Differential Modulation of Transcriptional Activity of Estrogen Receptors by Direct Protein-Protein Interactions with the T Cell Factor Family of Transcription Factors

Two major signaling pathways, those triggered by estrogen (E(2)) and by the Wnt family, interact in the breast to cause growth and differentiation. The estrogen receptors ER(alpha) and ER(beta) are activated by binding E(2) and act as ligand-dependent transcription factors. The effector for the Wnt family is the Tcf family of transcription factors. Both sets of transcription factors recognize discrete but different nucleotide sequences in the promoters of their target genes. By using transient transfections of reporter constructs for the osteopontin and thymidine kinase promoters in rat mammary cells, we show that Tcf-4 antagonizes and Tcf-1 stimulates the effects of activated ER/E(2). For mutants of the former promoter, the stimulatory effects of ER(alpha)/E(2) can be made to be dependent on Tcf-1, and for the latter promoter the effects of the T cell factors (TCFs) are dependent on ER/E(2). Direct interaction between ERs and Tcfs either at the Tcf/ER(alpha)-binding site on the DNA or in the absence of DNA is established by gel retardation assays or by coimmunoprecipitation/biosensor methods, respectively. These results show that the two sets of transcription factors can interact directly, the interaction between ERs and Tcf-4 being antagonistic and that between ERs and Tcf-1 being synergistic on the activity of the promoters employed. Since Tcf-4 is the major Tcf family member in the breast, it is suggested that the antagonistic interaction is normally dominant in vivo in this tissue.

La incidencia de los valores culturales en el voluntariado: el caso de Europa

La realidad del voluntariado es sumamente compleja hasta el punto de que resulta complicado definir y caracterizar el trabajo voluntario, dada la gran variedad de interpretaciones, motivaciones, variables sociodemográficas y aspectos culturales que configuran el perfil de los voluntarios. El objetivo de este trabajo es analizar la influencia conjunta de algunas variables sociodemográficas, así como de los valores culturales de índole secular o tradicional, sobre el perfil de los voluntarios en Europa. Además, se investiga qué variables orientan a los voluntarios hacia un determinado tipo de voluntariado u otro. Para ello se ha aplicado principalmente una metodología de regresión logística a partir de la información disponible en la European Value Study. Los resultados obtenidos ayudan a establecer una caracterización del voluntariado en Europa, y confirman la influencia de los valores culturales, en primer lugar, en la realización o no de trabajos de voluntariado, y en segundo lugar, en la elección que hacen estas personas del tipo de actividad con la que están comprometidos. Al analizar dos tipos de voluntariado de motivación supuestamente muy diferente, se concluye que existe un grupo de valores que influyen en ambos, aunque el sentido y la intensidad en la que lo hacen sea diferente; por otra parte, algunos valores tienen influencia o no en la realización de trabajos de voluntariado, dependiendo del tipo específico al que nos refiramos.

Differential effects of an anti-oxidant intervention on cardiomyocyte expression of adrenomedullin and intermedin and their receptor components in chronic nitric oxide deficiency

Background: Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial oxidative stress and hypertrophic remodeling. Up-regulation of the cardiomyocyte adrenomedullin (AM) / intermedin (IMD) receptor signaling cascade is also apparent in NO-deficient cardiomyocytes: augmented expression of AM and receptor activity modifying proteins RAMP2 and RAMP3 is prevented by blood pressure normalization while that of RAMP1 and intermedin (IMD) is not, indicating that the latter is regulated by a pressure-independent mechanism. Aims: to verify the ability of an anti-oxidant intervention to normalize cardiomyocyte oxidant status and to investigate the influence of such an intervention on expression of AM, IMD and their receptor components in NO-deficient cardiomyocytes. Methods: NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 35mg/kg/day) was given to rats for 8 weeks, with/without con-current administration of antioxidants (Vitamin C (25mg/kg/day) and Tempol (25mg/kg/day)). Results: In left ventricular cardiomyocytes isolated from L-NAME treated rats, increased oxidative stress was indicated by augmented (3.6 fold) membrane protein oxidation, enhanced expression of catalytic and regulatory subunits of pro-oxidant NADPH oxidases (NOX1, NOX2) and compensatory increases in expression of anti-oxidant glutathione peroxidase and Cu/Zn superoxide dismutases (SOD1, SOD3). Vitamin C plus Tempol did not reduce systolic blood pressure but normalized augmented plasma levels of IMD, but not of AM, and in cardiomyocytes: (i) abolished increased membrane protein oxidation; (ii) normalized augmented expression of prepro-IMD and RAMP1, but not prepro-AM, RAMP2 and RAMP3; (iii) attenuated (by 42%) increased width and normalized expression of hypertrophic markers, skeletal-�-actin and prepro-endothelin-1 similarly to blood pressure normalization but in contrast to blood pressure normalization did not attenuate augmented brain natriuretic peptide (BNP) expression. Conclusion: normalization specifically of augmented IMD/RAMP1 expression in NO-deficient cardiomyocytes by antioxidant intervention in the absence of blood pressure reduction indicates that these genes are likely to be induced directly by myocardial oxidative stress. Although oxidative stress contributed to cardiomyocyte hypertrophy, induction of IMD and RAMP1 is unlikely to be secondary to cardiomyocyte hypertrophy.

Differential Pharmacokinetics of Digoxin in Elderly Patients

Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.
For over 200 years debate has raged regarding the use of digitalis glycosides in cardiac disease. At present digoxin is the most commonly prescribed digitalis compound. This review describes the pharmacokinetics of digoxin and in particular how they are altered with increasing age. When considering the elderly population it is important to recognise the heterogeneity of response in this group, therefore there are no rules, with regards to prescribing, that can apply to the entire elderly population.

Differential cross section measurements for elastic scattering of electrons from Ar2+ and Xe2+

A crossed-beams energy-loss spectrometer has been used to investigate angular distributions for electron scattering from Ar2+ and Xe2+ ions, at a collision energy of 16 eV. For Ar2+ the measurements are compared with the predictions of a partial waves calculation based on a semi-empirical potential, where it is shown that the interference term governs the position of the observed minimum in the angular distribution.