Morphine peripheral analgesia depends on activation of the PI3K gamma/AKT/nNOS/NO/K(ATP) signaling pathway

Morphine is one of the most prescribed and effective drugs used for the treatment of acute and chronic pain conditions. In addition to its central effects, morphine can also produce peripheral analgesia. However, the mechanisms underlying this peripheral action of morphine have not yet been fully elucidated. Here, we show that the peripheral antinociceptive effect of morphine is lost in neuronal nitric-oxide synthase null mice and that morphine induces the production of nitric oxide in primary nociceptive neurons. The activation of the nitric-oxide pathway by morphine was dependent on an initial stimulation of PI3K gamma/AKT protein kinase B (AKT) and culminated in increasedactivation of K(ATP) channels. In the latter, this intracellular signaling pathway might cause a hyperpolarization of nociceptive neurons, and it is fundamental for the direct blockade of inflammatory pain by morphine. This understanding offers new targets for analgesic drug development.

Synthesis and in vitro activity of limonene derivatives against Leishmania and Trypanosoma

The synthesis and in vitro activity of R(+)-Limonene derivatives against Leishmania and Trypanosoma cruzi strains are reported. Seven compounds have shown better in vitro activity against Leishmania (V.)braziliensis than the standard drug pentamidine. Additionally, we have identified two promising new anti-T. cruzi limonene derivatives. (C) 2010 Elsevier Masson SAS. All rights reserved.

In vitro sensitivity of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis Brazilian isolates to meglumine antimoniate and amphotericin B

Resistance of Leishmania parasites to specific chemotherapy has become a well-documented problem in the Indian subcontinent in recent years but only a few studies have focused on the susceptibility of American Leishmania isolates. Our susceptibility assays to meglumine antimoniate were performed against intracellular amastigotes after standardizing an in vitro model of macrophage infection appropriate for Leishmania (Viannia) braziliensis isolates. For the determination of promastigote susceptibility to amphotericin B, we developed a simplified MTT-test. The sensitivity in vitro to meglumine antimoniate and amphotericin B of 13 isolates obtained from Brazilian patients was determined. L. (V.) braziliensis isolates were more susceptible to meglumine antimoniate than Leishmania (Leishmania) amazonensis. EC(50), EC(90) and activity indexes (calculated over the sensitivity of reference strains), suggested that all isolates tested were susceptible in vitro to meglumine antimoniate, and did not show association with the clinical outcomes. Isolates were also uniformly susceptible in vitro to amphotericin B.

Synthesis, characterization and evaluation of antileishmanial activity of copper(II) with fluorinated alpha-hydroxycarboxylate ligands

In this study, Cu(II) complexes with fluorinated ligands were produced aiming at the development of new, less toxic antileishmanial metallodrugs. Complexes of the general formula CuL(2) (L = lactate, trifluorolactate, 2-hydroxyisobutyrate, trifluoro-2-hydroxyisobutyrate) were synthesized in methanolic medium, purified by crystallization and characterized by elemental analysis and electronic and infrared spectroscopies. In vitro experiments with Leishmania amazonensis promastigotes showed that the trifluorolactate derivative more active than its non-fluorinated counterpart. Our results indicate that fluorinated chelators may be interesting to increase metal toxicity and/or open new paths for metallodrug chemotherapy against leishmaniasis.

Inhibitory activity of limonene against Leishmania parasites in vitro and in vivo

Limonene is a monoterpene that has antitumoral, antibiotic and antiprotozoal activity. In this study we demonstrate the activity of limonene against Leishmania species in vitro and in vivo. Limonene killed Leishmania amazonensis promastigotes and amastigotes with 50% inhibitory concentrations of 252.0 +/- 49.0 and 147.0 +/- 46.0 mu M, respectively. Limonene was also effective against Leishmania major, Leishmania braziliensis and Leishmania chagasi promastigotes. The treatment of L. amazonensis-infected macrophages with 300 mu M limonene resulted in 78% reduction in infection rates. L. amazonensis-infected mice treated topically or intrarectally with limonene had significant reduction of lesion sizes. A significant decrease in the parasite load was shown in the lesions treated topically with limonene by histopathological examination. The intrarectal treatment was highly effective in decreasing the parasite burden, healing established lesions and suppressing the dissemination of ulcers. Limonene presents low toxicity in humans and has been shown to be effective as an agent for enhancing the percutaneous permeation of drugs. Our results suggest that limonene should be tested in different experimental models of infection by Leishmania. (C) 2009 Elsevier Masson SAS. All rights reserved.

In Vitro and In Vivo Antiplasmodial Activities of Risedronate and Its Interference with Protein Prenylation in Plasmodium falciparum

The increasing resistance of malarial parasites to almost all available drugs calls for the identification of new compounds and the detection of novel targets. Here, we establish the antimalarial activities of risedronate, one of the most potent bisphosphonates clinically used to treat bone resorption diseases, against blood stages of Plasmodium falciparum (50% inhibitory concentration [IC(50)] of 20.3 +/- 1.0 mu M). We also suggest a mechanism of action for risedronate against the intraerythrocytic stage of P. falciparum and show that protein prenylation seems to be modulated directly by this drug. Risedronate inhibits the transfer of the farnesyl pyrophosphate group to parasite proteins, an effect not observed for the transfer of geranylgeranyl pyrophosphate. Our in vivo experiments further demonstrate that risedronate leads to an 88.9% inhibition of the rodent parasite Plasmodium berghei in mice on the seventh day of treatment; however, risedronate treatment did not result in a general increase of survival rates.

Tamoxifen as a potential antileishmanial agent: efficacy in the treatment of Leishmania braziliensis and Leishmania chagasi infections

The aim of this study was to evaluate the efficacy of tamoxifen in vivo in experimental models of cutaneous (CL) and visceral leishmaniasis (VL) caused by Leishmania braziliensis and Leishmania chagasi, respectively. Drug activity was assessed against intracellular amastigotes by treating infected macrophage cultures and evaluating the number of infected cells. In vivo efficacy of tamoxifen was tested in L. braziliensis-infected BALB/c mice and in L. chagasi-infected hamsters. Treatment with 20 mg/kg/day tamoxifen was administered for 15 days by the intraperitoneal route. Efficacy was evaluated through measurements of lesion size, parasite burden at the lesion site or liver and spleen and survival rate. Tamoxifen killed L. braziliensis and L. chagasi intracellular amastigotes with 50% inhibitory concentrations (IC(50)) of 1.9 +/- 0.2 and 2.4 +/- 0.3 mu M, respectively. Treatment of L. braziliensis-infected mice with tamoxifen resulted in significant reductions in lesion size and 99% decrease in parasite burden, compared with mock-treated controls. L. chagasi-infected hamsters treated with tamoxifen showed significant reductions in liver parasite load expressed as Leishman-Donovan units and 95% to 98% reduction in spleen parasite burden. All animals treated with tamoxifen survived while 100% of the mock-treated animals had died by 11 weeks after the interruption of treatment. Tamoxifen is effective in the treatment of CL and VL in rodent models.

An enhanced content selection mechanism for personalization of video news programmes

In this paper, we propose a content selection framework that improves the users` experience when they are enriching or authoring pieces of news. This framework combines a variety of techniques to retrieve semantically related videos, based on a set of criteria which are specified automatically depending on the media`s constraints. The combination of different content selection mechanisms can improve the quality of the retrieved scenes, because each technique`s limitations are minimized by other techniques` strengths. We present an evaluation based on a number of experiments, which show that the retrieved results are better when all criteria are used at time.

Evolutionary fuzzy clustering of relational data

This paper is concerned with the computational efficiency of fuzzy clustering algorithms when the data set to be clustered is described by a proximity matrix only (relational data) and the number of clusters must be automatically estimated from such data. A fuzzy variant of an evolutionary algorithm for relational clustering is derived and compared against two systematic (pseudo-exhaustive) approaches that can also be used to automatically estimate the number of fuzzy clusters in relational data. An extensive collection of experiments involving 18 artificial and two real data sets is reported and analyzed. (C) 2011 Elsevier B.V. All rights reserved.

Visual analysis of image collections

Multidimensional Visualization techniques are invaluable tools for analysis of structured and unstructured data with variable dimensionality. This paper introduces PEx-Image-Projection Explorer for Images-a tool aimed at supporting analysis of image collections. The tool supports a methodology that employs interactive visualizations to aid user-driven feature detection and classification tasks, thus offering improved analysis and exploration capabilities. The visual mappings employ similarity-based multidimensional projections and point placement to layout the data on a plane for visual exploration. In addition to its application to image databases, we also illustrate how the proposed approach can be successfully employed in simultaneous analysis of different data types, such as text and images, offering a common visual representation for data expressed in different modalities.

Blowout bifurcation and spatial mode excitation in the bubbling transition to turbulence

The transition to turbulence (spatio-temporal chaos) in a wide class of spatially extended dynamical system is due to the loss of transversal stability of a chaotic attractor lying on a homogeneous manifold (in the Fourier phase space of the system) causing spatial mode excitation Since the latter manifests as intermittent spikes this has been called a bubbling transition We present numerical evidences that this transition occurs due to the so called blowout bifurcation whereby the attractor as a whole loses transversal stability and becomes a chaotic saddle We used a nonlinear three-wave interacting model with spatial diffusion as an example of this transition (C) 2010 Elsevier B V All rights reserved

Bubbling transition to spatial mode excitation in an extended dynamical system

We investigated the transition to spatio-temporal chaos in spatially extended nonlinear dynamical systems possessing an invariant subspace with a low-dimensional attractor. When the latter is chaotic and the subspace is transversely stable we have a spatially homogeneous state only. The onset of spatio-temporal chaos, i.e. the excitation of spatially inhomogeneous modes, occur through the loss of transversal stability of some unstable periodic orbit embedded in the chaotic attractor lying in the invariant subspace. This is a bubbling transition, since there is a switching between spatially homogeneous and nonhomogeneous states with statistical properties of on-off intermittency. Hence the onset of spatio-temporal chaos depends critically both on the existence of a chaotic attractor in the invariant subspace and its being transversely stable or unstable. (C) 2008 Elsevier B.V. All rights reserved.

Compressible Sherrington-Kirkpatrick spin-glass model

We introduce a Sherrington-Kirkpatrick spin-glass model with the addition of elastic degrees of freedom. The problem is formulated in terms of an effective four-spin Hamiltonian in the pressure ensemble, which can be treated by the replica method. In the replica-symmetric approximation, we analyze the pressure-temperature phase diagram, and obtain expressions for the critical boundaries between the disordered and the ordered (spin-glass and ferromagnetic) phases. The second-order para-ferromagnetic border ends at a tricritical point, beyond which the transition becomes discontinuous. We use these results to make contact with the temperature-concentration phase diagrams of mixtures of hydrogen-bonded crystals.

Antiferromagnetic spherical spin-glass model

We study the thermodynamic properties and the phase diagrams of a multi-spin antiferromagnetic spherical spin-glass model using the replica method. It is a two-sublattice version of the ferromagnetic spherical p-spin glass model. We consider both the replica-symmetric and the one-step replica-symmetry-breaking solutions, the latter being the most general solution for this model. We find paramagnetic, spin-glass, antiferromagnetic and mixed or glassy antiferromagnetic phases. The phase transitions are always of second order in the thermodynamic sense, but the spin-glass order parameter may undergo a discontinuous change.

Ion beam assisted deposition of an organic light emitting diode electrode

This work presents the electro-optical characterization of metal-organic interfaces prepared by the Ion Beam Assisted Deposition (IBAD) method. IBAD applied in this work combines simultaneously metallic film deposition and bombardment with an independently controlled ion beam, allowing different penetration of the ions and the evaporated metallic elements into the polymer. The result is a hybrid, non-abrupt interface, where polymer, metal and ion coexists. We used an organic light emitting diode, which has a typical vertical-architecture, for the interface characterization: Glass/Indium Tin Oxide (ITO)/Poly[ethylene-dioxythiophene/poly{styrenesulfonicacid}]) (PEDOT:PSS) /Emitting Polymer/Metal. The emitting polymer layer comprised of the Poly[(9,9-dioctyl-2,7-divinylenefluorenylene)-alt-co-{2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylene}] (PFO) and the metal layer of aluminum prepared with different Ar(+) ion energies varying in the range from 0 to 1000 eV. Photoluminescence, Current-Voltage and Electroluminescence measurements were used to study the emission and electron injection properties. Changes of these properties were related with the damage caused by the energetic ions and the metal penetration into the polymer. Computer simulations of hybrid interface damage and metal penetration were confronted with experimental data. (C) 2010 Elsevier B.V. All rights reserved.