Papers by Charles Fontaine
Les etudes observationnelles (non-randomisees) sont principalement constituees de donnees ayant d... more Les etudes observationnelles (non-randomisees) sont principalement constituees de donnees ayant des particularites qui sont en fait contraignantes dans un cadre statistique classique. En effet, dans ce type d'etudes, les donnees sont rarement continues, completes et independantes du bras therapeutique dans lequel les observations se situent. Cette these aborde l'utilisation d'un outil statistique parametrique fonde sur la dependance entre les donnees a travers plusieurs scenarios lies aux etudes observationnelles. En effet, grâce au theoreme de Sklar (1959), les copules parametriques sont devenues un sujet d'actualite en biostatistique. Pour commencer, nous presentons les concepts de base relatifs aux copules et aux principales mesures d'association basees sur la concordance retrouvees dans la litterature. Ensuite, nous donnons trois exemples d'application des modeles de copules parametriques pour autant de cas de donnees particulieres retrouvees dans des etu...
BMC medical research methodology, Feb 15, 2017
Information and theory beyond copula concepts are essential to understand the dependence relation... more Information and theory beyond copula concepts are essential to understand the dependence relationship between several marginal covariates distributions. In a therapeutic trial data scheme, most of the time, censoring occurs. That could lead to a biased interpretation of the dependence relationship between marginal distributions. Furthermore, it could result in a biased inference of the joint probability distribution function. A particular case is the cost-effectiveness analysis (CEA), which has shown its utility in many medico-economic studies and where censoring often occurs. This paper discusses a copula-based modeling of the joint density and an estimation method of the costs, and quality adjusted life years (QALY) in a cost-effectiveness analysis in case of censoring. This method is not based on any linearity assumption on the inferred variables, but on a punctual estimation obtained from the marginal distributions together with their dependence link. Our results show that the p...
Metallomics, 2010
Our knowledge of the molecular mechanisms of intracellular homeostatic control of zinc ions is no... more Our knowledge of the molecular mechanisms of intracellular homeostatic control of zinc ions is now firmly grounded on experimental findings gleaned from the study of zinc proteomes and metallomes, zinc transporters, and insights from the use of computational approaches. A cell's repertoire of zinc homeostatic molecules includes cytosolic zinc-binding proteins, transporters localized to cytoplasmic and organellar membranes, and sensors of cytoplasmic free zinc ions. Under steady state conditions, a primary function of cytosolic zinc-binding proteins is to buffer the relatively large zinc content found in most cells to a cytosolic zinc(ii) ion concentration in the picomolar range. Under non-steady state conditions, zinc-binding proteins and transporters act in concert to modulate transient changes in cytosolic zinc ion concentration in a process that is called zinc muffling. For example, if a cell is challenged by an influx of zinc ions, muffling reactions will dampen the resulting rise in cytosolic zinc ion concentration and eventually restore the cytosolic zinc ion concentration to its original value by shuttling zinc ions into subcellular stores or by removing zinc ions from the cell. In addition, muffling reactions provide a potential means to control changes in cytosolic zinc ion concentrations for purposes of cell signalling in what would otherwise be considered a buffered environment not conducive for signalling. Such intracellular zinc ion signals are known to derive from redox modifications of zinc-thiolate coordination environments, release from subcellular zinc stores, and zinc ion influx via channels. Recently, it has been discovered that metallothionein binds its seven zinc ions with different affinities. This property makes metallothionein particularly well positioned to participate in zinc buffering and muffling reactions. In addition, it is well established that metallothionein is a source of zinc ions under conditions of redox signalling. We suggest that the biological functions of transient changes in cytosolic zinc ion concentrations (presumptive zinc signals) complement those of calcium ions in both spatial and temporal dimensions.
BioMetals, 2007
Several studies have shown intracellular Zn(2+) release and concomitant cell death after prolonge... more Several studies have shown intracellular Zn(2+) release and concomitant cell death after prolonged exposure to exogenous NO. In the present study, we investigated whether cortical neurons briefly exposured to exogenous NO would demonstrate similar levels of intracellular Zn(2+) release and subsequent cell death. Cortical neurons were loaded with the Zn(2+) selective fluorophore FluoZin-3 and treated with various concentrations of the NO generator, spermine NONOate. Fluorescence microscopy was used to detect and quantify intracellular Zn(2+) levels. Concomitant EDTA perfusion was used to eliminate potential effects of extracellular Zn(2+). Neurons were perfused with the heavy metal chelator TPEN to selectively eliminate Zn(2+) induced fluorescence changes. A significant increase of intracellular fluorescence was detected during a 5 min perfusion with spermine NONOate. The increase in intracellular Zn(2+) release appeared to peak at 1 microM spermine NONOate (123.8 +/- 28.5%, increase above control n = 20, P < 0.001). Further increases in spermine NONOate levels as high as 1 mM failed to further increase detectable intracellular Zn(2+) levels. The NO scavenger hemoglobin blocked the effects of spermine NONOate and the inactive analog of the spermine NONOate, spermine, was without effect. No evidence of cell death induced by any of the brief treatments with exogenous NO was observed; only prolonged incubation with much larger amounts of exogenous NO resulted in significant cell death. These data suggest that in vivo release of NO may cause elevations of intracellular Zn(2+) in cortical neurons. The possibility that release of intracellular Zn(2+) in response to NO could play a role in intracellular signaling is discussed.
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Papers by Charles Fontaine