Alterations in Postural Control during the World's Most Challenging Mountain Ultra-Marathon

We investigated postural control (PC) effects of a mountain ultra-marathon (MUM): a 330-km trail run with 24000 m of positive and negative change in elevation. PC was assessed prior to (PRE), during (MID) and after (POST) the MUM in experienced ultra-marathon runners (n = 18; finish time = 126+/-16 h) and in a control group (n = 8) with a similar level of sleep deprivation. Subjects were instructed to stand upright on a posturographic platform over a period of 51.2 seconds using a double-leg stance under two test conditions: eyes open (EO) and eyes closed (EC). Traditional measures of postural stability (center of pressure trajectory analysis) and stabilogram-diffusion analysis (SDA) parameters were analysed. For the SDA, a significantly greater short-term effective diffusion was found at POST compared with PRE in the medio-lateral (ML; Dxs) and antero-posterior (AP) directions (Dys) in runners (p<0.05) The critical time interval (Ctx) in the ML direction was significantly higher at MID (p<0.001) and POST (p<0.05) than at PRE in runners. At MID (p<0.001) and POST (p<0.05), there was a significant difference between the two groups. The critical displacement (Cdx) in the ML was significantly higher at MID and at POST (p<0.001) compared with PRE for runners. A significant difference in Cdx was observed between groups in EO at MID (p<0.05) and POST (p<0.005) in the ML direction and in EC at POST in the ML and AP directions (p<0.05). Our findings revealed significant effects of fatigue on PC in runners, including, a significant increase in Ctx (critical time in ML plan) in EO and EC conditions. Thus, runners take longer to stabilise their body at POST than at MID. It is likely that the mountainous characteristics of MUM (unstable ground, primarily uphill/downhill running, and altitude) increase this fatigue, leading to difficulty in maintaining balance.

Fast quantification of ten psychotropic drugs and metabolites in human plasma by ultra-high performance liquid chromatography tandem mass spectrometry for therapeutic drug monitoring.

A sensitive and selective ultra-high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method was developed for the fast quantification of ten psychotropic drugs and metabolites in human plasma for the needs of our laboratory (amisulpride, asenapine, desmethyl-mirtazapine, iloperidone, mirtazapine, norquetiapine, olanzapine, paliperidone, quetiapine and risperidone). Stable isotope-labeled internal standards were used for all analytes, to compensate for the global method variability, including extraction and ionization variations. Sample preparation was performed by generic protein precipitation with acetonitrile. Chromatographic separation was achieved in less than 3.0min on an Acquity UPLC BEH Shield RP18 column (2.1mm×50mm; 1.7μm), using a gradient elution of 10mM ammonium formate buffer pH 3.0 and acetonitrile at a flow rate of 0.4ml/min. The compounds were quantified on a tandem quadrupole mass spectrometer operating in positive electrospray ionization mode, using multiple reaction monitoring. The method was fully validated according to the latest recommendations of international guidelines. Eight point calibration curves were used to cover a large concentration range 0.5-200ng/ml for asenapine, desmethyl-mirtazapine, iloperidone, mirtazapine, olanzapine, paliperidone and risperidone, and 1-1500ng/ml for amisulpride, norquetiapine and quetiapine. Good quantitative performances were achieved in terms of trueness (93.1-111.2%), repeatability (1.3-8.6%) and intermediate precision (1.8-11.5%). Internal standard-normalized matrix effects ranged between 95 and 105%, with a variability never exceeding 6%. The accuracy profiles (total error) were included in the acceptance limits of ±30% for biological samples. This method is therefore suitable for both therapeutic drug monitoring and pharmacokinetic studies.

Traitement des tumeurs maligne du foie par radiologie interventionnelle: techniques intra-artérielles [Interventional radiology procedures for malignancies of the liver treatment: Intraarterial procedures].

Intraarterial procedures such as chemoembolization and radioembolization aim for the palliative treatment of advanced hepatocellular carcinoma (stage BCLC B and C with tumoral portal thrombosis). The combination of hepatic intraarterial chemotherapy and systemic chemotherapy can increase the probability of curing colorectal cancer with hepatic metastases not immediately accessible to surgical treatment or percutaneous ablation.

Biodistribution of anti-CEA F(ab')2 fragments after intra-arterial and intravenous injection in patients with liver metastases due to colorectal carcinoma.

The biodistribution of simultaneous intra-arterial and intravenous injections of a radiolabelled anti-CEA MAb F(ab')2 fragment was studied in three patients with liver metastases from colorectal cancer. Identical MAb fragments, labelled with either 125I or 131I, were injected over a period of 30 min into the hepatic artery and into a peripheral vein. After 1 or 2 days, biodistribution was measured in the surgically removed metastases, normal tissue samples and blood. By tissue radioactivity counting, tumour uptake in the range 6.3-9.1% of injected dose per gram was found. Superimposable metastasis-to-blood and metastasis-to-normal liver ratios were obtained for both iodine isotopes in all three patients. The results indicate that the intra-arterial injection of MAb F(ab')2 fragments gives no measurable advantage over more convenient injections into a peripheral vein.

Caspofungin for prevention of intra-abdominal candidiasis in high-risk surgical patients.

PURPOSE: Thirty to forty percent of patients with recurrent gastrointestinal perforation/anastomotic leakage or acute necrotizing pancreatitis develop intra-abdominal invasive candidiasis (IC). A corrected Candida colonization index (CCI) > or =0.4 is a powerful predictor of IC. Fluconazole prevents intra-abdominal IC in this setting, but azole-resistant Candida species are emerging. The aim of this study was to explore the efficacy and safety of caspofungin for prevention of intra-abdominal IC in high-risk surgical patients. METHODS: Prospective non-comparative single-center study in consecutive adult surgical patients with recurrent gastrointestinal perforation/anastomotic leakage or acute necrotizing pancreatitis. Preventive caspofungin therapy (70 mg, then 50 mg/day) was given until resolution of the surgical condition. Candida colonization index and CCI, occurrence of intra-abdominal IC and adverse events were monitored. RESULTS: Nineteen patients were studied: 16 (84%) had recurrent gastrointestinal perforation/anastomotic leakage and 3 (16%) acute necrotizing pancreatitis. The median duration of preventive caspofungin therapy was 16 days (range 4-46). The colonization index decreased significantly during study therapy, and the CCI remained <0.4 in all patients. Caspofungin was successful for prevention of intra-abdominal IC in 18/19 patients (95%, 1 breakthrough IC 5 days after inclusion). No drug-related adverse event requiring caspofungin discontinuation occurred. CONCLUSION: Caspofungin may be efficacious and safe for prevention of intra-abdominal candidiasis in high-risk surgical patients. This needs to be further investigated in randomized trials.

Peroxisome proliferator activated receptor BETA/DELTA as a central player in the skin response to ultra-violets radiation

Previous studies in the lab of Dr. Liliane Michalik, have shown thai the nuclear hormone receptor Peroxisome Proliferator Activated Receptor beta/delta (PPARß/ö) is an important regulator of skin homeostasis, being involved in the regulation of keratinocyte differentiation, inflammation, apoptosis, arid mouse skin wound healing. Studies of PPARß/ö knock out mice have suggested a possible role for this receptor in cancer. However, contradictory observations of the role for PPARß/ö on tumor growth have been published, depending on cellular contexts and biological models. Given the controversial role of PPARß/ö in skin carcinoma development, the main aim of this PhD work has been to further explore the implication of PPARß/ö in skin response to UV and skin tumor growth. This PhD dissertation is divided in four chapters. The first chapter describes the core part of the project, where I explored the changes in miRNA expression in the skin upon chronic UV irradiation of PPARß/ö wild type and knock-out mice. This analysis shed light on a miRNA- PPARß/ö signature and also predicted thai miR-21-3p (previously named miR-21*) is a key regulator of the PPARß/ö-dependent UV response in the pre-lesiona! skin. Using mice acutely UV-irradiated, ! further demonstrated that miR-21-3p is indirectly regulated by PPARß/ö through activation of Transforming Growth Factor (TGFß)-1 under UV exposure. I also show that miR-21-3p is deregulated in human cutaneous squamous celi carcinoma. In cultured keratinocytes, application of a miR-21 -3p mimic oligonucleotide sequence leads to the regulation of lipid metabolism-related pathway. In the second chapter, I demonstrate that the usage of an mRNA/miRNA combined bioinformatics analysis leads to the discovery of important pathways involved in the PPARß/ö-miRNA response of the skin to chronic UV irradiation, indeed, I validated angiogenesis and lipid metabolism as important functions regulated by PPARß/ö in this context. In the third chapter, we demonstrate that PPARß/5 knockout mice have decreased cutaneous squamous cell carcinomas incidence compared to wild type mice and that PPARß/5 directly activates the cSrc kinase gene. In the last chapter, we review novel insights into PPAR functions in keratinocytes and liver, with emphasis on PPARß/ö but also on PPARa. In summary, this PhD study shows that i) PPARß/5 is able to regulate biological function through regulation of miRNAs, and specifically through miR-21-3p, the passenger miRNA of the oncomiR miR-21, and that ii) the PPARß/5-dependent skin response to UV involves the regulation of angiogenesis and lipid metabolism. Furthermore, the bioinformatics study highlights the relevance of performing integrated mRNA and miRNA genome-wide studies in order to better screen mRNAs and/or miRNAs of interest in the biological context of diseases. - Des études préalables dans le laboratoire du Dr. Liliane Michalik ont démontré que le récepteur nucléaire PPARß/5 est un régulateur important de l'homéostasie de la peau, étant impliqué dans la régulation de la différenciation des keratinocytes, dans l'inflammation, dans l'apoptose et dans la cicatrisation de la peau chez !a souris. L'étude de souris knock-out pour le gène PPARß/5, ont suggérées un rôle possible de ce récepteur dans le cancer. Cependant, des observations opposées ont été publiées suggérant un rôle pro- ou anti- cancer selon le tissue impliqué et le type- cellulaire. En considérant cette controverse autour du rôle de PPARß/5 dans le développement des cancers de la peau, le but principal de mon projet de recherche aura été d'approfondir l'exploration du rôle de PPARß/5 dans la réponse de la peau aux UVs et dans le développement du cancer. Cette dissertation de thèse est divisée en quatre parties. Une première partie, représentant le coeur de mon travail de recherche, décrit la découverte de l'implication des microRNAs (rniRNAs) dans la réponse aux UVs de PPARß/ö et plus spécifiquement l'implication du miRNA miR- 21 -3p (précédemment nommé miR-21*). En étudiant un modèle de souris irradiées de manière aigüe aux UVs, nous montrons que ia régulation de miR-21-3p est PPARß/ö-däpenaante et que cette régulation à lieu par l'intermédiaire du facteur de transcription TGFß-1. Dans des cultures de keratinocytes Humains, la transfecticn d'une séquence oligonucléotidique similaire à celle de miR-21-3p (mimic), montre l'implication de rniR-21-3p dans des fonctions importantes pour le développement des cancers telles que le métabolisme des lipides. Dans un second chapitre, nous montrons que l'usage d'une méthode bioinformatique combinant l'expression des ARN messagers et des miRNAs permet de mettre en évidence des fonctions biologiques importantes lors de ia réponse de PPARß/ö à l'irradiation chronique. L'angiogenèse, le stress oxydatif et le métabolisme des lipides font partie de ces fonctions régulées par PPARß/5 dans la peau irradiée aux UVs. Nous mettons également en évidence la régulation du gène LpcatS par PPARß/5 dans la peau irradiée aux UV ainsi que dans des keratinocytes humains suggérant un rôle pour PPARß/5 dans le remodelage des lipides membranaires. Dans une troisième partie, nous établissons un lien entre la régulation de l'oncogène Src et l'activation de PPARß/5 dans les carcinomes spinocellulaires de la peau. Finalement dans un quatrième chapitre, nous faisons une revue des dernières recherches portées sur le rôle de PPARß/5 et de PPARa dans le foie et ia peau. En résumé ce projet de thèse représente un avancement pour la recherche sur rimplication de PPARß/5 dans la réponse aux UVs de la peau. Pour la première fois, un lien est établi entre ce facteur de transcription et la régulation de microRNAs dans le cadre du carcinome spinocellulare. Jusqu'alors resté dans l'ombre de rniR-21-5p, miR-21-3p est en fait fortement augmenté à la fois dans un modèle de souris d'irradiation aux UVs ainsi que dans ie carcinome spinocellulare chez i'humain. De nouvelles fonctions biologiques pour PPARß/5 ont été également mises en évidence dans ce travail, comme la régulation de l'angiogenèse ou du métabolisme des lipides dans Sa peau. De plus cette dissertation valorise l'intérêt d'une association entre le travail de laboratoire et celui de la bioinformatique.

Predicting present and future intra-specific genetic structure through niche hindcasting across 24 millennia.

Paleoclimatic reconstructions coupled with species distribution models and identification of extant spatial genetic structure have the potential to provide insights into the demographic events that shape the distribution of intra-specific genetic variation across time. Using the globeflower Trollius europaeus as a case-study, we combined (1) Amplified Fragment Length Polymorphisms, (2) suites of 1000-years stepwise hindcasted species distributions and (3) a model of diffusion through time over the last 24,000 years, to trace the spatial dynamics that most likely fits the species' current genetic structure. We show that the globeflower comprises four gene pools in Europe which, from the dry period preceding the Last Glacial Maximum, dispersed while tracking the conditions fitting its climatic niche. Among these four gene pools, two are predicted to experience drastic range retraction in the near future. Our interdisciplinary approach, applicable to virtually any taxon, is an advance in inferring how climate change impacts species' genetic structures.

Fast analysis of doping agents in urine by ultra-high-pressure liquid chromatography-quadrupole time-of-flight mass spectrometry I. Screening analysis.

The general strategy to perform anti-doping analyses of urine samples starts with the screening for a wide range of compounds. This step should be fast, generic and able to detect any sample that may contain a prohibited substance while avoiding false negatives and reducing false positive results. The experiments presented in this work were based on ultra-high-pressure liquid chromatography coupled to hybrid quadrupole time-of-flight mass spectrometry. Thanks to the high sensitivity of the method, urine samples could be diluted 2-fold prior to injection. One hundred and three forbidden substances from various classes (such as stimulants, diuretics, narcotics, anti-estrogens) were analysed on a C(18) reversed-phase column in two gradients of 9min (including two 3min equilibration periods) for positive and negative electrospray ionisation and detected in the MS full scan mode. The automatic identification of analytes was based on retention time and mass accuracy, with an automated tool for peak picking. The method was validated according to the International Standard for Laboratories described in the World Anti-Doping Code and was selective enough to comply with the World Anti-Doping Agency recommendations. In addition, the matrix effect on MS response was measured on all investigated analytes spiked in urine samples. The limits of detection ranged from 1 to 500ng/mL, allowing the identification of all tested compounds in urine. When a sample was reported positive during the screening, a fast additional pre-confirmatory step was performed to reduce the number of confirmatory analyses.

Diagnostic et traitement des tumeurs intra-oculaires chez l'enfant [Diagnosis and treatment of intraocular tumors in the child]

PURPOSE: To remind of the absolute necessity for early diagnosis in the presence of ocular signs in children giving rise to possible intraocular tumours. METHOD: Based on our own experience of intraocular tumours in children, together with findings from the literature, diagnostic criteria and methods of treatment are presented. RESULTS: Retinoblastoma is the predominant cause of intraocular tumours in children, representing over 80% of cases under the age of 15 years. Other diseases may give rise to the same initial signs, usually leukocoria, sometimes strabismus, more rarely other atypical signs. Elements taken into account for diagnosis include age, sex, laterality, heredity, size of the globe, clinical aspect of the tumours, presence of calcifications and vitreous seeding. Full fundus examination under general anaesthetic is usually necessary. Biological examination, ultrasonography, computerized tomography and MRI enable an accurate diagnosis to be made in the majority of doubtful cases. The management of retinoblastoma is adapted for each individual case from the wide range of treatments available. Enucleation, radioactive applicators (...), brachytherapy (...), cryo- and photocoagulation represent classical measures. Primary chemotherapy, combined with other treatments such as thermotherapy, has become the treatment of choice in those cases where external beam radiotherapy has been used up to now, or in some instances before enucleation. Enucleation is usually carried out for medullo-epitheliomas, but brachytherapy may offer an alternative. CONCLUSION: Any unexplained ocular sign in children should be considered as a possible retinoblastoma, making an accurate and certain diagnosis imperative. Early treatment may save not only the life but also the vision of patients carrying this highly malignant lesion.

Hémorragie intra-alvéolaire [Alveolar hemorrhage].

Diffuse alveolar hemorrhage (DAH) is defined by the presence of red blood cells originating from the lung capillaries or venules within the alveoli. The diagnosis is established on clinical features, radiological pattern, and especially bronchoalveolar lavage. Diffuse alveolar hemorrhage may have many immune or non-immune causes. Immune causes of DAH include vasculitides, connective tissue diseases, especially systemic lupus erythematosus, and antiglomerular basement membrane antibody disease (Goodpasture's syndrome). Treatment is both supportive and causal, often based on high dose corticosteroids and immunosuppressive therapy (especially intravenous cyclophosphamide). Plasma exchanges are performed in antiglomerular basement membrane antibody disease and systemic lupus erythematosus, and are considered in systemic vasculitis. Non-immune causes of DAH mainly include heart diseases, coagulation disorders, infections, drug toxicities and idiopathic DAH. Treatment of non-immune DAH is that of its cause. Whatever the cause, DAH is an emergency requiring prompt assessment and early treatment.