Molecular modeling and QSAR studies of a set of indole and benzimidazole derivatives as H(4) receptor antagonists

Histamine is an important biogenic amine, which acts with a group of four G-protein coupled receptors (GPCRs), namely H(1) to H(4) (H(1)R - H(4)R) receptors. The actions of histamine at H(4)R are related to immunological and inflammatory processes, particularly in pathophysiology of asthma, and H(4)R ligands having antagonistic properties could be helpful as antiinflammatory agents. In this work, molecular modeling and QSAR studies of a set of 30 compounds, indole and benzimidazole derivatives, as H(4)R antagonists were performed. The QSAR models were built and optimized using a genetic algorithm function and partial least squares regression (WOLF 5.5 program). The best QSAR model constructed with training set (N = 25) presented the following statistical measures: r (2) = 0.76, q (2) = 0.62, LOF = 0.15, and LSE = 0.07, and was validated using the LNO and y-randomization techniques. Four of five compounds of test set were well predicted by the selected QSAR model, which presented an external prediction power of 80%. These findings can be quite useful to aid the designing of new anti-H(4) compounds with improved biological response.

Antinociceptive and anti-inflammatory properties of 7-hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain

Objectives In the present study we investigated the anti nociceptive, anti-inflammatory and antipyretic effects of 7-hydroxycoumarin (7-HC) in animal models. Methods The effects of oral 7-HC were tested against acetic acid-induced writhing, formalin test, tail flick test, complete Freund`s adjuvant (CFA)-induced hypemociception, carrageenan-induced paw oedema, lipopolysaccharide-induced fever and the rota rod test. Key findings 7-HC (3-60 mg/kg) produced a dose-related antinociception against acetic acid-induced writhing in mice and in the formalin test. In contrast, treatment with 7-HC did not prevent thermal nociception in the tail flick test. A single treatment with 7-HC, 60 mg/kg, produced a long-lasting antinociceptive effect against CFA-induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7-HC produced a continuous antinociceptive effect against CFA-induced hypernociception. 7-HC (30-120 mg/kg) produced anti-inflammatory and antipyretic effects against carrageenan-induced inflammation and lipopolysaccharide-induced fever, respectively. Moreover, 7-HC was found to be safe with respect to ulcer induction. In the rota rod test, 7-HC-treated mice did not show any motor performance alterations. Conclusions The prolonged antinociceptive and anti-inflammatory effects of 7-HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.

Anti-inflammatory and antinociceptive effects of Baccharis dracunculifolia DC (Asteraceae) in different experimental models

Aim of the study: The aerial parts of Baccharis dracunculifolia D.C., popularly known as ""alecrim do campo"" are used in folk medicine as anti-inflammatory. The aim of the present study was to evaluate the anti-inflammatory and antinociceptive activities of the crude hydroalcoholic extract obtained from leaves of Baccharis dracunculifolia (BdE), which have not been reported. Matetials and methods: BdE was analyzed by HPLC and in vivo evaluated (doses ranging from 50 to 400 mg/kg, p.o.) by using the acetic acid-induced abdominal constrictions, paw oedema induced by carrageenan or histamine, overt nociception models using capsaicin, glutamate or phorbol myristate acetate (PMA), formalin-induced nociception and mechanical hypernociception induced by carrageenan or complete Freund adjuvant (CFA). As positive controls it was used paracetamol in both acetic acid and formalin tests; dipyrone in capsaicin, glutamate and PMA-induced nociception; indomethacin in CFA and carrageenan-induced hypernociception models. In addition, the in vitro effects of BdE on COX-2 activity and on the activation of NF-kappa B were also evaluated. Results: BdE (50-400 mg/kg, p.o.) significantly diminished the abdominal constrictions induced by acetic acid, glutamate and CFA. Furthermore, BdE also inhibited the nociceptive responses in both phases of formalin-induced nociception. BdE, administered orally, also produced a long-lasting anti-hypernociceptive effect in the acute model of inflammatory pain induced by carrageenan. It was also observed the inhibition of COX-2 activity by BdE. Conclusion: In summary, the data reported in this work confirmed the traditional anti-inflammatory indications of Baccharis dracunculifolia leaves and provided biological evidences that Baccharis dracunculifolia, like Brazilian green propolis, possess antinociceptive and anti-inflammatory activities. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Antiulcerogenic Activity of the Essential Oil of Baccharis dracunculifolia on Different Experimental Models in Rats

Baccharis dracunculifolia DC (Asteraceae), a native plant from Brazil, commonly known as `Alecrim-do-campo` is widely used in folk medicine to treat inflammation, hepatic disorders and stomach ulcers, and it is the most important botanical source of Southeastern Brazilian propolis, known as green propolis. Its essential oil is composed of non-oxygenated and oxygenated terpenes. In this work, the effects of the essential oil obtained from the aerial parts of R dracunculifolia on gastric ulcers were evaluated. The antiulcer assays were undertaken using the following protocols in rats: nonsteroidal antiinflammatory drug (NSAID)-induced ulcer, ethanol-induced ulcer, stress-induced ulcer, and determination of gastric secretion using ligated pylorus. The treatment in the doses of 50, 250 and 500 mg/kg of R dracunculifolia essential oil significantly diminished the lesion index, the total lesion area and the percentage of lesions in comparison with both positive and negative control groups. With regard to the model of gastric secretion a reduction of gastric juice volume and total acidity was observed, as well as an increase in the gastric pH. No sign of toxicity was observed in the acute toxicity study. Considering the results, it is suggested that the essential oil of B. dracunculifolia could probably be a good therapeutic agent for the development of new phytotherapeutic medicine for the treatment of gastric ulcer. Copyright (C) 2009 John Wiley & Sons, Ltd.

Defining a role for the subthalamic nucleus within operative theoretical models of subcortical participation in language

Objective:To investigate the effects of bilateral, surgically induced functional inhibition of the subthalamic nucleus (STN) on general language, high level linguistic abilities, and semantic processing skills in a group of patients with Parkinson’s disease. Methods:Comprehensive linguistic profiles were obtained up to one month before and three months after bilateral implantation of electrodes in the STN during active deep brain stimulation (DBS) in five subjects with Parkinson’s disease (mean age, 63.2 years). Equivalent linguistic profiles were generated over a three month period for a non-surgical control cohort of 16 subjects with Parkinson’s disease (NSPD) (mean age, 64.4 years). Education and disease duration were similar in the two groups. Initial assessment and three month follow up performance profiles were compared within subjects by paired t tests. Reliability change indices (RCI), representing clinically significant alterations in performance over time, were calculated for each of the assessment scores achieved by the five STN-DBS cases and the 16 NSPD controls, relative to performance variability within a group of 16 non-neurologically impaired adults (mean age, 61.9 years). Proportions of reliable change were then compared between the STN-DBS and NSPD groups. Results:Paired comparisons within the STN-DBS group showed prolonged postoperative semantic processing reaction times for a range of word types coded for meanings and meaning relatedness. Case by case analyses of reliable change across language assessments and groups revealed differences in proportions of change over time within the STN-DBS and NSPD groups in the domains of high level linguistics and semantic processing. Specifically, when compared with the NSPD group, the STN-DBS group showed a proportionally significant (p

Redefining functional models of basal ganglia organisation: Role for the posteroventral pallidum in linguistic processing?

Traditionally the basal ganglia have been implicated in motor behavior, as they are involved in both the execution of automatic actions and the modification of ongoing actions in novel contexts. Corresponding to cognition, the role of the basal ganglia has not been defined as explicitly. Relative to linguistic processes, contemporary theories of subcortical participation in language have endorsed a role for the globus pallidus internus (GPi) in the control of lexical-semantic operations. However, attempts to empirically validate these postulates have been largely limited to neuropsychological investigations of verbal fluency abilities subsequent to pallidotomy. We evaluated the impact of bilateral posteroventral pallidotomy (BPVP) on language function across a range of general and high-level linguistic abilities, and validated/extended working theories of pallidal participation in language. Comprehensive linguistic profiles were compiled up to 1 month before and 3 months after BPVP in 6 subjects with Parkinson's disease (PD). Commensurate linguistic profiles were also gathered over a 3-month period for a nonsurgical control cohort of 16 subjects with PD and a group of 16 non-neurologically impaired controls (NC). Nonparametric between-groups comparisons were conducted and reliable change indices calculated, relative to baseline/3-month follow-up difference scores. Group-wise statistical comparisons between the three groups failed to reveal significant postoperative changes in language performance. Case-by-case data analysis relative to clinically consequential change indices revealed reliable alterations in performance across several language variables as a consequence of BPVP. These findings lend support to models of subcortical participation in language, which promote a role for the GPi in lexical-semantic manipulation mechanisms. Concomitant improvements and decrements in postoperative performance were interpreted within the context of additive and subtractive postlesional effects. Relative to parkinsonian cohorts, clinically reliable versus statistically significant changes on a case by case basis may provide the most accurate method of characterizing the way in which pathophysiologically divergent basal ganglia linguistic circuits respond to BPVP.

Modulational Instability in Periodic Quadratic Nonlinear Materials

We investigate the modulational instability of plane waves in quadratic nonlinear materials with linear and nonlinear quasi-phase-matching gratings. Exact Floquet calculations, confirmed by numerical simulations, show that the periodicity can drastically alter the gain spectrum but never completely removes the instability. The low-frequency part of the gain spectrum is accurately predicted by an averaged theory and disappears for certain gratings. The high-frequency part is related to the inherent gain of the homogeneous non-phase-matched material and is a consistent spectral feature.

Elliptic Gaudin models and elliptic KZ equations

The Gaudin models based on the face-type elliptic quantum groups and the XYZ Gaudin models are studied. The Gaudin model Hamiltonians are constructed and are diagonalized by using the algebraic Bethe ansatz method. The corresponding face-type Knizhnik–Zamolodchikov equations and their solutions are given.

Algebraic Bethe ansatz method for the exact calculation of energy spectra and form factors: applications to models of Bose-Einstein condensates and metallic nanograins

In this review we demonstrate how the algebraic Bethe ansatz is used for the calculation of the-energy spectra and form factors (operator matrix elements in the basis of Hamiltonian eigenstates) in exactly solvable quantum systems. As examples we apply the theory to several models of current interest in the study of Bose-Einstein condensates, which have been successfully created using ultracold dilute atomic gases. The first model we introduce describes Josephson tunnelling between two coupled Bose-Einstein condensates. It can be used not only for the study of tunnelling between condensates of atomic gases, but for solid state Josephson junctions and coupled Cooper pair boxes. The theory is also applicable to models of atomic-molecular Bose-Einstein condensates, with two examples given and analysed. Additionally, these same two models are relevant to studies in quantum optics; Finally, we discuss the model of Bardeen, Cooper and Schrieffer in this framework, which is appropriate for systems of ultracold fermionic atomic gases, as well as being applicable for the description of superconducting correlations in metallic grains with nanoscale dimensions.; In applying all the above models to. physical situations, the need for an exact analysis of small-scale systems is established due to large quantum fluctuations which render mean-field approaches inaccurate.

On the nonlinear Neumann problem with critical and supercritical nonlinearities

We investigate the solvability of the Neumann problem (1.1) involving a critical Sobolev exponent. In the first part of this work it is assumed that the coeffcients Q and h are at least continuous. Moreover Q is positive on overline Omega and lambda > 0 is a parameter. We examine the common effect of the mean curvature and the shape of the graphs of the coeffcients Q and h on the existence of low energy solutions. In the second part of this work we consider the same problem with Q replaced by - Q. In this case the problem can be supercritical and the existence results depend on integrability conditions on Q and h.

Nodal solutions for nonlinear eigenvalue problems

We are concerned with determining values of, for which there exist nodal solutions of the boundary value problems u" + ra(t) f(u) = 0, 0 < t < 1, u(O) = u(1) = 0. The proof of our main result is based upon bifurcation techniques.

Review of recent results on excursion set models

Many images consist of two or more 'phases', where a phase is a collection of homogeneous zones. For example, the phases may represent the presence of different sulphides in an ore sample. Frequently, these phases exhibit very little structure, though all connected components of a given phase may be similar in some sense. As a consequence, random set models are commonly used to model such images. The Boolean model and models derived from the Boolean model are often chosen. An alternative approach to modelling such images is to use the excursion sets of random fields to model each phase. In this paper, the properties of excursion sets will be firstly discussed in terms of modelling binary images. Ways of extending these models to multi-phase images will then be explored. A desirable feature of any model is to be able to fit it to data reasonably well. Different methods for fitting random set models based on excursion sets will be presented and some of the difficulties with these methods will be discussed.

An improved novel method for solving nonlinear boundary value problems

A modified formula for the integral transform of a nonlinear function is proposed for a class of nonlinear boundary value problems. The technique presented in this paper results in analytical solutions. Iterations and initial guess, which are needed in other techniques, are not required in this novel technique. The analytical solutions are found to agree surprisingly well with the numerically exact solutions for two examples of power law reaction and Langmuir-Hinshelwood reaction in a catalyst pellet.

Language policy spread: Learning from health and social policy models

Except for a few large scale projects, language planners have tended to talk and argue among themselves rather than to see language policy development as an inherently political process. A comparison with a social policy example, taken from the United States, suggests that it is important to understand the problem and to develop solutions in the context of the political process, as this is where decisions will ultimately be made.