Risk factors for colonisation of newborn infants during an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in an intermediate-risk neonatal unit

We describe a cross-sectional, survey to identify risk factors for colonisation of neonates by extended-spectrum P-Lactamase (ESBL)-producing Klebsiella pneumoniae. This occurred following exposure to a colonised healthcare worker during an outbreak in an intermediate-risk neonatal. unit. In total, 120 neonates admitted consecutively during a three-month period were screened for ESBL-producing K. pneumoniae by rectal swabbing and 27 were identified as colonised. Multivariate analysis showed colonisation to be independently associated with use of antibiotics and absence of breastfeeding. Previous use of antibiotics presented an odds ratio (OR) of 12.3 [95% confidence interval. (Cl): 3.66-41.2, P < 0.001]. The most commonly used antibiotics were penicillin and amikacin. Breastfeeding was associated with reduced risk for colonisation (OR: 0.22; 95% Cl: 0.05-0.99; P = 0.049). Nine isotates recovered during the first stage of the outbreak and 27 isolates from surveillance cultures were typed thereafter by pulsed-field gel electrophoresis, revealing six different profiles (A-F). Clones A, C, and E were implicated in the first stage of the outbreak, whereas among the 27 strains recovered from surveillance cultures, all six clones were identified. Clone A was also found on the hand of a nursing auxiliary with onychomycosis. We concluded that prior antimicrobial use predisposed to colonisation. The possible role of breastfeeding as a protective factor needs to be further elucidated. Detection of different genotypes of ESBL-producing K. pneumonioe suggests that dissemination of mobile genetic elements bearing the ESBL gene may have been superimposed on the simple dissemination of a clone during the outbreak. (c) 2008 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.

Two-level network design with intermediate facilities: An application to electrical distribution systems

We consider the two-level network design problem with intermediate facilities. This problem consists of designing a minimum cost network respecting some requirements, usually described in terms of the network topology or in terms of a desired flow of commodities between source and destination vertices. Each selected link must receive one of two types of edge facilities and the connection of different edge facilities requires a costly and capacitated vertex facility. We propose a hybrid decomposition approach which heuristically obtains tentative solutions for the vertex facilities number and location and use these solutions to limit the computational burden of a branch-and-cut algorithm. We test our method on instances of the power system secondary distribution network design problem. The results show that the method is efficient both in terms of solution quality and computational times. (C) 2010 Elsevier Ltd. All rights reserved.

Fragment mass distributions in the fission of heavy nuclei by intermediate- and high-energy probes

Recent experiments have shown that the multimode approach for describing the fission process is compatible with the observed results. Asystematic analysis of the parameters obtained by fitting the fission-fragment mass distribution to the spontaneous and low-energy data has shown that the values for those parameters present a smooth dependence upon the nuclear mass number. In this work, a new methodology is introduced for studying fragment mass distributions through the multimode approach. It is shown that for fission induced by energetic probes (E > 30 MeV) the mass distribution of the fissioning nuclei produced during the intranuclear cascade and evaporation processes must be considered in order to have a realistic description of the fission process. The method is applied to study (208)Pb, (238)U, (239)Np and (241)Am fission induced by protons or photons.

Opinion dynamics of learning agents: does seeking consensus lead to disagreement?

We study opinion dynamics in a population of interacting adaptive agents voting on a set of issues represented by vectors. We consider agents who can classify issues into one of two categories and can arrive at their opinions using an adaptive algorithm. Adaptation comes from learning and the information for the learning process comes from interacting with other neighboring agents and trying to change the internal state in order to concur with their opinions. The change in the internal state is driven by the information contained in the issue and in the opinion of the other agent. We present results in a simple yet rich context where each agent uses a Boolean perceptron to state their opinion. If the update occurs with information asynchronously exchanged among pairs of agents, then the typical case, if the number of issues is kept small, is the evolution into a society torn by the emergence of factions with extreme opposite beliefs. This occurs even when seeking consensus with agents with opposite opinions. If the number of issues is large, the dynamics becomes trapped, the society does not evolve into factions and a distribution of moderate opinions is observed. The synchronous case is technically simpler and is studied by formulating the problem in terms of differential equations that describe the evolution of order parameters that measure the consensus between pairs of agents. We show that for a large number of issues and unidirectional information flow, global consensus is a fixed point; however, the approach to this consensus is glassy for large societies.

Fragment-Based QSAR and Molecular Modeling Studies on a Series of Discodermolide Analogs as Microtubule-Stabilizing Anticancer Agents

Inhibition of microtubule function is an attractive rational approach to anticancer therapy. Although taxanes are the most prominent among the microtubule-stabilizers, their clinical toxicity, poor pharmacokinetic properties, and resistance have stimulated the search for new antitumor agents having the same mechanism of action. Discodermolide is an example of nontaxane natural product that has the same mechanism of action, demonstrating superior antitumor efficacy and therapeutic index. The extraordinary chemical and biological properties have qualified discodermolide as a lead structure for the design of novel anticancer agents with optimized therapeutic properties. In the present work, we have employed a specialized fragment-based method to develop robust quantitative structure - activity relationship models for a series of synthetic discodermolide analogs. The generated molecular recognition patterns were combined with three-dimensional molecular modeling studies as a fundamental step on the path to understanding the molecular basis of drug-receptor interactions within this important series of potent antitumoral agents.

Analyzing Ru(III)-dmso and Ru(III)-dms motifs in compounds used in the synthesis of the antimetastatic agents

The chemistry of Ru(III) complexes containing dmso as a ligand has become an interesting area in the cancer treatment field. Because of this, structural knowledge and chemistry of the moiety Ru(III)-dmso have become important to cancer research. The crystal structures of the compounds mer-[RuCl(3)(dms)(3)] (1) and mer-[RuCl(3)(dms)(2)(dmso)]:mer-[RuCl(3)(dms)(3)] (2) were determined by X-ray crystallography and a speciation of the presence of intramolecular hydrogen bond in these structures has been studied. Compound (1) crystallizes in the orthorhombic space group, Pna2(1); a = 16.591(8) angstrom, b = 8.724(2) angstrom. c = 10.547(3) angstrom; Z = 12 and (2) crystallizes in the space group, P2(1)/C: a = 11.9930(2) angstrom, b = 7.9390(2) angstrom, c = 15.8700(3) angstrom, beta = 93.266(1)degrees, Z = 2. From the X-ray structures solved in this work, were possible to suggest an interpretation for the broad lines observed in the EPR spectra of the Ru(III) compounds explored here. Also, the exchange interactions detected by EPR spectroscopy in solid state and in solution, confirm the presence of van der Waals interactions such as C-H center dot center dot center dot Cl in the compounds (1), (2) and (3). The use of techniques such as IR, UV-vis, (1)H NMR and EPR Spectroscopy and Cyclic Voltammetry were applied in this work to analyze the behavior of these metallocompounds. (c) 2008 Elsevier B.V. All rights reserved.

Three-dimensional quantitative structure-activity relationships for a large series of potent antitubercular agents

Comparative molecular field analysis (CoMFA) studies were conducted on a series of 100 isoniazid derivatives as anti-tuberculosis agents using two receptor-independent structural data set alignment strategies: (1) rigid-body fit, and (2) pharmacophore-based. Significant cross-validated correlation coefficients were obtained (CoMFA(1), q(2) = 0,75 and CoMFA(2), q(2) = 0.74), indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results.

Natural products biological screening and ligand-based virtual screening for the discovery of new antileishmanial agents

In the course of our research program to discover novel antileishmanial agents, a biological screening of natural products against Leishmania major promastigotes allowed the identification of a furoquinoline alkaloid (1) and a furanocoumarin (2) as new hits. Subsequently, an integrated ligand-based virtual screening approach was employed to search for new antileishmanial compounds using these naturally occurring molecules as templates. Fourteen out of 40 compounds selected from a database of about 800,000 compounds (extracted from ZINC, a free database for virtual screening) were experimentally confirmed to possess significant in vitro antileishmanial properties. The application of ligand-based virtual screening as a complementary approach to experimental natural product screening was a useful strategy to facilitate the identification of new promising lead candidates.

Fragment-based and classical quantitative structure-activity relationships for a series of hydrazides as antituberculosis agents

Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. Multidrug-resistant Mycobacterium tuberculosis is an emerging problem of great importance to public health, and there is an urgent need for new anti-TB drugs. In the present work, classical 2D quantitative structure-activity relationships (QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 91 isoniazid derivatives. Significant statistical models (classical QSAR, q(2) = 0.68 and r(2) = 0.72; HQSAR, q(2) = 0.63 and r(2) = 0.86) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 24 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(pred)(2) = 0.87; classical QSAR, r(pred)(2) = 0.75).

Cathepsin X cleaves the beta 2 cytoplasmic tail of LFA-1 inducing the intermediate affinity form of LFA-1 and alpha-actinin-1 binding

The motility of T cells depends on the dynamic spatial regulation of integrin-mediated adhesion and de-adhesion. Cathepsin X, a cysteine protease, has been shown to regulate T-cell migration by interaction with lymphocyte function associated antigen-1 (LFA-1). LFA-1 adhesion to the ICAM-1 is controlled by the association of actin-binding proteins with the cytoplasmic tail of the beta(2) chain of LFA-1. Cleavage by cathepsin X of the amino acid residues S(769), E(768) and A(767) from the C-terminal of the beta(2) cytoplasmic tail of LFA-1 is shown to promote binding of the actin-binding protein alpha-actinin-1. Furthermore, cathepsin X overexpression reduced LFA-1 clustering and induced an intermediate affinity LFA-1 conformation that is known to associate with a-actinin-1. increased levels of intermediate affinity LFA-1 resulted in augmented cell spreading due to reduced attachment of T cells to the ICAM-1-coated surface. Gradual cleavage of LFA-1 by cathepsin X enables the transition between intermediate and high affinity LFA-1, an event that is crucial for effective T-cell migration.

Probing conformational changes in orphan nuclear receptor: The NGFI-B intermediate is a partially unfolded dimer

Human nerve growth factor-induced B (NGFI-B) is a member of the NR4A subfamily of orphan nuclear receptors (NRs). Lacking identified ligands, orphan NRs show particular co-regulator proteins binding properties, different from other NRs, and they might have a non-classical quaternary organization. A body of evidence suggests that NRs recognition of and binding to ligands, DNA, homo- and heterodimerization partners and co-regulator proteins involve significant conformational changes of the NR ligand-binding domains (LBDs). To shed light on largely unknown biophysical properties of NGFI-B, here we studied structural organization and unfolding properties of NGFI-B ligand (like)-binding domain induced by chemical perturbation. Our results show that NGFI-B LBD undergoes a two-state guanidine hydrochloride (GndHCl) induced denaturation, as judged by changes in the a-helical content of the protein monitored by circular dichroism spectroscopy (CD). In contrast, changes in the tertiary structure of NGFI-B LBD, reported by intrinsic fluorescence, reveal a clear intermediate state. Additionally, SAXS results demonstrate that the intermediate observed by intrinsic fluorescence is a partially folded homodimeric structure, which further unfolds without dissociation at higher GndHCl concentrations. This partially unfolded dimeric assembly of NGFI-B LBD might resemble an intermediate that this domain access momentarily in the native state upon interactions with functional partners. (C) 2008 Elsevier B.V. All rights reserved.

Evaluation of petrogenetic models for intermediate and silicic plutonic rocks from the Sierra de Valle Fertil-La Huerta, Argentina: Petrologic constraints on the origin of igneous rocks in the Ordovician Famatinian-Puna paleoarc

The whole Valle Fertil-La Huerta section appears as a calc-alkaline plutonic suite typical of a destructive plate margin. New Sr and Nd isotopic whole-rock data and published whole-rock geochemistry suggest that the less-evolved intermediate (dioritic) rocks can be derived by magmatic differentiation, mainly by hornblende + plagioclase +/- Fe-Ti oxide fractional crystallization, from mafic (gabbroic) igneous precursors. Closed-system differentiation, however, cannot produce the typical intermediate (tonalitic) and silicic (granodioritic) plutonic rocks, which requires a preponderant contribution of crustal components. Intermediate and silicic plutonic rocks from Valle Fertil-La Huerta section have formed in a plate subduction setting where the thermal and material input of mantle-derived magmas promoted fusion of fertile metasedimentary rocks and favored mixing of gabbroic or dioritic magmas with crustal granitic melts. Magma mixing is observable in the field and evident in variations of chemical elemental parameters and isotopic ratios, revealing that hybridization coupled with fractionation of magmas took place in the crust. Consideration of the whole-rock geochemical and isotopic data in the context of the Famatinian-Puna magmatic belt as a whole demonstrates that the petrologic model postulated for the Sierra Valle Fertil-La Huerta section has the potential to explain the generation of plutonic and volcanic rocks across the Early Ordovician paleoarc from central and northwestern Argentina. As the petrologic model does not require the intervention of old Precambrian continental crust, the nature of the basement on which thick accretionary turbiditic sequences were deposited remains a puzzling aspect. Discussion in this paper provides insights into the nature of magmatic source rocks and mechanisms of magma generation in Cordilleran-type volcano-plutonic arcs of destructive plate margins. (C) 2010 Elsevier Ltd. All rights reserved.

Short-time behaviour of demand and price viewed through an exactly solvable model for heterogeneous interacting market agents

We introduce a stochastic heterogeneous interacting-agent model for the short-time non-equilibrium evolution of excess demand and price in a stylized asset market. We consider a combination of social interaction within peer groups and individually heterogeneous fundamentalist trading decisions which take into account the market price and the perceived fundamental value of the asset. The resulting excess demand is coupled to the market price. Rigorous analysis reveals that this feedback may lead to price oscillations, a single bounce, or monotonic price behaviour. The model is a rare example of an analytically tractable interacting-agent model which allows LIS to deduce in detail the origin of these different collective patterns. For a natural choice of initial distribution, the results are independent of the graph structure that models the peer network of agents whose decisions influence each other. (C) 2009 Elsevier B.V. All rights reserved.

Polymethine cyanine dyes in beta-cyclodextrin solution: multiple equilibria and chemical oxidation

Absorption and fluorescence spectroscopy, electrochemical techniques, and semiempirical calculations were employed to characterize the multiple complexation equilibria between two polymethine cyanine dyes (IR-786 and Indocyanine green-ICG, 5) and beta-cyclodextrin (beta-CD, L), as well as the chemical reactivity of the complexed and uncomplexed species against the oxidizing agents hypochlorite (HC) and hydrogen peroxide (HP). IR-786 dimerization is favored with the increase in beta-CD concentration in the form of (SL)(2) complexes. In the case of ICG, free dimers (D) and SL complexes are favored. Both IR-786 and ICG react and discolor in the presence of HC and HP. For IR-786, the reaction with HP and HC proceeds with observed rate constants of 10(-3) and 0.28 s(-1) and second-order rate constants (k(2)) of similar to 10(-3) and 10(4) M(-1) s(-1), respectively. The intermediate species observed in the bleaching reactions of IR-786 and ICG were shown, by cyclic voltammetry and VIS absorption, to result from one electron oxidation. IR-786 complexed with beta-CD is protected against bleaching in the presence of HP and HC by factors of 20 and 4, respectively. This protection was not observed in ICG complexes. Superdelocalizability profile of both dyes and frontier orbital analysis indicates that beta-CD does not protect ICG from oxidation by HP or HC, whereas the 2:2 IR-786/beta-Cd complex is able to avoid the oxidation of IR-786. We concluded that the decrease in the chemical reactivity of the dyes against oxidant agents in the presence of beta-CD is due to the formation of (SL)(2) complexes. Copyright (C) 2010 John Wiley & Sons, Ltd.

Designing Novel Antitrypanosomal Agents from a Mixed Graph-Theoretical Substructural Approach

Chagas disease is nowadays the most serious parasitic health problem. This disease is caused by Trypanosoma cruzi. The great number of deaths and the insufficient effectiveness of drugs against this parasite have alarmed the scientific community worldwide. In an attempt to overcome this problem, a model for the design and prediction of new antitrypanosomal agents was obtained. This used a mixed approach, containing simple descriptors based on fragments and topological substructural molecular design descriptors. A data set was made up of 188 compounds, 99 of them characterized an antitrypanosomal activity and 88 compounds that belong to other pharmaceutical categories. The model showed sensitivity, specificity and accuracy values above 85%. Quantitative fragmental contributions were also calculated. Then, and to confirm the quality of the model, 15 structures of molecules tested as antitrypanosomal compounds (that we did not include in this study) were predicted, taking into account the information on the abovementioned calculated fragmental contributions. The model showed an accuracy of 100% which means that the ""in silico"" methodology developed by our team is promising for the rational design of new antitrypanosomal drugs. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 31: 882-894. 2010