Dopamine D1, D2 and mu-opioid receptors are co-expressed with adenylyl cyclase 5 and phosphodiesterase 7B mRNAs in striatal rat cells

El pdf es la versión post-print.Intracellular cAMP levels are regulated by cAMP synthesis and degradation rate. Nine isoforms of cAMP-synthesizing enzymes called adenylyl-cyclases (ACs) and eleven phosphodiesterases (PDEs) that degrade cyclic nucleotides have been identified. Both types of enzymes exhibit variations not only in their expression pattern distribution throughout the brain, but also in their regulatory characteristics. Different isoforms of ACs and PDEs may be co-expressed in a single cell, thus a gradient of cAMP intracellular levels is formed, which accounts for the diversity of cell responses. Among these isoforms, AC5 and PDE7B are highly expressed in striatum, where the cAMP pathway is implicated in diverse behavioural functions. Striatal AC5 is involved in drug reinforcing actions and motor activity. Less is known about the role of the PDE7B isoenzyme. We performed a double in situ hybridization analysis of the co-expression patterns of AC5 and PDE7B with μ-opioid-receptor (MOR), D1- and D2-receptor mRNAs to contribute to a better understanding in the regulation of cAMP levels under dopamine or opioidergic pathway activation in striatum. We found co-expression of AC5 and PDE7B mRNAs in caudate-putamen and nucleus accumbens; we also encountered that more than 50% of MOR, D2- and D1-expressing cells contained AC5 and PDE7B mRNAs. The presence of AC5 and PDE7B mRNAs in D1- and D2-containing cells suggests the participation of these enzymes in striatal functions involving dopaminergic pathways. Co-localization of both isoenzyme mRNAs with MOR expressing cells suggests their involvement in opioid reinforcing effects. © 2009 Elsevier B.V. All rights reserved.P. de G. is on sabbatical leave supported by Ministerio de Educación y Ciencia (SAB2005-0106). This research was supported by a grant from Ministerio de Educación y Ciencia (SAF2006-10243). Support from the Generalitat de Catalunya (Grup de Recerca de Qualitat 2005-SGR0758) is also acknowledged.Peer Reviewe

Management of elderly patients with acute promyelocytic leukemia: progress and problems

Despite substantial progress in the management and outcome of acute promyelocytic leukemia (APL) during the last decades, older age remains a prominent negative prognostic factor. The improvement of long-term stabilization and cure of older APL patients is therefore a particular challenge. Data of unselected population-based studies suggest a high rate of exclusion from clinical trials in older age. The comparison of registry and study data indicates that study patients represent a positive selection. Older APL patients seem as sensitive to therapy as younger patients. With conventional therapy, based on all-trans retinoic acid (ATRA) and chemotherapy, over 50 % of older APL patients can probably be cured. Special problems of advanced age are the high rate of early death before or during induction therapy and the high frequency of death in remission with negative influence on the outcome. Both may be related in part to a higher vulnerability against the common treatment with ATRA and chemotherapy. Alternative less toxic approaches including arsenic trioxide (ATO) with or without ATRA and combinations with gemtuzumab ozogamicin or with reduced chemotherapy can induce long-lasting remission in all stages of APL. Considering the high curative potential and the excellent tolerance of ATO in newly diagnosed and relapsed APL, older patients are probably a particular target group for a chemotherapy-free approach with ATO

Picard, Louis; Buss, Terry (2009): A Fragile Balance, Re-examining the history of foreign aid, security, and diplomacy, Kumarian Press, Sterling.

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Hi Tech Rec: Are We Losing the Real Pleasures of Life?

In this paper, the impact of advanced technology on the future and basic philosophy of leisure is analyzed from a quantitative and qualitative point of view. The marriage of science, technology, and leisure is examined in its present state and the implied conditions of the future. The inferences of newly emerging man-machine systems in the leisure industry are explored

Neue Inhibitoren der Amyloid-Aggregation als potentielle Therapeutika der Alzheimerschen Erkrankung

Statins are classically used in the treatment and prevention of hypercholesterolaemia due to their ability to inhibit the biosynthesis of cholesterol by blocking HMG-CoA-reductase, which is the rate limiting enzyme in cholesterol biosynthesis. Meanwhile, some studies have suggested the possible use of statins as potential therapeutics in the treatment of Alzheimer’s disease. Different pathways apart from their inhibitory activity on HMG-CoA-reductase have been explored. It has been shown that statins influence the release of β-amyloid, which aggregates to senile plaques, a pathological hallmark of AD. Although the mechanism has still not been fully discerned, it has been attributed to decreased cholesterol levels as well as decreased isoprenoid biosynthesis, which directly influences APP processing. NO-releasing substances have also been advocated to be of potential use in antidementive therapy due to their anti-inflammatory effect and their ability to improve the blood circulation. Notion behind this work was to determine the potential inhibitory effect of statins on β-amyloid-aggregation, as another possible pathway of their mode of action. Another goal was to prepare nitrate-statin-hybrid molecules in order to assess the extent to which the combination of these two promising pharmacophores would lead to a synergistic effect. Furthermore, some selected compounds were tested for their cholesterol-lowering and vasodilatory potencies to determine the influence of the structural modification on the biological activity. A novel nitratoacylated-stimvastatin derivative was obtained by cleaving the ester-side-chain, followed by selective protection of the lactonic alcohol and introduction of the nitrated-side-chain by acylation. Introduction of an organic nitrate to the simvastatin-scaffold resulted in only a slight decrease in the HMG-CoA-reductase inhibitory potency. In contrast, modification of the lactonic OH-group, which is crucial for inhibitory activity, either through acylation or elimination resulted in almost a complete loss of inhibitory potency. As expected all tested nitratoacylated compounds showed a vasodilatory effect. Since all tested derivatives encompass the same carrier molecule, the relaxation potency of the organic nitrates correlated with the number of nitrate groups in the molecule. In conclusion, the introduction of the bulky organic statin-scaffold did not result in a decrease of the vasodilatory potencies. A cell-free Aβ40-aggregation assay was successfully established, to investigate the possible direct effect of statin derivatives on β-amyloid-aggregation. For this purpose, the inhibitory activity of statins on Aβ40-aggregation was assessed as a function of the fluorescence of thioflavin T. The inhibitory activity, which was observed by the decrease of the measured fluorescence intensities, was further confirmed by electron microscopy