The acute effects of daily nicotine intake on heart rate--a toxicokinetic and toxicodynamic modelling study.

Abstract Joint physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) modelling was applied to simulate concentration–time profiles of nicotine, a well-known stimulant, in the human body following single and repeated dosing. Both kinetic and dynamic models were first calibrated by using in vivo literature data for the Caucasian population. The models were then used to estimate the blood and liver concentrations of nicotine in terms of the Area Under Curve (AUC) and the peak concentration (Cmax) for selected exposure scenarios based on inhalation (cigarette smoking), oral intake (nicotine lozenges) and dermal absorption (nicotine patches). The model simulations indicated that whereas frequent cigarette smoking gives rise to high AUC and Cmax in blood, the use of nicotine-rich dermal patches leads to high AUC and Cmax in the liver. Venous blood concentrations were used to estimate one of the most common acute effects, mean heart rate, both at rest and during exercise. These estimations showed that cigarette smoking causes a high peak heart rate, whereas dermal absorption causes a high mean heart rate over 48 h. This study illustrates the potential of using PBTK/TD modelling in the safety assessment of nicotine-containing products

Escritura Ignaciana y “cosecha javeriana” del P. Mayr en la Misión de Moxos

La etapa más fecunda de la Misión de Moxos es consecuencia directa de la llegada de misioneros extranjeros que se intensificó a partir de 1715. La producción epistolar del P. Dominik Mayr, proveniente de la Provincia de Alemania Superior y fiel seguidor de San Francisco Javier, es un ejemplo de la difusión de la correspondencia misional a través de la red de comunicación jesuita. Mi trabajo tiene como objetivo ahondar, en primer lugar, en la práctica de la escritura dentro de la misma Orden; y, en segundo, en el ministerio pastoral y la “cosecha javeriana”, como el mismo Mayr la describe, del jesuita alemán que sirvió en Moxos desde 1717 hasta su muerte en 1735. La publicación póstuma de sus cartas y el relato de viaje hacia las Indias Occidentales también lo emparentan con la figura del santo patrono de los misioneros. El éxito de la labor jesuita por las cuatro partes del mundo ad maiorem gloriam Dei, dependía en gran medida del movimiento de sus miembros y del conocimiento que implementaban en sus diferentes campos de acción.</p

TELEPENSOUTH project: Measurement of the Earth gravitomagnetic field in a terrestrial laboratory

We will expose a preliminary study on the feasibility of an experiment leading to a direct measurement of the gravitomagnetic field generated by the rotational motion of the Earth. This measurement would be achieved by means of an appropriate coupling of a TELEscope and a Foucault PENdulum in a laboratory on ground, preferably at the SOUTH pole. An experiment of this kind was firstly proposed by Braginski, Polnarev and Thorne, 18 years ago, but it was never re-analyzed.Comment: 7 pages, LaTeX, Springer style files included. Contribution to the Proceedings of the Spanish Relativity Meeting-ERE-2001 (Madrid, September 2001). To appear in the book "Relativistic Astrophysics", Lecture Notes in Physics, Springer Verlag (2002), edited by L. Fernandez-Jambrina, L.M. Gonzalez-Romer

In vitro-to-in vivo correlation of the skin penetration, liver clearance and hepatotoxicity of caffeine

Abstract This work illustrates the use of Physiologically-Based Toxicokinetic (PBTK) modelling for the healthy Caucasian population in in vitro -to- in vivo correlation of kinetic measures of caffeine skin penetration and liver clearance (based on literature experiments), as well as dose metrics of caffeine-induced measured HepaRG toxicity. We applied a simple correlation factor to quantify the in vitro and in vivo differences in the amount of caffeine permeated through the skin and concentration-time profiles of caffeine in the liver. We developed a multi-scale computational approach by linking the PBTK model with a Virtual Cell-Based Assay to relate an external oral and dermal dose with the measured in vitro HepaRG cell viability. The results revealed higher in vivo skin permeation profiles than those determined in vitro using identical exposure conditions. Liver clearance of caffeine derived from in vitro metabolism rates was found to be much slower than the optimised in vivo clearance with respect to caffeine plasma concentrations. Finally, HepaRG cell viability was shown to remain almost unchanged for external caffeine doses of 5–400 mg for both oral and dermal absorption routes. We modelled single exposure to caffeine only

Coautoría de «Sainetes y mojigangas» de Calderón y Emilio Carballido (México, 1985)

Emilio Carballido tenía la convicción de que el teatro es una herramienta pedagógica capaz de formar a los adolescentes. No se detuvo con poner en escena varias obras que dialogan con el teatro clásico español, sino que realizó refundiciones de piezas de los Siglos de Oro. Así hizo con los «Sainetes y mojigangas» que aparecen en Teatro para adolescentes bajo su autoría y la de Calderón de la Barca: La tía, El desafío de Juan Rana, La rabia y La muerte (Editores Mexicanos Unidos, 1985). La ficticia coautoría intentaba no solo difundir la dramaturgia clásica entre el pueblo mexicano, sino también acercar a los jóvenes lectores/actores a autores en apariencia lejanos. Este trabajo estudia la función y adaptación del teatro breve calderoniano en manos de Emilio Carballido a través del análisis de sus técnicas de composición, refundición y recursos escénicos. La doble autoría trasplanta de tiempo y espacio dichas piezas para hacerlas inteligibles a un público al que no se dirigía el autor español originalmente, defendiendo así la vigencia e importancia del teatro clásico en nuestros días.For Emilio Carballido, theatre was a pedagogical tool that could reach young people. Not only did he put several plays that dialogue with Spanish classical theater on stage, but also went on further and recast Golden Age dramas. That is what he did with «Sainetes y mojigangas», published in Teatro para adolescentes, sharing authorship with Calderon de la Barca: La tía, El desafío de Juan Rana, La rabia, and La muerte (Editores Mexicanos Unidos, 1985). The fictitious co-authorship was not only meant to circulate classical drama among Mexican people, but also brought young readers/actors close to apparently remote authors. This article studies the function and the adaptation of Calderonian interludes on the hands of Emilio Carballido through an analysis of their composition techniques, recasting, and scenic resources. The double authorship transplants the plays in time and space to make them intelligible to an audience that the Spanish author did not address originally; thus, defending the validity and importance of classical theatre today

Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression

Neuroactive steroids in depression and anxiety disorders: Clinical studies

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3 alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium of 3 alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3 alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone. The modulation of GABA(A) receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds. Copyright (c) 2006 S. Karger AG, Basel

Quantitative trait locus analysis identifies Gabra3 as a regulator of behavioral despair in mice

The Tail Suspension Test (TST), which measures behavioral despair, is widely used as an animal model of human depressive disorders and antidepressant efficacy. In order to identify novel genes involved in the regulation of TST performance, we crossed an inbred strain exhibiting low immobility in the TST (RIIIS/J) with two high-immobility strains (C57BL/6J and NZB/BlNJ) to create two distinct F2 hybrid populations. All F2 offspring (n = 655) were genotyped at high density with a panel of SNP markers. Whole-genome interval mapping of the F2 populations identified statistically significant quantitative trait loci (QTLs) on mouse chromosomes (MMU) 4, 6, and X. Microarray analysis of hippocampal gene expression in the three parental strains was used to identify potential candidate genes within the MMUX QTLs identified in the NZB/BlNJ × RIIIS/J cross. Expression of Gabra3, which encodes the GABAA receptor α3 subunit, was robust in the hippocampus of B6 and RIIIS mice but absent from NZB hippocampal tissue. To verify the role of Gabra3 in regulating TST behavior in vivo, mice were treated with SB-205384, a positive modulator of the α3 subunit. SB-205384 significantly reduced TST immobility in B6 mice without affecting general activity, but it had no effect on behavior in NZB mice. This work suggests that GABRA3 regulates a behavioral endophenotype of depression and establishes this gene as a viable new target for the study and treatment of human depression