between levels of care is necessary and has to be built on strong bedrock composed by common conceptual framework, reciprocal knowledge and recognition of professionals and organizations’ complementarity and synergy. On this basis, implementation of supporting tools and mechanisms for integration of care should be facilitated. The added value of a coordination structure, for the organizational dimension of integration of care at the local level, should also be considered in the Belgian health system. [less ▲]

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See detailMethods and models for brain connectivity assessment across levels of consciousness
Amico, Enrico ULiege

Doctoral thesis (2016)

The human brain is one of the most complex and fascinating systems in nature. In the last decades, two events have boosted the investigation of its functional and structural properties. Firstly, the ... [more ▼]

The human brain is one of the most complex and fascinating systems in nature. In the last decades, two events have boosted the investigation of its functional and structural properties. Firstly, the emergence of novel noninvasive neuroimaging modalities, which helped improving the spatial and temporal resolution of the data collected from in vivo human brains. Secondly, the development of advanced mathematical tools in network science and graph theory, which has recently translated into modeling the human brain as a network, giving rise to the area of research so called Brain Connectivity or Connectomics. In brain network models, nodes correspond to gray-matter regions (based on functional or structural, atlas-based parcellations that constitute a partition), while links or edges correspond either to structural connections as modeled based on white matter fiber-tracts or to the functional coupling between brain regions by computing statistical dependencies between measured brain activity from different nodes. Indeed, the network approach for studying the brain has several advantages: 1) it eases the study of collective behaviors and interactions between regions; 2) allows to map and study quantitative properties of its anatomical pathways; 3) gives measures to quantify integration and segregation of information processes in the brain, and the flow (i.e. the interacting dynamics) between different cortical and sub-cortical regions. The main contribution of my PhD work was indeed to develop and implement new models and methods for brain connectivity assessment in the human brain, having as primary application the analysis of neuroimaging data coming from subjects at different levels of consciousness. I have here applied these methods to investigate changes in levels of consciousness, from normal wakefulness (healthy human brains) or drug-induced unconsciousness (i.e. anesthesia) to pathological (i.e. patients with disorders of consciousness). [less ▲]

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See detailNietzsche & la neurologie
JEDIDI, Haroun ULiege

Master of advanced studies dissertation (2016)

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See detailApproche des troubles cognitifs en unité de mouvements anormaux
DEPIERREUX, Frédérique ULiege

Master of advanced studies dissertation (2016)

Cet ouvrage, présenté en sept 2016 pour l'obtention du DU Maladie d'Alzheimer et démences apparentées, aborde les aspects cognitifs (sur le plan du diagnostic, de la mise au point clinique et paraclinique ... [more ▼]

Cet ouvrage, présenté en sept 2016 pour l'obtention du DU Maladie d'Alzheimer et démences apparentées, aborde les aspects cognitifs (sur le plan du diagnostic, de la mise au point clinique et paraclinique à effectuer, etc.) rencontrés dans diverses pathologies du mouvement, dont la maladie de Parkinson mais également les syndromes parkinsoniens atypiques [less ▲]

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See detailContribution to the study of the mineral hypothesis in relation to the Kashin-Beck disease in Tibet Autonomous Region
DERMIENCE, Michael ULiege

Doctoral thesis (2016)

A little known disease called Kashin-Beck disease (KBD) plagues the poor and rural populations in the Tibet Autonomous Region (T.A.R.) and in other provinces of the People’s Republic of China. It is an ... [more ▼]

A little known disease called Kashin-Beck disease (KBD) plagues the poor and rural populations in the Tibet Autonomous Region (T.A.R.) and in other provinces of the People’s Republic of China. It is an endemic and chronic osteochondropathy affecting long bones and joints, sometimes as soon as of the early childhood. Although the etiology of this disease is not clearly established, little doubt remains as to the implication of multiple environmental factors. Intoxication by mycotoxins in cereals and by organic acids in water, deficiencies in selenium and iodine, are all factors having a place in the multifactorial etiology hypothesized. In T.A.R., diet, notably, differentiates the rural community, affected by KBD, from the other communities (nomads and city-dwellers), who remain unaffected. Because more than one chemical element is essential to a healthy bone metabolism, and because there is scarce data, if not any, on the topic, this thesis had to primary objective to investigate the mineral and trace element dietary status of young Tibetan children living in areas endemic for KBD. The first logical action step led us to determine which elements are involved in bone and joints metabolism through an exhaustive review of the scientific literature. Thirty elements were highlighted, and a dozen was deemed relevant in this context. An exploratory study on the Tibetan food composition concluded on a high risk of introducing important bias by using the existing food composition tables for nutritional assessment in T.A.R. Being inescapable tools, a specific food composition table was elaborated for our area of investigation with the close collaboration of the China National Center for Food Safety Risk Assessment (CFSA). During a scientific internship of 7 month in the CFSA, 19 chemical elements were analyzed in not less than 1119 samples of sixteen traditional foods and beverages of rural T.A.R. In order to assess the nutritional status of the children, a cross-sectional study was implemented. 250 preschool children aged 3 to 5 years old from three rural counties around Lhasa were enrolled. They were interviewed twice, at six month of interval, via the 24-hour recall method. The results suggest several imbalances in their dietary mineral intakes compared to the Chinese recommendations. Sodium and manganese intakes are too high, while they are too low for potassium, calcium, zinc, copper and selenium. The Tibetan diet is rich in fiber and in phytic acid, which are susceptible to decrease the bioavailability and to aggravate the deficiencies of the later elements. For this reason, we conducted an animal experimentation on a rat model to assess the apparent digestibility, the fecal excretion and the urinary excretion of minerals and trace elements in the traditional Tibetan dish called tsampa pag. This traditional dish consisting of roasted barley flour mixed with yak butter tea is the mainstay of the Tibetan diet. The results of this experiment suggest low bone mineral density, a possible secondary copper deficiency, and a possible manganese excess in rats that consumed tsampa pag. In view of the results presented, it would be interesting to compare the mineral intake between children living in endemic areas and in non-endemic areas. It would also be interesting to include more of elements known to affect bone metabolism in future studies. [less ▲]

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See detailActivation de la coagulation par la Transition Epithélio-Mésenchymateuse: impact sur la colonisation métastatique
Bourcy, Morgane ULiege

Doctoral thesis (2016)

Au cours de la cascade métastatique, des cellules tumorales quittent la tumeur primaire et envahissent le sang (Cellules Tumorales Circulantes, CTCs) pour former des métastases dans des organes ... [more ▼]

Au cours de la cascade métastatique, des cellules tumorales quittent la tumeur primaire et envahissent le sang (Cellules Tumorales Circulantes, CTCs) pour former des métastases dans des organes secondaires. Le processus métastatique est hautement sélectif et seule une faible proportion de CTCs survit dans la circulation et colonise les sites secondaires pour former des métastases. Les cellules tumorales subissent des changements phénotypiques qui leur procurent des propriétés migratoires et invasives ainsi que des capacités de survie accrue leur permettant de franchir ces différentes étapes. A ce jour, il est largement accepté que les processus de Transition Epithélio-Mésenchymateuse (TEM) sont impliqués dans cette plasticité cellulaire et participent à la libération et à la biologie des CTCs. Des données de la littérature indépendantes ainsi que des résultats du laboratoire suggèrent, par ailleurs, que les processus de coagulation pourraient favoriser les étapes précoces de la dissémination métastatique (survie, persistance, arrêt et extravasation). Au cours de ce travail de doctorat, nous avons examiné l’acquisition potentielle de propriétés pro-coagulantes par les CTCs dérivées d’une TEM impliquant l’expression du Facteur Tissulaire (FT), l’initiateur cellulaire clé de la cascade de coagulation. De telles propriétés coagulantes permettraient la formation d’une matrice de fibrine protectrice autour des CTCs favorisant, ainsi, leur survie dans la circulation sanguine et la colonisation métastatique. A l’aide de divers modèles cellulaires in vitro, nous avons montré que les processus de TEM sont associés à une expression accrue du FT et à des propriétés pro-coagulantes. Ensuite, nous avons fonctionnellement lié les processus de TEM à ces régulations en y impliquant des facteurs de transcription de la TEM, ZEB1 et Snail. De plus, en utilisant des modèles de métastases expérimentales, nous avons montré que l’axe TEM/FT/coagulation procure aux CTCs des propriétés de survie et des capacités de colonisation métastatique accrues. Enfin, nous avons apporté une validation clinique à ces résultats en observant des CTCs positives pour le FT et la vimentine, un marqueur mésenchymateux, dans le sang de patientes atteintes d’un cancer du sein métastatique. L’ensemble de nos résultats met en évidence un nouvel axe de régulation TEM/FT permettant une activation locale de la coagulation par les CTCs TEM+ favorisant la colonisation métastatique précoce. [less ▲]

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See detailQuelle place pour les diplômés en sciences biomédicales dans le système de santé belge de demain ?
Detaille, Emilie ULiege

Master's dissertation (2016)

The SBIM (biomedical sciences) program appeared in Belgium as early as 1997 in a lot of universities in order to offer an alternative to medical studies. That year corresponds with the introduction of ... [more ▼]

The SBIM (biomedical sciences) program appeared in Belgium as early as 1997 in a lot of universities in order to offer an alternative to medical studies. That year corresponds with the introduction of federal quotas from the INAMI (National Institute for Health and Disability Insurance) and admission procedures to medical and dentistry studies. In the framework of a reflection on the role of biomedical sciences graduates in the Belgian health system, given their sometimes close proximity with the health care professions, an investigation was conducted among the graduates of the past five years (classes 2011 to 2015) but also the first- and final-year students in biomedical sciences of the academic year 2015-2016, so as to achieve a detailed description of the current situation. The aim of this exploratory study was to get an overall vision of the training, experience and daily practice of the graduates as Master in biomedical sciences issued by the Belgian universities. In 2016, the Master in biomedical sciences no longer attracts only students leaving medical studies leave. It is now organized by 10 Belgian universities, offering altogether 44 specific orientations in 25 different areas and awarding 350 diplomas per year. The lack of training standards and the diversity of available orientations do not allow us to have a precise idea of the competency profiles and professions of those graduates. All this creates ambiguities in terms of professional practice, competencies identification and profession. Our enquiries unveiled an orientation with multiple paradoxes which, given this legislative gap sometimes lead the SBIMs to work illegally. This work thus gives an overview of the present situation, providing potential solutions to the future place of the SBIMs in the Belgian health system of tomorrow, so they would not be performing medicine illegally anymore. [less ▲]

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See detailDéveloppement et optimisation de nanovecteurs de type lipoplexes pour une application vaginale en vue de traiter des lésions induites par HPV
Lechanteur, Anna ULiege

Doctoral thesis (2016)

Le cancer du col de l’utérus est associé à une infection par des papillomavirus à haut risque (HPV-HR) et est le troisième cancer le plus meurtrier chez la femme, à travers le monde. Bien que des vaccins ... [more ▼]

Le cancer du col de l’utérus est associé à une infection par des papillomavirus à haut risque (HPV-HR) et est le troisième cancer le plus meurtrier chez la femme, à travers le monde. Bien que des vaccins prophylactiques soient commercialisés, la prévalence est actuellement de 12 % et les traitements proposés sont liés à de nombreux effets indésirables et des risques importants de comorbidités. Le développement d’un nouveau traitement moins agressif et efficace contre des lésions (pré)cancéreuses induites par plusieurs HPV-HR serait donc intéressant. L’utilisation des small interfering RNA (siRNA) est actuellement une approche thérapeutique attractive contre de nombreuses pathologies comme les infections virales ou les cancers. Cependant, la stabilité et l’efficacité des siRNA sont conditionnées par le développement de nanovecteurs qui permettent de véhiculer les siRNA au travers des barrières biologiques. Le but de ce travail est de développer un nouveau traitement des lésions cervicales (pré)néoplasiques induites par HPV, grâce à une application topique de siRNA encapsulés dans des liposomes PEGylés. Pour ce faire, nous avons tout d’abord sélectionné une combinaison de siRNA efficace contre plusieurs lignées cellulaires HPV 16 et HPV 18 positives. Cette combinaison cible simultanément les ARNm codant pour l’oncoprotéine E7 du génome HPV 16 et pour la protéine ubiquitaire anti-apoptotique MCL-1. Nous avons ensuite développé plusieurs lipoplexes recouverts de différents types de PEG, les DSPE-PEG2000, les DSPE-PEG750 et les Céramide-PEG2000, greffés en différentes densités. Cette étude a mis en évidence les propriétés physico-chimiques déterminant l’efficacité des siRNA et la toxicité du nanovecteur. Suite à ces essais, la formulation de lipoplexes contenant 20 % de Céramide-PEG2000, efficace et non toxique a été sélectionnée. Enfin, la capacité de cette formulation à diffuser dans le mucus cervico-vaginal et à pénétrer au sein d’une muqueuse vaginale a été évaluée in vitro, ex vivo et in vivo. Les lipoplexes contenant 20 % de Céramide-PEG2000 semblent diffuser efficacement dans le mucus et distribuer le siRNA dans toutes les couches de l’épithélium. Le nouveau nanovecteur lipidique développé dans ce travail semble être un candidat adéquat pour l’administration de siRNA au niveau vaginal, dans le but de traiter des lésions (pré)cancéreuses induites par l’infection d’HPV-HR. [less ▲]

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See detailEtude des effets du Plasma Riche en Plaquettes (PRP) sur les monodiscopathies peu évoluées
Charneux, Laurent ULiege

Master's dissertation (2016)

Objectives: Pre-clinical testing to study the potential tissue regeneration of Platelet-Rich Plasma (PRP) in the case of a monodiscopathy. After analysing the available literature on the subject, a ... [more ▼]

Objectives: Pre-clinical testing to study the potential tissue regeneration of Platelet-Rich Plasma (PRP) in the case of a monodiscopathy. After analysing the available literature on the subject, a research team was established at the CHU. The objective is to standardise the PRP and use it within the restrictive framework of the monodiscopathy on the human in order to supplement knowledge relating to this biological therapy. Equipment and Method: The recruitment of a panel of ten patients was launched in January 2016. Once admitted in the study, the patients are followed for one year with an MRI, an EVA, an inclinometry and the questionnaires of Roland Morris and Tampa. The infiltration of PRP is carried out in the middle of the nucleus pulposus using a discography. Results: Only one patient underwent the intervention, which could not be finished because we were unable to reach the L5-S1 disc. The objective was to inject 1.5 ml of PRP within the L5-S1 disc. Conclusions: The infiltration of PRP still needs to be studied in order to set the limits, the advantages and the disadvantages of this infiltration. The literature suggests that this might be an effective solution, however it is impossible to make generalised conclusions due to the lack of uniformity between existing studies. [less ▲]

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See detailPrévalence de l’hypovitaminose D chez la femme enceinte : quelle est la situation en région liégeoise ?
VRANKEN, Laura ULiege

Master of advanced studies dissertation (2016)

Vitamin D deficiency is a worldwide health problem, also during pregnancy, especially in women with limited access to sunlight due to minimal outdoor activity or heavy use of sunscreen, cultural practices ... [more ▼]

Vitamin D deficiency is a worldwide health problem, also during pregnancy, especially in women with limited access to sunlight due to minimal outdoor activity or heavy use of sunscreen, cultural practices or traditional clothing, and among women with dark skin pigmentation and poor dietary habits. Inadequate maternal vitamin D status in pregnancy is associated with poor fetal growth, impaired bone development and rickets in infants after birth. Furthermore, higher rates of preeclampsia and gestational diabetes are associated with low maternal vitamin D status during pregnancy. Toxicity of vitamin D is rare. Most countries recommend vitamin D supplementation during pregnancy but guidelines are controversial and inadequate compared to real mother’s and child’s needs. Wath’s the best strategy to follow and supplement mother during pregnancy? [less ▲]

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See detailCaractérisation phénotypique, morphologique et fonctionnelle des éosinophiles résidents du poumon
Raulier, Stéfanie ULiege

Doctoral thesis (2016)

Eosinophils have long been considered as destructive effector cells implicated in parasitic infections and allergic reactions such as asthma. This traditional restrictive view of eosinophils has now been ... [more ▼]

Eosinophils have long been considered as destructive effector cells implicated in parasitic infections and allergic reactions such as asthma. This traditional restrictive view of eosinophils has now been considerably extended. Indeed, beside their pro-inflammatory functions, eosinophils are also able to finely shape local innate and adaptative immune responses. Moreover, recent studies indicate that steady-state resident eosinophils are now thought to contribute to immune homeostasis at mucosal sites such as the gut. In the normal lung, resident eosinophils (rEOS) have been little-studied so far. Here, we report that in mice, steady-state pulmonary rEOS are parenchymal Siglec-Fint CD125int cells characterized by a ring-shaped nucleus. [less ▲]

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See detailLes itinéraires cliniques en support aux mesures transversales d’organisation des soins au patient : expérience de gestion de projet bottom-up
ERPICUM, Marie ULiege

Doctoral thesis (2016)

Our work contributes to the study of the health care organization’s evolution, by an integrating approach of clinical, research and teaching fields, in a bottom-up project management which aims ... [more ▼]

Our work contributes to the study of the health care organization’s evolution, by an integrating approach of clinical, research and teaching fields, in a bottom-up project management which aims integration of multidisciplinary and transversal care processes. From a research project was born a service project for the development of a blood management program in cardiac surgery. This project led to the development of a clinical pathway in cardiac surgery. The methodology of clinical pathways has been integrated in the new institutional strategic plan; the concept of “Care pathways” is developed to reinforce the implementation of "patient's pathway" and "Integrated Care" measures. This concept also finds an echo in the legislative and accreditation standards. Our researches and projects highlight the value of nurses for the integration of research and clinical care process. This approach is taught to Public Health Science Master’s students through educational missions in the Advanced Practice Nursing Science. [less ▲]

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See detailGestion des stupéfiants au bloc opératoire
LOMMEL, Isabelle ULiege

Master of advanced studies dissertation (2016)

La gestion des stupéfiants est une obligation légale. Dans le travail quotidien de l’infirmier de salle d’opération, la redondance d’écritures et le manque de disponibilités entrainent une banalisation de ... [more ▼]

La gestion des stupéfiants est une obligation légale. Dans le travail quotidien de l’infirmier de salle d’opération, la redondance d’écritures et le manque de disponibilités entrainent une banalisation de cette obligation. On oublie que ce médicament ‘différent’ est source de danger, d’addiction, de deal et qu’il peut être mortel. Ce travail est le résultat d’une analyse de la situation existante et de son adéquation avec la loi et la littérature scientifique. Sa conclusion permet de mettre en évidence que les participants au flux des stupéfiants doivent être conscientisés que leurs actions doivent être guidées par une logique. Cette logique de processus doit être institutionnelle. La philosophie Lean est d’application dans ce travail. Par la publication d’une synthèse des pistes de perfectionnement sous forme de délivrable ‘A3’, cette étude sera remise aux dirigeants du bloc opératoire Selon cette philosophie, il faut impérativement implémenter des méthodes de brainstorming consistant à mettre en évidence, entre collègues, les raisons de mal-fonctionnement. C’est également en équipe que des moyens d’amélioration de la situation doivent être élaborés, ce sans bouleversement majeur, c’est la méthode des petits pas. L’équipe du bloc doit mettre en place: 1. Un descriptif de la situation existante. 2. La pose en groupe d’indicateurs de bon fonctionnement. 3. L’étude collégiale de méthodes d’optimalisation des processus existants via des standards de travail. 4. Le suivi des indicateurs pour constater les améliorations et les amplifier par ajustement des processus. 5. Le bénéfice doit être visible tant au niveau de la sécurité du patient et du personnel que du stress ambiant. Cette philosophie doit perdurer dans le temps et s’intégrer dans le LEAN institutionnel. [less ▲]

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See detail« Analyse de l’implantation d’un protocole d’entraînement de la vitesse dans une équipe de football »
Lombard, Gilles ULiege

Master's dissertation (2016)

L’organisation défensive des équipes de football et la densité des joueurs ont significativement augmenté depuis 40 ans (Wallace et Norton, 2014). Ceci influence les qualités physiques des joueurs qui se ... [more ▼]

L’organisation défensive des équipes de football et la densité des joueurs ont significativement augmenté depuis 40 ans (Wallace et Norton, 2014). Ceci influence les qualités physiques des joueurs qui se doivent d’être plus rapides pour faire la différence. Aujourd’hui, la filière anaérobie alactique, bien que minoritaire au niveau quantitatif (Mohr et al., 2003), est la déterminante principale de la performance sur le plan physique (Cometti et al., 2001). Etant donné l’importance de cette qualité physique, nous avons voulu examiner si l’introduction d’un travail spécifique de la vitesse durant 8 semaines aurait un impact significatif sur la performance fonctionnelle du joueur de football. Méthodologie L’échantillon de 18 joueurs est réparti dans des groupes contrôle et expérimental. Trois tests de terrain sont utilisés pour mesurer l’évolution du paramètre anaérobique avant et après le protocole de 8 semaines : un test de vitesse sur 10 mètres (Wilson et al., 1993), un test de zigzags sur 20 mètres (Little et Williams, 2005) et un counter movement jump avec les bras (Slinde et al., 2008). Durant 8 semaines, le groupe expérimental bénéficie, en plus de l’entraînement normal, de deux séances hebdomadaire de 30 minutes visant le développement de la vitesse. A la fin de l'étude, aucun résultat significatif n'a été trouvé que ce soit au niveau de la vitesse sur courte distance, en course brisée ou de la détente en squat jump et counter movement jump. [less ▲]

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See detailModel-Based Prediction of the Response to Vascular Filling Therapy
Pironet, Antoine ULiege

Doctoral thesis (2016)

Vascular filling is one of the most frequent interventions in intensive care units. Its expected effect is to increase cardiac output. However, this increase is only observed in approximately 50 % of ... [more ▼]

Vascular filling is one of the most frequent interventions in intensive care units. Its expected effect is to increase cardiac output. However, this increase is only observed in approximately 50 % of cases. In addition, excessive vascular filling can lead to deleterious effects, such as pulmonary oedema, which increase length of ventilation, stay, mortality and cost. Clinicians are thus looking for indices to provide a priori knowledge of the effect of vascular filling. This thesis focuses on a mathematical model-based approach to predict the response to vascular filling. Mathematical models are sets of equations representing the behaviour of a given system as, for instance, the cardiovascular system. To understand the concept of vascular filling, basic elements of cardio-vascular anatomy and physiology are presented in the first part of this thesis. Then, fur- ther details about vascular filling therapy are given, as well as the current indices used by clinicians to predict its effects. The static indices are easy to obtain, but do not perform well. The dynamic indices, based on cardio-pulmonary interac- tions, perform better, but are difficult and highly invasive to implement clinically. A new index, total stressed blood volume, also seems to perform well, but is not easy to obtain clinically. This work develops and then uses models of the cardio- vascular system to make this parameter available to clinicians. Building on the elements of physiology provided in the first part, the second part of this thesis describes ways to model the components of the cardio-vascular system as lumped elements, such as chambers, valves and resistances. Two mod- els of the cardio-vascular system, comprising respectively three and six cham- bers, are built from such elements. These two models involve a small number of parameters, including the total stressed volume in the model. The third part of this thesis describes the potential and methods to identify the parameters of the two cardio-vascular system models. Parameter identifica- tion aims at finding the parameter values that make model simulations as close as possible to measured data. The available data is thus first described, accord- ing to whether it is collected in an experimental laboratory or an intensive care unit. Then, it is mathematically demonstrated that all model parameters can the- oretically be identified from data available in an intensive care unit. However, practically speaking, some parameters are difficult to identify, because they have little influence on the simulations, or have the same effect as other parameters. Fi- nally, computational methods to perform parameter identification are presented and compared. The last part of this thesis presents two applications of the cardio-vascular system models to experimental data. First, all parameters of the six-chamber cardio-vascular system model are identified from data recorded during a preload reduction experiment. This result provides the first quantitative validation of the six-chamber model in transient conditions. Second, all parameters of the three-chamber cardio-vascular system model, including total stressed volume, are identified from data recorded during vascular filling experiments. The total stressed volume parameter is shown to be systematically related to the change in cardiac output after vascular filling. This last index thus provides, for the first time, a model-based means of predicting the response to vascular filling. [less ▲]

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See detailRégulation de la transcription du virus T-lymphotrope humain de type I (HTLV-1) par le complexe MiniChromosome Maintenance 2-7 (MCM2-7)
Barez, Pierre-Yves ULiege

Doctoral thesis (2016)

First oncogenic retrovirus discovered, the human T-lymphotropic virus type 1 (HTLV-1) infects approximately 5 to 10 millions of individuals worldwide. HTLV-1 is the etiological agent of adult T-cell ... [more ▼]

First oncogenic retrovirus discovered, the human T-lymphotropic virus type 1 (HTLV-1) infects approximately 5 to 10 millions of individuals worldwide. HTLV-1 is the etiological agent of adult T-cell leukemia and a neurodegenerative disorder called HAM/TSP (HTLV-1 associated myelopathy/Tropical spastic paraparesis). The HTLV-1 Tax protein interacts with the minichromosome maintenance MCM2-7 helicase, through the amino-terminal part of MCM3. This interaction accelerates firing of late DNA replication origins (ORI) in infected cells. Since Tax acts on the long terminal repeat (LTR), we hypothesized that the MCM2-7 complex could also be recruited to the viral promoter. Using chromatin immunoprecipitation, we show that MCM2-7 indeed interacts with LTR sequences. However, loading of the MCM complex does not fire DNA replication in an autonomous plasmid replication assay. In contrast, MCM2-7 activates viral transcription in luciferase reporter assays and in the context of a proviral clone. Short hairpin RNA interference of MCM2-7 inhibits LTR-driven Tax transactivation in lymphocytes. Finally, siRNAs targeting MCM3 reduce viral transcription in HTLV-1 infected cell lines. Together, our data thus indicate that the presence of the MCM2-7 complex on the HTLV-1 promoter is involved in viral transcription. [less ▲]

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See detailTherapy of Adult T-cell Leukemia by inhibition of the DNA repair mechanisms
Carpentier, Alexandre ULiege

Doctoral thesis (2016)

The Tax oncoprotein plays a central role in viral persistence and pathogenesis of human T-cell leukemia virus type 1 (HTLV-1). Indeed, Tax transforms primary cells and induces tumors in transgenic mouse ... [more ▼]

The Tax oncoprotein plays a central role in viral persistence and pathogenesis of human T-cell leukemia virus type 1 (HTLV-1). Indeed, Tax transforms primary cells and induces tumors in transgenic mouse models. Mechanistically, Tax accelerates the S phase of the cell cycle by firing late replication origins. This modification of the replication timing program induces an oncogenic stress that generates DNA damage such as double-strand breaks. Tax thus provides a selective advantage that promotes proliferation but also exposes host cells to potentially harmful clastogenic damage. How Tax-expressing cells handle this oncogenic stress is currently unknown. In this thesis, we show that Tax-expressing cells activate the DNA Damage Response (DDR). We quantified the repair efficiencies of DNA double-strand breaks. We demonstrate that Tax induces the recruitment of DNA repair core proteins (Ku70, RAD51 and RAD52) on chromatin. We further show that the efficiency of homologous recombination (HR) is inhibited by Tax. In contrast, non-homologous end joining (NHEJ) and single-strand annealing (SSA) are activated in the presence of Tax. Taking advantage of the addiction of Tax-expressing cells on improved DNA repair, we show that pharmacological inhibition of these pathways in HTLV-1 infected lymphocytes leads to an accumulation of DNA damage and apoptosis. We propose a novel therapeutic approach for the treatment of ATL based on the use of inhibitors targeting DNA repair pathways. [less ▲]

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See detailDEVELOPMENT OF PHARMACOLOGICAL TOOLS FOR THE IDENTIFICATION OF G PROTEIN-COUPLED RECEPTORS LIGANDS
Gilissen, Julie ULiege

Doctoral thesis (2016)

G protein-coupled receptors (GPCRs) represent the protein family most successfully targeted for treating human diseases. They couple to G proteins to mobilize second messenger pathways that lead to ... [more ▼]

G protein-coupled receptors (GPCRs) represent the protein family most successfully targeted for treating human diseases. They couple to G proteins to mobilize second messenger pathways that lead to cellular responses and ultimately to physiological changes. However many are poorly characterized with few ligands reported or remain completely orphans. Therefore, there is a growing need for screening-compatible and sensitive assays in order to identify new ligands. The present project aims at developing pharmacological tools to characterize the pharmacology and physiology of GPCRs. Our approach rely on i) development of receptor models and assays for the identification of ligands, ii) screening of chemical and virtual small molecules libraries and iii) analysis of structure-activity relationships study of active molecules. The project has been divided in two parts. To set-up assays for the evaluation of GPCRs activation, we selected the understudied succinate receptor 1 (SUCNR1) that is proposed to affect cellular metabolism and pathophysiology of diseases in multiple organs. Nevertheless the receptor has never been validated as a drug target because very few ligands have been described. So, developing pharmacological tools for SUCNR1 remains of great interest in therapeutic drug discovery. First, we have started by examining SUCNR1 signaling pathways in HEK293 cells. Our investigations have highlighted the efficient coupling to Gαi and thus the negative modulation of intracellular cAMP levels. Consequently we have implemented an assay sensitive to cAMP variations to identify ligands able to induce SUCNR1 activation. However, an important drawback to track agonists for Gαi-coupled receptors is the mandatory stimulation of cAMP levels. Inducers such as forskolin must be used and are sources of variations and errors. In order to avoid these artifacts we have set-up and validated a cAMP-inducer free method based on the GloSensor biosensor. This real time assay was amenable to high-throughput screening for the detection of Gαi-coupled receptors agonists. The strategy monitoring basal cAMP levels compared to the stimulated cAMP levels allowed to decrease recording time and artifcats from forskolin use, leading to the identification of fewer false positives and unidentified false negatives. Although both methods found agonists in the chemical library screened, no active new scaffolds on SUCNR1 were discovered. We infer that this method could facilitate the study and screening of Gαi-coupled receptors for active ligands. Secondly, given the interesting potential of SUCNR1 for promising therapeutic advances, we have carried out the study of the receptor interaction with its natural ligand, succinate. We have optimized the previous three-dimensional model for SUCNR1 binding pocket by means of more detailed structure-activity relationships study of succinate related molecules. The study of structure-activity relationships performed by Pierre Geubelle, in parallel to this work, allowed the deduction of the structural elements required to be active on SUCNR1. Thus we have defined a pharmacophore for activity on the receptor and subsequently evaluated various cycloalkanes. With our cAMP assay, Pierre Geubelle has highlighted the (1R, 2S)-1,2-cyclopropanedicarboxylate to be able to activate SUCNR1. We confirmed the activity of this compound on SUCNR1 capacity to recruit arrestin 3 and determined the pharmacological properties of this new ligand as SUCNR1 agonist, in vitro and in vivo. To confirm our in vitro results, we have also assessed the hypertensive properties of this cyclic analogue. Intravenous addition at the dose of 0.1 mg.kg-1 in rats has been demonstrated to increase blood pressure in the same range as succinate. Consequently we have demonstrated that (1R, 2S)-1,2-cyclopropanedicarboxylate could be regarded as an original synthetic full agonist for SUCNR1. In addition, the pharmacophore for SUCNR1 should help to generate synthetic compounds characterized by an increased potency and/or efficacy compared to succinate. [less ▲]

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See detailValidation of a Multiplex HPLC MS/MS assay for the measurement of steroid hormones
Rademaker, Gilles ULiege

Master's dissertation (2016)

Facing an improvement of the quality assurance in all the laboratory, the validation of methods has become a step that cannot be got round. The objective of this work is the validation of a Protein ... [more ▼]

Facing an improvement of the quality assurance in all the laboratory, the validation of methods has become a step that cannot be got round. The objective of this work is the validation of a Protein-Precipitation HPLC-MS/MS method for the measurement of steroid hormones (Aldosterone, Androstenedione, Cortisol, 17-OH Progesterone, DHEAS and Testosterone). To achieve this purpose, a precision, recovery, linearity, carry over assay and a limit of quantification are performed. After collection of the data, results are calculated and statistically analysed. They allow to set boundaries to the method and to understand more easily how we could improve it. The results show that the method is effective for all hormones except the aldosterone, for which the method still has to be improved. Moreover, a comparison of the analysis of the testosterone between Cobas and HPLC MS/MS is made. In the lab, this hormone is analysed with Cobas but a transition to the HPLC MS/MS can be done because the results are satisfactory. [less ▲]

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See detailBonding properties of innovative CAD-CAM composite biomaterials for dental prostheses
Ebroin, Marie ULiege

Master's dissertation (2016)

Nowadays the tendency in dentistry is to use less invasive techniques to restore damaged dental tissues in a minimally invasive way using partial bonded ceramic and composite prostheses. Recently the ... [more ▼]

Nowadays the tendency in dentistry is to use less invasive techniques to restore damaged dental tissues in a minimally invasive way using partial bonded ceramic and composite prostheses. Recently the industry has developed various innovative composites materials to perform customized Computer-Aided Designed and Manufactured (CAD-CAM) dental prostheses. Two sub-classes of CAD-CAM composites can be distinguished in function of their microstructure: the dispersed filler and the polymer-infiltrated ceramic network (PICN) materials. Currently there is a lack of data regarding the bonding properties of those recent biomaterials to resin cement and consequently to tooth tissues. The objectives of this study are to evaluate interfacial toughness of the different classes of CAD-CAM composites (Dispersed filler and PICNs) with resin cement after different surface pretreatments and aging, and to correlate the results with material surface parameters, particularly micro- and nanostructure. In this study, two dispersed filler (Lava Ultimate, 3M ESPE and Cerasmart, GC America), two PICNs (Vita Enamic, Vita Zahnfabrik and experimental PICN, MaJEB Sprl) and one glass-ceramic (IPS e.max CAD, Ivoclar Vivadent) materials were tested. Composite prisms (6X6X6X12mm) were manufactured from CAD-CAM blocks. Samples (n total=270, n per group=30) were split into two parts and surfaces to be bonded were pretreated either with hydrofluoric acid etching or with alumina particles sandblasting followed by silanization (Monobond Plus, Ivoclar Vivadent). All specimens were bonded using Variolink DC (Ivoclar Vivadent) resin cement and submitted to thermocycling aging (10000 cycles). The interfacial toughness was measured using the Notchless Triangular Prism (NTP) test. Surface characterization was performed using optical profilometry to measure the developed interfacial area ratio (Sdr) and scanning electron microscopy. Results showed that PICNs exhibit higher bonding ability to resin cement than dispersed filler materials. Moreover, due to their specific microstructure PICNs were shown to perform better with an etching surface pretreatment while dispersed filler materials gave better results with sandblasting. Experimental PICN gave the best results, higher than the glass-ceramic material, which is currently considered as the gold standard. Those results were explained by the micro- and nanostructure of the etched material, which was characterized by the highest Sdr measurements. This work introduces interesting perspectives regarding the indications of PICN materials in minimally invasive treatments. [less ▲]

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See detailInfluence du tabagisme sur la santé parodontale
SALHI, Leila ULiege

Master of advanced studies dissertation (2016)

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See detailSupercritical Fluid Chromatography for pharmaceutical analysis : New perspectives
Dispas, Amandine ULiege

Doctoral thesis (2016)

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See detailMise au point d'un biomatériau à base de chitosan pour le traitement de l'arthrose
Oprenyeszk, Frédéric ULiege

Doctoral thesis (2015)

L'arthrose est une pathologie dont la prévalence est élevée avec un retentissement socioéconomique important. À ce jour, les traitements de l’arthrose sont essentiellement symptomatiques. Le remplacement ... [more ▼]

L'arthrose est une pathologie dont la prévalence est élevée avec un retentissement socioéconomique important. À ce jour, les traitements de l’arthrose sont essentiellement symptomatiques. Le remplacement de l'articulation arthrosique par une prothèse est réservé aux formes les plus évoluées de la maladie. Dans ce contexte, il existe un réel besoin de nouveaux traitements bien tolérés et capables de prévenir ou de retarder la progression de la maladie. Dans ce but, nous avons développé des nouveaux biomatériaux sous la forme de billes ou d'hydrogel composés de chitosan d'origine non animale. Dans la première partie de ce travail, nous avons étudié in vitro le comportement des chondrocytes humains, provenant de cartilage arthrosique, incorporés dans des billes de chitosanalginate. Nous avons mesuré la quantité de médiateurs pro-infl ammatoires, cataboliques et anaboliques produite par les chondrocytes. Dans la deuxième partie, nous avons étudié les effets des billes de chitosan-alginate, injectées dans l’articulation, sur la progression de l’arthrose induite chez le lapin par section du ligament croisé antérieur. In vitro, nous avons mis en évidence les effets bénéfi ques et prometteurs des billes de chitosanalginate sur le métabolisme des chondrocytes humains arthrosiques. Dans ces conditions, ils produisaient moins de médiateurs infl ammatoires et cataboliques tout en maintenant la synthèse de composants spécifi ques de la matrice du cartilage. L'étude chez le lapin a montré que l’injection des billes de chitosan-alginate dispersées dans un hydrogel de chitosan prévenait le pincement de l’interligne articulaire - évalué sur une radiographie standard - et réduisait de façon signifi cative la gravité des lésions histologiques du cartilage ainsi que la synovite. En conclusion, la bille de chitosan-alginate est une matrice intéressante pour la thérapie cellulaire des lésions du cartilage et représente une alternative à l’acide hyaluronique pour la viscosupplémentation. [less ▲]

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See detailL'estétrol et le développement tumoral
Gallez, Anne ULiege

Master's dissertation (2015)

A l’heure actuelle, le risque augmenté de troubles thromboemboliques et de cancer du sein chez les femmes sous hormonothérapie est un problème majeur de santé publique. La découverte de nouvelles ... [more ▼]

A l’heure actuelle, le risque augmenté de troubles thromboemboliques et de cancer du sein chez les femmes sous hormonothérapie est un problème majeur de santé publique. La découverte de nouvelles molécules procurant une sécurité sanitaire accrue aux utilisatrices est donc nécessaire. L’estétrol (E4) est proposé comme candidat potentiel. L’E4 est une hormone stéroïdienne, de type « œstrogène », retrouvée naturellement chez l’humain et synthétisée uniquement par le foie fœtal durant la grossesse. Sa grande biodisponibilité orale et son temps de demi-vie de 28 heures chez l’humain le rendent intéressant en tant qu’hormonothérapie de substitution (ERT/HRT). L’E4 est capable de traiter efficacement les symptômes principaux de la ménopause (les bouffées de chaleur, l’atrophie vaginale et l’ostéoporose) et ce, dès une concentration de 0,3 mg/kg/jour. L’étude de son impact sur le cancer du sein est au centre de ce mémoire, puisque c’est l’une des conséquences majeures de l’utilisation prolongée d’œstrogènes et que les données de la littérature restent controversées Des résultats préliminaires obtenus au laboratoire ont montré que l’E4 (3 mg/kg/jour) augmentait le poids des tumeurs dans le modèle murin de carcinogenèse mammaire MMTV-PyMT, contrairement à l’ovariectomie et au traitement au Tamoxifène. Au terme de ce mémoire, nos recherches démontrent que l’E4 utilisé aux doses 0,3 et 7 mg/kg/jour n’influence pas significativement la croissance tumorale. Par contre, l’E4 à 3 mg/kg/jour majore le poids tumoral et la dissémination métastatique chez des animaux ovariectomisés et intacts. De plus, l’E4 délivré à 3 mg/kg/jour est capable d’augmenter l’angiogenèse et de diminuer la nécrose et l’hypoxie intra-tumorale, de manière similaire à l’oestradiol (E2) alors que la dose de 0,3mg/kg/jour n’est pas suffisante pour observer cet effet. En conclusion, les travaux menés pendant mon mémoire de Master ont permis de caractériser les effets de l’E4 sur la carcinogenèse mammaire hormonodépendante, la dissémination métastatique et l'angiogenèse tumorale. Au vu de nos résultats, nous ne pensons pas qu'il soit judicieux d'utiliser l'E4 comme traitement anti-tumoral, comme cela a été suggéré par certains auteurs. Au contraire, nos données suggèrent que pour éviter un effet de l’E4 sur la croissance tumorale et l’angiogenèse, il est nécessaire de privilégier le développement d’un traitement clinique de la ménopause avec de faibles concentrations d’E4. [less ▲]

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