Limited Activity Of Miltefosine In Murine Models Of Cryptococcal Meningoencephalitis And Disseminated Cryptococcosis

Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 to 45 mg/kg of body weight orally once daily) began at either 1 h or 1 day postinoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend toward improved survival with miltefosine at 7.2 mg/kg against disseminated cryptococcosis with the H99 strain but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections.Pharmac

Incertitude scientifique et décision publique: le recours au Principe de Précaution

International audienceIn this paper, we formalize two criteria of decisions which try to convey two different interpretations of the Precautionary principle. The first criterion corresponds to the maximization of the minimum of the expected utility whereas the second criterion corresponds to the minimization of the maximum of the regret expectation. We apply those two criteria in an economic problem where uncertainty is assessed by a family of probabilities. We show that there is a distance of probabilities for which the choices induced by the two criteria are different. Especially, we show that in this case, the second criterion always induces the more cautious decision contrary to the first criterion, decisions are the same elsewhere.Dans cet article, nous formalisons deux critères de décisions qui tentent de rendre compte de deux logiques différentes d'interprétation du Principe de précaution. Le premier critère correspond à la maximisation du minimum de l'espérance d'utilité alors que le second critère correspond à la minimisation du maximum de l'espérance de regret. Les deux critères de décisions sont appliqués à un problème économique où l'incertitude est mesurée par une famille de probabilités. Nous montrons qu'il existe un intervalle de probabilités sur lequel les choix relatifs aux deux critères divergent. Plus particulièrement, nous montrons que sur cet intervalle, le second critère à la différence du premier, conduit toujours à retenir la décision la plus précautionneuse, les décisions étant identiques sur les autres intervalles

Incertitude scientifique et décision publique: le recours au Principe de Précaution

Dans cet article, nous formalisons deux critères de décisions qui tentent de rendre compte de deux logiques différentes d'interprétation du Principe de précaution. Le premier critère correspond à la maximisation du minimum de l'espérance d'utilité alors que le second critère correspond à la minimisation du maximum de l'espérance de regret. Les deux critères de décisions sont appliqués à un problème économique où l'incertitude est mesurée par une famille de probabilités. Nous montrons qu'il existe un intervalle de probabilités sur lequel les choix relatifs aux deux critères divergent. Plus particulièrement, nous montrons que sur cet intervalle, le second critère à la différence du premier, conduit toujours à retenir la décision la plus précautionneuse, les décisions étant identiques sur les autres intervalles.décision publique, information, précaution

Polarization-based Tests of Gravity with the Stochastic Gravitational-Wave Background

The direct observation of gravitational waves with Advanced LIGO and Advanced Virgo offers novel opportunities to test general relativity in strong-field, highly dynamical regimes. One such opportunity is the measurement of gravitational-wave polarizations. While general relativity predicts only two tensor gravitational-wave polarizations, general metric theories of gravity allow for up to four additional vector and scalar modes. The detection of these alternative polarizations would represent a clear violation of general relativity. The LIGO-Virgo detection of the binary black hole merger GW170814 has recently offered the first direct constraints on the polarization of gravitational waves. The current generation of ground-based detectors, however, is limited in its ability to sensitively determine the polarization content of transient gravitational-wave signals. Observation of the stochastic gravitational-wave background, in contrast, offers a means of directly measuring generic gravitational-wave polarizations. The stochastic background, arising from the superposition of many individually unresolvable gravitational-wave signals, may be detectable by Advanced LIGO at design-sensitivity. In this paper, we present a Bayesian method with which to detect and characterize the polarization of the stochastic background. We explore prospects for estimating parameters of the background, and quantify the limits that Advanced LIGO can place on vector and scalar polarizations in the absence of a detection. Finally, we investigate how the introduction of new terrestrial detectors like Advanced Virgo aid in our ability to detect or constrain alternative polarizations in the stochastic background. We find that, although the addition of Advanced Virgo does not notably improve detection prospects, it may dramatically improve our ability to estimate the parameters of backgrounds of mixed polarization.Comment: 24 pages, 20 figures; Accepted by PRX. This version includes major changes in response to referee comments and corrects an error in Eq. E

Interneurons in the mouse visual thalamus maintain a high degree of retinal convergence throughout postnatal development

Background The dorsal lateral geniculate nucleus (dLGN) of the mouse thalamus has emerged as a powerful experimental system for understanding the refinement of developing sensory connections. Interestingly, many of the basic tenets for such developmental remodeling (for example, pruning of connections to form precise sensory maps) fail to take into account a fundamental aspect of sensory organization, cell-type specific wiring. To date, studies have focused on thalamocortical relay neurons and little is known about the development of retinal connections onto the other principal cell type of dLGN, intrinsic interneurons. Here, we used a transgenic mouse line in which green fluorescent protein (GFP) is expressed within dLGN interneurons (GAD67-GFP), making it possible to visualize them in acutely prepared thalamic slices in order to examine their morphology and functional patterns of connectivity throughout postnatal life. Findings GFP-expressing interneurons were evenly distributed throughout dLGN and had highly complex and widespread dendritic processes that often crossed eye-specific borders. Estimates of retinal convergence derived from excitatory postsynaptic potential (EPSP) amplitude by stimulus intensity plots revealed that unlike relay cells, interneurons recorded throughout the first 5 weeks of life, maintain a large number (approximately eight to ten) of retinal inputs. Conclusions The lack of pruning onto interneurons suggests that the activity-dependent refinement of retinal connections in dLGN is cell-type specific. The high degree of retinal convergence onto interneurons may be necessary for these cells to provide both widespread and local forms of inhibition in dLGN

Thermal resistant environmental barrier coating

A process for preparing a silicon based substrate with a protective coating having improved thermal resistance at temperature up to at least 1500.degree. C., and the resulting article