Fast uncertainty quantification of activation sequences in patient-specific cardiac electrophysiology meeting clinical time constraints.

We present a fast, patient-specific methodology for uncertainty quantification in electrophysiology, aimed at meeting the time constraints of clinical practitioners. We focus on computing the statistics of the activation map, given the uncertainties associated with the conductivity tensor modeling the fiber orientation in the heart. We use a fast parallel solution method implemented on a graphics processing unit for the eikonal approximation, in order to compute the activation map and to sample the random fiber field with correlation on the basis of geodesic distances. While this enables to perform uncertainty quantification studies with a manageable computational effort, the required time frame still exceeds clinically suitable time expectations. In order to reduce it further by 2 orders of magnitude, we rely on Bayesian multifidelity methods. In particular, we propose a low-fidelity model that is patient-specific and free from the additional training cost associated with reduced models. This is achieved by a sound physics-based simplification of the full eikonal model. The low-fidelity output is then corrected by the standard multifidelity framework. In practice, the complete procedure only requires approximately 100 new runs of our eikonal graphics processing unit solver for producing the sought estimates and their associated credible intervals, enabling a full online analysis in less than 5 minutes.

Androgens selectively protect against apoptosis in hippocampal neurones.

Androgens can protect neurones from injury, although androgen neuroprotection is not well characterised in terms of either specificity or mechanism. In the present study, we compared the ability of androgens to protect neurones against a panel of insults, empirically determined to induce cell death by apoptotic or non-apoptotic mechanisms. Three criteria defining but not inclusive of apoptosis are: protection by caspase inhibition, protection by protein synthesis inhibition and the presence of pyknotic nuclei. According to these criteria, beta-amyloid, staurosporine, and Apoptosis Activator II induced cell death involving apoptosis, whereas hydrogen peroxide (H(2)O(2)), iron, calcium ionophore and 3-nitropropionic acid induced cell death featuring non-apoptotic characteristics. Pretreatment of hippocampal neurones with testosterone or dihydrotestosterone attenuated cell death induced by beta-amyloid, staurosporine and Apoptosis Activator II, but none of the other insults. The anti-oxidant Trolox did not reduce cell death induced by beta-amyloid, staurosporine and Apoptosis Activator II, but did protect against H(2)O(2) and iron. Similarly, a supra-physiological concentration of oestrogen reduced cell death induced by H(2)O(2) and iron, an effect not observed with androgens. We also show that activation of oestrogen pathways was not necessary for androgen neuroprotection. These data suggest that androgens directly activate a neuroprotective mechanism specific to inhibition of cell death involving apoptosis. Determining the specificity of androgen neuroprotection may enable the development of androgen compounds for the treatment of neurodegenerative disorders.

TNF-alpha enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B.

Breast tumors are usually classified according to their response to estrogens as hormone-dependent or -independent. In this work, we investigated the role of the proinflammatory cytokine TNF-alpha on the estrogen-receptor-positive T47D breast ductal tumor cells. We have found that TNF-alpha exerts a mitogenic effect, inducing cyclin D1 expression and activation of the transcription factor NF-kappaB. Importantly, activation of NF-kappaB was required for estrogen-induced proliferation and cyclin D1 expression. TNF-alpha enhanced the estrogen response by increasing the levels and availability of NF-kappaB. Chromatin immunoprecipitation analysis suggested that the action of estrogens is mediated by a protein complex that contains the activated estrogen receptor, the nuclear receptor coactivator RAC3 and a member of the NF-kappaB family. Finally, our results demonstrate that activation of this transcription factor could be one of the key signals for estrogen-mediated response.

Posthatch oral estrogen exposure impairs adult reproductive performance of zebra finch in a sex-specific manner.

We determined whether short-term, posthatch oral exposure to estradiol benzoate (EB) or the industrial surfactant octylphenol (OP) could impair the reproductive performance of zebra finches. If so, naturally occurring phytoestrogens and xenoestrogens might influence reproduction in wild populations. Chicks were given oral administration of 10 or 100 nmol EB per gram of body mass (earlier work showed the latter to be the minimum oral dose required to maximally masculinize female song nuclei) or an equimolar amount of OP daily from 5 through 11 days of age. Canola oil was used as a vehicle and control. Reproductive testing was done either in individual pair cages or in communal cages that permitted self-selection of mates, N = 10 pairs per group. Pairs consisted of EB-treated males and females, EB-treated males paired with canola-treated females, vice versa, and canola-treated males and females. Posthatch EB treatment produced sex-specific impairments in reproduction that, in some instances, were additive when both sexes were treated. Egg production was reduced and egg breakage was increased in 100 nmol/g EB-treated male and female pairs. The incidence of missing eggs was increased in 10 nmol/g EB-treated male and female pairs. Candled fertility was reduced in both groups containing 100 nmol/g EB-treated males. The number of hatched chicks was severely reduced in all EB-treated groups. No adverse effects of OP treatment were detected. These significant treatment effects (all P < 0.05) show that posthatch EB treatment profoundly disrupts the reproductive performance of zebra finches, suggesting that exposure to estrogens in the wild could impair the reproductive performance of wild populations.