Il est connu aujourd'hui qu'une petite sous-population de cellules au sein des tumeurs possède une puissante capacité d'auto-renouvellement et est impliquée dans la progression tumorale, l'agressivité et la résistance à la fois à la chimiothérapie et la radiothérapie. Ces cellules, nommées cellules souches cancéreuses(CSC), sont connues pour exprimer les facteurs de souchitude Oct4 et Nanog, quand elles sont pluripotentes. Le but de ma thèse était d'analyser les effets de petites molécules pharmacologiques en mesure de cibler chez les SCCces régulateurs d'auto-renouvellement, afin d'apporter de nouvelles thérapies efficaces contre le cancer. Plus précisément, ma thèse avait pour but d'étudier l'activité anticancéreuse sélective d'une flavagline synthétique, à savoir FL3, sur un modèle de SCC peu différencié et très malin (tératocarcinome) qui exprime les facteurs de souchitude. Nous avons également utilisé un modèle de cellules souches normales restreintes (NSC) (de type fibroblastique), pour évaluer l'effet sélectif de ce médicament. Nous avons constaté que, contrairement aux NSCs, FL3 était capable de déclencher un processus pro-apoptotique mitochondriale dans les CSCs, via l'activation dep38 MAPK et de la cas pase 3, suivie par une régulation négative de Oct4 et Nanog. Nous avons ensuite étudié le mécanisme moléculaire impliqué dans la protection des NSCs contre les effets cytotoxiques de la drogue. Nous avons constaté que FL3 active sélectivement les protéines pro-survie Akt et Bad dans les NSCs. En effet, l'inhibition de la sur-expression de ces protéines a déclenché un processus pro-apoptotique lié à la caspase-3 dans les NSCs traitées par FL3. Dans une deuxième étape, nous avons montré que FL3 à faible concentration, était capable d'induire la différenciation des CSCs par la régulation négative de l'expression d'Oct4 et de Nanog, tant au niveau de la traduction que de la transcription. Cet effet a coïncidé avec une régulation à la hausse de l'expression de plusieurs marqueurs neuronaux. Pris dans leur ensemble, les résultats présentés dans ma thèse démontrent clairement que la flavagline synthétique FL3 est un composé anticancéreux puissant, agissant comme un agent sélectif pro-apoptotique et pro-différenciation sur les cellules souches cancéreuses, sans effets sur les cellules souche normales. / It is believed that small subpopulation of cells within the tumor, with powerful self-renewal capacity, are involved in tumor progression, aggressiveness and resistance to both chemo- and radio-therapy. These cells, named cancer stem cells (CSCs), are known to express the stemness factors Oct4 and Nanog, when they are highly pluripotent. The aim of my thesis was therefore to analyze the effects of small pharmacological molecules which are able to target in CSCs these self-renewal regulators, in order to bring new effective therapies for cancer. More specifically, this thesis was aimed to study the selective anticancer activity of a synthetic flavagline, namely FL3,on a poorly differentiated and highly malignant CSC model (i.e. the teratocarcinomal stem-like cell) that expresses the stemness factors. Here in we also used a model of very restricted normal stem cell (NSC) (i.e. the fibroblasticstem-like cell), to evaluate the selective effect of this drug. We found that, unlike in NSCS, FL3 was able to trigger a mitochondrial pro-apoptotic process in CSCS, via the activation of p38 MAPK and caspase3, followed by a downregulation of Oct4 and Nanog. We newt investigated the molecular mechanism involved in the protection ofNSCS against the cytotoxic effects of the drug. We found that FL3 selectively activated the prosurvival proteins Akt and Bad in NSCS. Indeed, forced inhibition of the expression of these proteins triggered a caspase-3 proapoptotic process in FL3-treated NSCS. In a next step, we showed that the drug, at low concentration, was able to induce the differentiation of CSCS, by downregulating the expression of Oct4 and Nanog at both transcriptionand translation levels. This effect coincided with an upregulation of the expression of several neural markers. Taken as a whole, the results reported in my thesis clearly demonstrate that the synthetic flavagline FL3 is a powerful anticancer compound, since it acts as a selective proapoptotic and pro-differentiating agent on cancer stem-like cells, without having any effect on normal stem-like cells.

Les prokinéticines sont des hormones angiogéniques qui exercent leurs fonctions biologiques par l’intermédiaire de deux récepteurs couplés aux protéines G : PKR1 et PKR2. PKR1 a été révélé comme crucial dans l’homéostasie cardiovasculaire. L’objectif de ce projet de thèse était de développer un nouvel agoniste non–peptidique à PKR1 pour la cardioprotection et la régénération cardiaque. Les premiers résultats ont permis de caractériser le premier ligand spécifique à PKR1 : IS20. L’étude in vivo a démontré qu’IS20 est capable de prévenir les lésions après induction d’un infarctus du myocarde chez la souris. Ce composé améliore les fonctions cardiaques en activant la prolifération de cellules progénitrices cardiaques et la néovascularisation (Gasser et al, PlosOne, 2015). Dans une deuxième étude, nous avons évalué le potentiel cardioprotecteur d’IS20 face à la toxicité induite par la doxorubicine (DOX), un anticancéreux de la famille des anthracyclines très efficace mais cardiotoxique. Les résultats montrent qu’IS20 atténue l’apoptose des cardiomyocytes H9c2 et des cellules progénitrices humaines de types EPDC, induite par la doxorubicine, sans affecter la cytotoxicité de la doxorubicine sur les cellules cancéreuses. In vivo, le traitement par IS20 atténue la diminution de la prolifération provoquée par la doxorubicine dans un modèle de cardiotoxicité juvénile. Dans un modèle de cardiotoxicité chronique, IS20 maintient l’intégrité cellulaire et tissulaire des vaisseaux et protège des défaillances produites par DOX. Par ses effets cytoprotecteurs des cardiomyocytes et des cellules progénitrices cardiaques, l’IS20 présente un potentiel thérapeutique prometteur pour protéger les patients cancéreux des effets cardiotoxiques des anthracyclines. / Prokineticins are angiogenic hormones that activate two G protein-coupled receptors (GPCRs): PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. The aim of this thesis project was to develop a first non-peptide PKR1 agonist stimulates cardioprotection and cardiac regeneration in mouse model of myocardial infarction (MI) or anti-cancer drug mediated cardiotoxicity. Collaboration with chemist and biomodelization team, we characterized the first selective/specific PKR1 agonist, named IS20. In vivo study demonstrated IS20 prevented cardiac lesion formation and improved cardiac function after myocardial infarction in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis (Gasser et al., 2015). Since use of a very potent anthracycline chemotherapeutic, Doxorubicin (DOX) is limited by cardiotoxicity, we hypothesized that IS20 could protect heart against DOX-mediated cardiotoxicity. Indeed, IS20 attenuated apoptosis induced by DOX in H9c2 cardiomyocytes and human epicardial progenitors in vitro. However, IS20 did not affect antineoplastic or cytostatic effect of DOX in cancer cell lines. In vivo, in the juvenile model of cardiotoxicity, IS20 significantly attenuated DOX-induced decrease in viability and proliferation cardiac progenitor cells. In the chronic cardiotoxicity model by DOX, IS20 improves heart structure and function by the activation of cardiac progenitor cells, diminishing cardiac cell death, improving vascular stability. IS20 has translational potential for cardioprotection in patients with cancer receiving anthracyclines.

La goutte est une maladie inflammatoire particulièrement prévalente causée par la formation de dépôts articulaires et péri-articulaires de cristaux d’urate monosodique (UMS ou MSU) et dépendante de la cytokine interleukine-1β (IL-1β). En 2006, l’inflammasome NLRP3 a été montré comme nécessaire pour la maturation de l’IL-1β, in vitro, en réponse aux cristaux de MSU. Néanmoins, sa nécessité in vivo est un sujet de controverse. Mon travail de thèse a porté sur la caractérisation d’un modèle murin d’inflammation aiguë uratique et l’analyse de la contribution des inflammasomes dans cette pathologie. J’ai d’abord montré que notre modèle par injection sous-cutanée de cristaux de MSU donne lieu une forte inflammation des tissus mous comme cela est souvent observé lors des crises de goutte chez l’Homme. L’emploi de souris invalidées génétiquement et d’inhibitions pharmacologiques m’a permis de décrire son indépendance vis-à-vis de plusieurs composants des inflammasomes et confirme le rôle majeur de l’IL-1β. De manière intéressante, j’ai ensuite montré qu’il est possible de réduire fortement l’inflammation dans ce modèle par un traitement topique à base d’imiquimod (crème ALDARA®), un ligand synthétique de TLR7. Des expériences réalisées in vivo et in vitro m’ont permis de relier l’effet de l’imiquimod à une baisse importante de l’Il1b au niveau transcriptionel, via une signalisation faisant probablement intervenir les interférons de type I et possiblement le facteur RUNX3. Mes données montrent donc que la production d’IL-1β, dans ce modèle, est visiblement indépendante de NLRP3 mais peut être fortement abaissée par l’application topique d’imiquimod. L’imiquimod pourrait ainsi représenter une piste thérapeutique attractive. / Gout is a prevalent inflammatory disease caused by the deposition of monosodium urate crystals (MSU) in articular/periarticular areas, which strongly depends on interleukine-1β (IL-1β). In 2006, the NLRP3 inflammasome has been shown to perform IL-1β maturation in vitro after MSU crystal exposure. However, its in vivo dependence is still matter of controversy. In my thesis project, I focused on the characterization of a murine acute uratic inflammation and analysed the contribution of inflammasome components. I first showed that the subcutaneous injection of MSU crystals in mice generate a strong soft tissue inflammation as observed in human gouty crises. Then, by using genetically-modified mouse lines and pharmacological inhibitions, I demonstrated that this model is inflammasome-independent, while still requiring IL-1β secretion. Interestingly, I observed that the topical application of imiquimod (ALDARA® cream), which is a synthetic TLR7 ligand, strongly dampens inflammation. In vivo and in vitro experiments further demonstrated that this effect is linked to reduced Il1b gene expression, which linkely involves type I interferon signaling and eventually the transcription factor RUNX3. Altogether, my results show that IL-1β production is NLRP3-independent in this mouse model but can be strongly decreased by topical application of imiquimod. Therefore, imiquimod might be an attractive therapeutic option for gouty patients.

Les récepteurs P2X, activés par l’ATP extracellulaire et cations non-sélectifs, sont impliqués dans de nombreux rôles physiopathologiques. Le manque de sélectivité de molécules pharmacologiques est un inconvénient majeur pour leur étude. La résolution de leurs structures cristallographiques a permis de les comprendre à l’échelle moléculaire, cependant les mécanismes impliqués dans les transitions allostériques restent mal compris. Au laboratoire, deux outils, dérivés d’azobenzène, permettant l’activation des récepteurs P2X en absence d’ATP et par la lumière ont été développés. L’utilisation de ces outils ont permis l’étude de la transition allostérique de l’état ouvert à l’état désensibilisé, mettant en avant une zone de régulation efficace dans les espaces transmembranaires. De plus, leur utilisation a permis l’investigation biophysique d’une mutation présente sur P2X2 humain, responsable d’une surdité non-syndromatique. Cette mutation entraine un rétrécissement du pore, impactant le passage de gros cations impliqués dans le processus d’audition. Enfin, la relation entre le diamètre du pore ionique et le passage de gros cations a été établi. / P2X receptors, activated by extracellular ATP and non-selective cations, are involved in many physiopathological roles. The lack of selectivity of pharmacological molecules is a major drawback for their study. The resolution of their crystallographic structures provided a molecular framework, but the mechanisms involved in allosteric transitions remain misunderstood. In the laboratory, two tools have been developed, derived from azobenzene, allowing the activation of P2X receptors in the absence of ATP and by light. The use of these tools allowed the study of the allosteric transition from the open to the desensitized state, highlighting an effective regulatory zone in transmembrane spaces. In addition, their use provided the biophysical investigation of a mutation present on hP2X2, responsible for non-syndromatic hearing loss. This mutation leads to a narrowing of the pore, affecting the large cations flow involved in hearing process. Finally, the relationship between the diameter of the ionic pore and the passage of large cations has been established.

Copies of author's previously published articles inserted / Describes the exploratory clinical development of tucaresol, consisting of three studies performed on humans and subsequent in vitro and animal studies investigating the possible effects on the immune system. Demostrates that rational drug design may be an efficient way of selecting potential therapeutic candidates. / xxi, 265 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995

The concentrations of some drug solutions are often expressed as ratios or percentages. This system simplified prescription and dispensing when Imperial measures such as grains and minims were used. Ampoules of powerful vasoactive drugs such as catecholamines and potentially toxic local anaesthetics are still labelled as ratios and percentages, seemingly through habit or tradition than for any useful clinical reason. This thesis argues that adherence to this outdated system is confusing, causes drug administration errors, and puts patients at risk. Internet-based questionnaires were used to quantify medical students’ and doctors’ understanding of ratios and percentages. A substantial minority of almost 3000 doctors could not convert between ratios, percentages and mass concentration correctly, made dosing errors of up to three orders of magnitude in written clinical scenarios, and struggled with conversions between metric units. These findings are strong arguments for expressing drug concentrations as mass concentration and providing better drug administration teaching. High fidelity patient simulation was used to examine the influence of clearer ampoule labelling and intensive drug administration teaching. This allowed critical incidents to be reproduced realistically, clinical performances to be assessed, and outcome measures to be accurately recorded. Randomised controlled trials were conducted that demonstrated positive influences of both interventions for doctors and students. The difficulties that nurses encounter when preparing infusions of these drugs on critical care units were also studied and are reported. The findings presented should be sufficient to persuade regulatory authorities to remove ratios and percentages from ampoule labels – a straightforward, cheap, commonsense intervention. The lack of effective clinical error reporting systems and the extreme practical difficulties of conducting clinical trials in this field mean that a firm link between this intervention and patient outcome is unlikely ever to be made, but this should not be an excuse for maintaining the status quo.

Title on spine: Pharmacokinetic investigations of triamterine and its metabolites / Erratum slip inserted / Bibliography: leaves 227-239 / ii, [248] leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1988

Σκοπός της παρούσας μελέτης είναι η εκτίμηση της συσχέτισης ανάμεσα στην κυτταροτοξικότητα και την μείωση της ακεραιότητας λιποσωμικών μεμβρανών που προκαλούνται από έκδοχα. Εάν υπάρχει, μπορεί να προταθεί η χρήση των λιποσωμάτων ως in vitro τεχνική για την εκτίμηση της κυτταρο-τοξικότητας εκδόχων. Μελετήθηκε η κυτταροτοξικότητα σε 4 κυτταρικές σειρές ( A549, PC3, MDA-MB, MCF-7 ) και η επίδραση στην ακεραιότητα λιποσωμάτων των παρακάτω εκδόχων που χρησιμοποιούνται σε σκευάσματα τοπικής χορήγησης: Labrafac Hydro, Labrafac CC, Transcutol, Cremofor, DL- Lactic acid και Capmul σε συγκεντρώσεις 1% και 10% (v/v) Για την μέτρηση της κυτταροτοξικότητας (στις 6 και 24 ώρες επώασης) χρησιμοποιήθηκε η μέθοδος του MTT (Thiazolyl Blue Tetrazolium Bromide) ενώ για την εκτίμηση της μεμβρανικής ακεραιότητας λιποσωμάτων [χρησιμοποιήθηκαν MLV (πολυστοιβαδιακά) και SUV (μικρά μονοστοιβαδιακά) λιποσώματα, με διάφορες λιπιδικές συστάσεις [PC (φωσφατιδυλοχολίνη), HPC (υδρογονωμένη φωσφατιδυλοχολίνη) και DSPC( διστεαρουλο φωσφατιδυλοχολίνη) με ή χωρίς Chol (χοληστερόλη)] μετρήθηκε η διαφυγή της εγκλωβισμένης στα λιποσώματα καλσεΐνης. Τα πειραματικά αποτελέσματα, έδειξαν ότι η επιβίωση-πολλαπλασιασμός των κυττάρων επηρεάζεται λιγότερο ή περισσότερο από τα έκδοχα: Labrafac Hydro (1% και 10%), Transcutol (10%), Cremofor (1% και 10%), Capmul (1% και 10%) και Lactic acid (1% και 10%) ενώ πολύ λιγότερο από τα έκδοχα Labrafac CC(1% και 10%) καθώς και από το Transcutol 1%. Σε ότι αναφορά την ακεραιότητα των λιποσωμάτων ( έως 24 ώρες επώασης) τα έκδοχα Cremofor, Labrafac, Capmul, Lactic acid και Labrafac hydro επηρεάζουν όλες τις λιπιδικές συστάσεις και τύπους λιποσωμάτων που μελετήθηκαν, ενώ τα έκδοχα Transcutol και Labrafac CC επηρεάζουν πολύ λιγότερο τις πιο ρευστές λιπιδικές μεμβράνες, και σχεδόν καθόλου τις σκληρές. Φαίνεται ότι είναι πιθανή η συσχέτιση των δύο σειρών αποτελεσμάτων. / The aim of this thesis is to study if a correlation may exist between the cytotoxicity of excipients and their effect on the integrity of liposomal membranes. If such a correlation exists perhaps the effect on liposome integrity may be used as an in vitro system to predict excipient cytotoxicity. Methods: The cell toxicity in four cell lines ( A549, PC3, MDA-MB, MCF-7 ) and the influence on liposome integrity of several commonly used excipients was studied. The following excipients which are used in topical formulations were studied: Labrafac Hydro, Labrafac CC, Transcutol, Cremofor, DL- Lactic acid and Capmul at concentrations of 1% and 10% (v/v). For the measurement of cell toxicity (6 and 24 hours of incubation) the MTT-assay (Thiazolyl Blue Tetrazolium Bromide) was used, whereas for the evaluation of the liposome membrane integrity MLV (MultiLaminar Vesicles) and SUV (Small Unilaminar Vesicles) liposomes with different lipid compositions [PC (phosphatidyl choline), HPC (hydrogenated phospatidyl choline) and DSPC (distearoylphosphatidylcholine) with or without Chol (cholesterol)] were prepared and the escape of the calcein encapsulated in the liposomes was measured at different time points during their incubation in presence of the excipients. Results: The experimental results showed that the cell survival-proliferation is influenced more or less by the following excipients (in increasing effect order): Labrafac Hydro (1% and 10%), Transcutol (10%), Cremofor (1% and 10%), Capmul (1% and 10%) and Lactic acid (1% and 10%) while the effect of Labrafac CC(1% and 10%) as well as Transcutol 1%, is minimal. As far as the integrity of the liposomes (up to 24 hours of incubation) is concerned, the excipients Cremofor, Labrafac, Capmul, Lactic acid and Labrafac hydro affect all the lipidic compositions and types of liposomes that were studied, whereas the excipients Transcutol and Labrafac CC influenced only minimally the more liquid membranes and had no effect on the more rigid lipid compositions. It seems that a correlation between the two series of results is possible.

Articular cartilage plays a vital role in load-bearing joints, providing an almost frictionless surface to articulating bones. However, the avascular nature and low cell density of the tissue means that following injury, there is limited potential for regeneration and repair. With the ageing population, the prevalence and economic burden associated with osteoarthritis (OA) is increasing rapidly, but as of yet there are no fully effective ways to treat the condition. Research into novel therapies has therefore become a popular avenue of investigation, and human mesenchymal stem/stromal cells (hMSCs) have been highlighted as particularly promising targets. However, current, methods for inducing the chondrogenic differentiation of hMSCs, which typically employ the use of transforming growth factor beta 1 or 3 (TGFβ1/3), result in the production of hypertrophic rather than hyaline tissue, hampering translational progress. Growth differentiation factor 5 (GDF5) belongs to the TGFβ superfamily of proteins and is vital for skeletal formation, however its use in cartilage tissue engineering (TE) strategies has been somewhat neglected. Here we demonstrate that GDF5 significantly increases aggrecan gene expression (a marker of articular cartilage), without affecting collagen type X expression (a marker of chondrocyte hypertrophy), in chondrocyte pellet cultures derived from hMSCs, making it a promising target for the formation of permanent articular cartilage. The therapeutic application of growth factors is, at present, limited due to their expense, susceptibility to proteolytic degradation, and rapid clearance, leading to large quantities being required to get anywhere near the desired outcome. The highly sulfated glycosaminoglycan (GAG), heparin, is already extensively used in the clinic as an anticoagulant, and is also able to bind and potentiate the activity of a wide range of growth factors. As such, researchers are now using it to enhance stem cell expansion/ differentiation protocols, as well as to improve the delivery/ activity of growth factors in TE strategies. Here, we identify GDF5 as a novel heparin/heparan sulfate (HS)-binding protein, and show that endogenous HS proteoglycans (HSPGs) are vital for localizing GDF5 to the cell surface, but are not required for its signalling activity. Importantly, we report that clinically relevant doses of heparin (≥ 10 nM), but not equivalent concentrations of HS, inhibit GDF5’s biological activity, in both hMSC-derived chondrocyte pellet cultures, and in the skeletal cell line ATDC5. We demonstrate that these inhibitory effects are due to heparin (but not HS) inhibiting both GDF5 binding to endogenous HSPGs and GDF5-induced induction of Smad 1/5/8 signalling. This study may therefore explain the variable (and disappointing) results seen with heparin-loaded biomaterials for skeletal TE, and the adverse skeletal effects, such as osteoporosis, that have been reported in the clinic following long-term heparin treatment. Together, our results caution the use of heparin in the clinic and in TE applications, and prompt the transition to using more specific GAGs (e.g. HS derivatives or synthetics), with better-defined structures and fewer off-target effects, if optimal therapy is to be achieved. In the case of GDF5, we have used a variety of developed techniques to begin uncovering important structural and functional information regarding the HS-GDF5 interaction, which are hoped to ultimately pave the way towards achieving this aim. Although further analysis is necessary, our data indicate that relatively long HS sequences are required for binding, and that both ionic and non-ionic interactions play a role in the interaction. In addition we suggest that low- rather than high-affinity HS variants may be key to potentiating the activity of this growth factor.

Staphylococcus aureus est une des espèces bactériennes les plus fréquemment responsable des cas d’endophtalmie et d’arthrite aiguës chez l’homme. Nous avons étudié la pharmacodynamie oculaire du linézolide et de la daptomycine, ainsi que leur toxicité, dans un modèle d’endophtalmie expérimentale chez le lapin. Il est apparu que seule une dose très élevée delinézolide administrée par voie intravitréenne (30mg/0,1mL) présentait une efficacité bactérioclinique. Aucune altération de la fonction visuelle n’a été mise en évidence. La dose intravitréenne efficace de daptomycine (1mg/0,1mL) était quant à elle responsable d’une altération significative de l’intégrité fonctionnelle de la rétine. Enfin, la pharmacodynamie de ces deux antibiotiques dans le compartiment oculaire présentait des différences significatives avec les autres sites tissulaires d’infection étudiés à ce jour. Dans la deuxième partie de nos travaux nous nous sommes intéressés à une nouvelle technique d’IRM, associée à des particules d’USPIOs (Ultrasmall SuperParamagnetic Iron Oxide). Nous avons montré que cette techniqued’imagerie permettait d’une part la mise en évidence de l’infiltration des macrophages dans la synoviale infectée, et, d’autre part, la visualisation de la guérison de l’articulation, contrairement à l’imagerie conventionnelle à base de chélates de gadolinium. Cette technique innovante offre donc une nouvelle dimension à l’imagerie ostéo-articulaire grâce à une mise en évidence in vivo plus spécifique des phénomènes pathologiques. / Staphylococcus aureus (S. aureus) is a frequent cause of acute endophthalmitis and arthritis in humans. In the first part, we investigated the ocular pharmacodynamics and safety of two recently approved antistaphylcoccal antibiotics, linezolid and daptomycin. Only a very high intravitreal dose of linezolid (30 mg / 0.1 mL) showed a bactericidal and clinical efficacy. Suchintraocular concentrations appeared to be safe for the retinal function, and linezolide could be considered as a promising therapeutic alternative. The effective intravitreal dose of daptomycin (1 mg / 0.1 mL) was responsible for a significant impairment of the functional integrity of the retina. Finally, the ocular pharmacodynamics of these two antibiotics showed special features in comparison with the one of other types of tissue infection. In a second part, we evaluated a newimaging method in experimental infectious arthritis, by using MRI enhanced by ultrasmall superparamagnetic iron oxide (USPIO). We first showed this method can depict the macrophage infiltration in infected synovium, and secondly it can demonstrate resolution of joint infection, in contrast to conventional MRI performed by gadolinium chelates. This in vivo non invasive imaging method therefore presents a new dimension in musculoskeletal imaging by accurately helping monitor bacterial joint infection.